The first lecture outline
Historical Introduction
Purves et al., Chapter 1 and figures from Chapters 6 & 27 and Appendix
A
(there will also be a review that introduces you to the Sylvius CD)
(some of this is a review of "Bio 1" and "Cell biology")
Brain - ancient history
Hippocrates (460-379 BC), of "hippocratic oath" fame, understood
the influence of the brain in determining normal and abnormal functions,
emotions, learning, insanity.
Appendix A Fig. A21
(this human brain view shows cerebrum, cerebellum, ventricles)
Galen (AD 130-200) did careful dissections. He thought, from texture, that
the cerebrum was sensory and cerebellum was motor. This was remarkably (not
completely) correct, though for the wrong reasons. There was interest in
the ventricles (filled with cerebro-spinal fluid [CSF]), and this fit in
with belief in vital "humors."
Neuroanatomy terms:
Appendix A Fig. A10A
(view of exterior of human brain)
sulcus (plural=sulci) = fissure
For instance, central sulcus is major landmark
gyrus (plural=gyri) = convolution -> lobes (a larger area)
For instance, precentral gyrus is motor cortex
And postcentral gyrus is somatosensory (touch) cortex
Appendix A Fig. A3
(colored view of exterior and mid-sagittal section of human brain)
Emphasis is on "localization of function" in different lobes
For instance, occipital lobe is where vision projects
And Temporal lobe is where audition projects
just to put into perspective the degree to which much of this information
is background,
TRANSPARENCY shows the version of this picture the Biology Department teaches
to freshmen
CNS = central nervous system (brain and spinal cord)
PNS = peripheral nervous system
Appendix A Fig. A14
(human brain drawing showing coronal sections, to reveal basal ganglia)
shows the coronal sections indicated
white matter, bundles of myelinated axons (Tracts in CNS, Nerve in PNS)
[misnomer - optic "nerve," second cranial nerve, is actually a
tract since retina and optic nerve are considered part of the CNS on embryological
grounds]
and
gray matter (Nuclei in CNS, Ganglia in PNS)
[misnomers - basal ganglia are nuclei and ganglion cells in retina]
Fig 1.9
(cross section of human spinal cord)
white matter and gray matter
(nerve connections to and in the spinal cord)
Nerve (peripheral nervous system [PNS])
Tract (central nervous system [CNS])
Fig. 1.7
(diagram of knee jerk reflex)
Afferent (toward CNS)- Efferent (away from CNS)
Appendix A Fig. A12A
This shows a mid-sagittal section
Decussation- crossing of fibers
The biggest is the corpus callosum
Appendix A Fig. A1A
(brain with directions drawn in)
Rostral (toward the front)- Caudal (toward the back)
Superior (above) Inferior (below)
(not shown) Lateral - Medial
Appendix A Fig. A1B
(brain with sections drawn in)
Coronal (would be cross section if human brain were anterior)
Horizontal vs Sagittal - (would be like longitudinal sections)
Some more recent historical figures and issues
Appendix A Fig. A16A
(blood supply of brain)
Thomas Willis (1621-1675) (English) circle of Willis
fed by both internal carotids, a block would not deprive half of brain of
blood supply
Here is
the equivalent picture from our sheep brain dissection
Fig. 26.1
Pierre-Paul Broca (1824-1880) (France) brain surgery
patient with damage in left hemisphere shows speech loss => lateral localization
vs. Lashley (cortical lesions in learning experiments) mass action
and equipotentiality
In the old days, stroke (defects while living and damage in post-mortem)
was the way to make conclusions in humans; now there are imaging techniques.
In animal models, stereotactic lesions can be made.
Electrical stimulation can also be applied, and, in general, it has the
opposite effect of lesioning.
Fig. 27.2
(Brodmann areas drawn onto human brain)
Korbinian Brodmann (early 20th century) has lots of brain areas with numbers
famous ones: 17-vision, 4-motor, based on cellular cytoarchitecture
Stroke
Current affairs Jan 5, 2006, Israel's premier Ariel Sharon has a stroke
complicated by being on blood thinners.
Box A, Appendix
Brain's need of oxygen makes interruption in blood flow dangerous
3rd leading cause of death in US
(1) thrombus (local occlusion) 50%
(2) embolus (object in blood stream) 30%
(such interruption in blood supply is called "ischemia")
(3) hemorrhage (e.g. from aneurism) 20 %
Tissue plasminogen activator (TPA) to dissolve clot
Recent reading: CM DeLude "Widening the window" (news scan,
medicine) pp 21-22 Scientific American August 2005
Few get TPA because they come in too late for it to be effective (<3
hr)
If neurons are not dead, TPA may still work; newer CT and MRI scans can
now show this.
Giving oxygen also buys time.
New drug: Desmoteplase (from vampire saliva) like TPA (breaks fibrin) but
more potent and selective.
Structure of the Nerve cell
Fig. 1.2F -
(Purkinje cell)
1836 Jan Purkinje (Czech) - Purkinje cells in cerebellum - these are highlighted
with Golgi (see below) staining
Fig. 1.7
(diagram of knee jerk reflex) [again]
1865 Otto Deiters (Bonn) - motor neuron
Fig. 1.3A
(cells and connections in brain)
axis cylinder -> axon, dendrites (branches)
reticular theory (connected like blood stream) vs. cell theory (cells
are separate)
1885 Camillo Golgi (Italy) - potassium dichromate fix silver impregnation,
still believed reticular theory
1888-> Santiago Ramon y Cajal - real thorough descriptions of many systems,
believed in cell theory
1906 Nobel
Prize in Physiology and Medicine for "the structure of the nervous
system"
Advancements in cell anatomy methodology
Figs 1.3, 1.4, 1.5 & 1.6 are amazing preview of many semester topics
Beyond the level discussed above, tracts could be found by dissection. Looking
ahead to the sheep brain dissection, this tract dissection of the midsagittal
cut reveals the fornix, the mammilo-thalamic tract and the habenulo-peduncular
tract. See slide
11
Fluorescence. Excitation with short wavelength. While electron is in excited
state, there is some radionless de-excitation. When electron comes to ground
state, it has less energy, so photon emitted has less energy (longer wavelength).
Here is a fluorescence
microscope.
Short wavelength comes (through color filters) from above, hence "epi-illumination"
or "incident illuminator."
Of course, there is a camera.
Fig. 6.11A
In the 1960s there was a lot of excitement about how specialized techniques
(histochemical fluorescence) allowed researchers to trace the pathways used
by a specific neurotransmitter substance. Fig. 6.11 shows dopamine pathways
from the substantia nigra to the striatum and the cerebral cortex.
Fig. 1.6 E-H
Nissl stain shows cells (like cell layers in cortex)
Fig. 1.6 A,B
Golgi technique only colors a few cells so they can be viewed in their entirety.
Fig. 1.6 C
a fluorescent dye can be injected.
Here is a figure
I prepared to explain how antibodies could be used in the electron microscope
to localize proteins. The protein is an antigen. An antibody, binds to an
epitope on the protein. A secondary antibody with an electron dense attachment
(colloidal gold for electron microscopy or a fluorescent label for fluorescence
microscopy) binds the antibody. Here
is a figure I found subsequently) in this
very useful site.
Here is a micrograph
where Rh1, the rhodopsin of one type of photoreceptor in the Drosophila
compound eye, is labeled ("decorated") with immunogold (Sapp et
al, J. Neurocytol. 20, 597-608, 1991)
Here is a laser scanning
confocal microscope, a fancy fluorescence microscope.
This machine is from a grant obtained by Prof.
Spencer (and a few others of us).
For a light source, a laser is used.
Light is measured and fed to a computer for image acquisition.
Low depth of field (only one plane is in focus) provides "optical sectioning"
Images are very clear.
Here is Rh1
labeled with a fluorescent antibody in the confocal
Fig. 1.4 A
Tau (red) (microtubular binding protein in axons) accumulates in Alzheimer's,
tubulin (green) in cells
Fig. 1.4 B
Developing cell in culture has actin in growing tips.
Confocal
I will give you a demonstration of some unique imaging using confocal microscopy.
Review utilizing Sylvius
An access code came with your book and we will use it for various views
of :
Broca's area, Wernicke's area, motor cortex, auditory cortex
Brodman's areas, famously 4 (precentral gyrus=motor cortex), 17 (visual
cortex)
Occipital lobe
Postcentral gyrus
Spinal cord (including cervical and lumbar enlargements of gray matter for
fore- and hind-limbs
Striatum
Substantia nigra
Brain imaging techniques
(Box A - three figures) MRI
Alumnus research in neuroscience
Adrian A. Epstein, SLU class of 2002, took this course from me in 2002 (and
introductory biology earlier). After that, he went to Washington University
and is a research assistant in biological imaging (in the Department of
Radiological Sciences). He is first author of several abstracts (convention
presentations) and is coauthor of J. S. Shimony et al., Diffusion tensor
imaging reveals white matter reorganization in early blind humans, Cerebral
Cortex, 2006. Here, they use a specialized technique called diffusion tensor
imaging to trace tracts (hence DTT= diffusion tensor tractography) to compare
the visual projection in normal and blind subjects.
Some useful information and links
Neuroscience at SLU is centered in Medical school departments of Center
of Anatomical Science and Education and Department
of Pharmacology-Physiology. Outlines from my signal
course in biology might be helpful sometimes. Dr.
Anch in Psychology teaches 4 courses in physiological psychology relevant
to Neuroscience, PSY-A415-01: Science
of Sleep, PSY-A513-01: Advanced
Physiological Psychology, PSY-A413-01: Physiological
Psychology, and PSY-A414-01: Drugs
and Behavior. Dr.
Spaziano's CH-A445 Principles of Medicinal Chemistry is also somewhat
relevant to this topic. There is a philosophy professor, Dr. Terzis, who
teaches a relevant course PL A-482-01 "Biology and Mind" which
is relevant to this topic.
Here are some web sites for your present and future reference:
Society for Neuroscience
Neurosciences on the internet
Exam questions from 2005 - 2007 related to this outline
What makes it so that Tau, a microtubule-binding protein, fluoresces red
in the confocal microscope?
need to bind antibodies tagged with fluorescent dye
What function is localized to Brodmann area 17 in the occipital lobe?
vision
Why was the technique developed by Golgi and utilized by Ramon y Cajal so
useful for studies of cellular architecture?
by staining very few cells (in their entirety) they could be seen even though
many other cells were nearby
For the knee jerk reflex, where (be specific) is the cell body of the motor
neuron?
ventral horn of gray matter in spinal cord
One of the most famous examples of localization of function is Broca's area,
used for what?
language
Why would tissue plasminogen activator (TPA) be contraindicated in 20% of
stroke victims?
do not want to interfere with clotting if there is hemorrhage
A coronal section of the brain was shown revealing the caudate, putamen
and globus pallidus, involved in coordinating motor movements. These structures
are collectively referred to as what?
basal ganglia
Why is the optic "nerve" (the second cranial "nerve")
actually a tract?
eye and this "nerve" are part of the CNS
What information (and in what direction) is carried by axons of the cells
in the dorsal root ganglion?
somatosensory (also muscle stretch, etc.) afferent
Why might half of your brain be saved it there were a unilateral occlusion
affecting one internal carotid artery?
because the circle of Willis would bring blood from the other side
What is the huge decussation seen as white matter in a midsagittal section
of the brain?
corpus callosum
If Santiago Ramon y Cajal (famous proponent of cell theory) knew what we
knew now, how would he have used the chemical synapse in his arguments against
Camillo Golgi's reticular theory?
Cells, being separate, must communicate
What is the function of Brodmann's area #4, the precentral gyrus?
Motor cortex
The text figures with several proteins (like tau plus tubulin) labeled different
colors in a nerve cell look really nice! One reason is that out-of-focus
cells do not degrade the image. How did "they" acheive this?
Confocal microscope (optical sectioning, low depth of field)
The "nigro-striatal dopamine tract" is implicated in Parkinson's
disease. It goes to the striatum. Where does it come from?
substantia nigra
Under what circumstances would you label your antibody with colloidal gold
vs a fluorescent dye?
coloidal gold for electron microscopy, fluorescent dye for standard and
confocal fluorescence microscopes
What is the function of the choroid plexus situated in the ventricles?
secrete cerebro spinal fluid (CSF)
Why are the "basal ganglia" called "basal nuclei" in
some treatments (like the transparency from the introductory book that I
showed)?
cells and connections in the CNS are called nuclei
What substance is missing in gray matter (but is present in white matter
and makes white matter white)?
myelin
What colossal body is seen in mid-sagittal section that connects left and
right hemispheres?
corpus callosum
What is the anatomical name of the combined medulla, pons and midbrain?
brain stem
For which kinds of stroke might you use desmoteplase (from vampire saliva)?
those caused by thrombus or embolism
How could all the details of the dendritic tree of a cerebellar Purkinje
cell be revealed when that cell is in the neighborhood of "zillions"
of other cells?
Golgi staining technique only highlights one cell out of how many
What optical phenomenon, important in microscopy, was demonstrated when
I shined an untraviolet (UV) light (that you could not see) onto my shoe
laces and they shined a bright blue?
fluorescence
Suppose I'm interested in the subcellular localization of a protein (such
as tau, actin, tubulin or rhodopsin). Why do I need two antibodies to visualize
the protein?
one to bind the protein of interest, the secondary directed against the
first with fluorescent or electron dense label
Scientists in Brocca's time needed to wait until autopsy to find the localization
of function damaged by stroke (or tumor or whatever). What allows us to
see into the brain of a subject or patient nowadays?
imaging (CT, PET, MRI)
Low depth of field and optical sectioning allow unique computer-generated
views in which a stack of optical sections can be rotated. What technique
is this?
Confocal microscopy
This page was last updated 1/10/08
Neurons and glia
from Purves et al., Chapter 1, Figures from Chapters 3, 6, 16, 22, Appendix
Diseases of the nervous system are significant
in the overall health care system
and in fulfilling the optimum quality of life
Examples: Boxes
Neurons
Fig. 1.3A
Typical neuron (Nerve cell) soma, perikaryon
nerve cells have typical organelles, nucleus, rough ER, Golgi apparatus,
mitochondria
axon hillock, dendrites
Fig. 1.3C
terminal bouton, synapse
vesicles (small, electron lucent)
post-synaptic density
Fig. 1.4 E Dendrites have protrusions (spines) tubulin is labeled
Fig. 1.4 F spines, actin is labeled
TRANSPARENCY shows a freshman biology view of a "typical" neuron
like a spinal motor neuron
Fig. 16.5 (shows how motor nerve branches to innervate all the muscle cells
of one "motor unit" collateral)
Not in text (but it was in second edition)
Cytoskeleton
important and, in neurons, have unique properties
microtubules 25 nm diameter
Axon transport as fast as 400 mm/day
discovered by Paul Weiss (American) in 1940's - based on microtubules
kinesin moves toward + end of microtubule, anterograde (orthograde)
put radioactive proline in eye - use autoradiography for neuroanatomy
dynein moves toward - end, retrograde
herpes and rabies viruses ascend by retrograde transport
Slow (1 mm / day)
Glia
Fig. 1.5 ABC astrocyte, oligodendrocyte, microglial cell
astrocytes - support, repair, grouping, regulate ions, neurotransmitters
microglia -> macrophages (Virchow noted phagocytosis in pathology)
Fig. A18 (Appendix) Astrocyte end feet involved, along with capillary endothelium,
in blood brain barrier
central nervous system is well sequestered from the immune system
Fig. 22.12 ABC radial glia provide "railroad tracks" for migrating
cells in development (but how did they get there?)
Myelin
oligodendroglia (CNS) and Schwann cells (PNS) to make myelin
Fig. 1.3D myelin
also
Fig. 1.3G node of Ranvier between adjacent patches of myelin
Fig. 1.5 B oligodendrocyte
Fig. 1.5F myelin is red, lots of channels at node of Ranvier green
Fig. 3.13 A,C
Myelin - cytoplasm squeezed out - multiple layers of membrane, high resistance,
high capacitance
Channels at nodes of Ranvier
Here is an osmium tetroxide "stained" transmission electron micrograph
of the many layers of membrane in myelin
nodes of Ranvier 1-2 micro meters (microns), Schwann cells 1 mm
"Saltatory" (leaping) conduction
oligodendrocyte myelinates several axons
Here is a classic diagram
of an oligodendeocyte. Note that the cell myelinates several axons. Note
also that the major dense line is where the cytoplasm was squeezed out and
the minor dense line is where the outsides of the membranes fuse.
Recent reading: J. K. Huang et al., Glial membranes at the node of
Ranvier prevent neurite outgrowth, Science 310, 1813-1817, 2005. A protein
called OMgp (oligodendrocyte glycoprotein) is associated with a decrease
in axonal sprouting after injury. This protein is not in myelin but in "oligodendrocyte-like
cells" that make a wrapping around nodes of Ranvier. This understanding
may be important in therapy and relates to the long standing dogma that
there is no regeneration in the mammalian CNS.
Myelin diseases
Chapter 3 Box D multiple sclerosis
Polio (poliomyelitis) is a viral disease that damages myelin in peripheral
nervous system causing paralysis; then the nerve cell degenerates.
Salk (1955, injected) then Sabin (eat sugar cube) vaccines in the 1950s,
before that, only passive immunity from gamma globulin from people who had
polio.
Serious cases required an iron lung.
FDR had polio.
Neuron's trophic effect on muscle is seen as muscle (not directly diseased)
deteriorates.
It is thought that there is some recovery where motor neurons branch more
(they already branch to innervate all of the muscle cells [fibers] of one
motor unit) so that surviving neurons innervate muscle cells "abandoned"
by lost nerve cells.
But at middle age, there is increased fatigue, pain and weakness (post-polio
syndrome).
Cause: those sprouts are lost.
L.S. Halstead Post -polio syndrome, Scientific American, April 1998 42-47
Multiple sclerosis (MS) (Anette Funicello, Montell Williams, Richard Prior,
"the president" in West Wing) damages myelin in the central nervous
system
Might aflict motor function, vision, or others
Hits people 20-40, with deterioration but sometimes episodic, i.e. with
remissions
Animal model - EAE (experimental allergic [autoimmune] encephalitis) to
myelin basic protein.
Such a disorder used to happen with rabies vaccination when virus was grown
in brain (before it was grown in eggs).
As you see from the box, there is lots of speculation as to the cause
Guillain-Barre syndrome peripheral myelin immune attack lose sensation and
have weakness, sometimes severe, sometimes goes away, comes after illness,
difficult to diagnose, controversy over whether it came after immunization
for swine flu in Ford administration
Gina Kolata, Flu: The story of the great influenza pandemic of 1918 and
the search for the virus that caused it, New York, Farrar Straus and Giroux,
1999.
In 2006. graduate student Matthew Hulvey gave a presentation on MS, and
here is
a pdf of his power point show
Test questions from 2005 - 2008 that apply to this outline
Explain the reason for the prefix "oligo-" in "oligodendrocyte."
they myelinate several axons
EAE (experimental allergic [autoimmune] encephalitis) is an animal model
for what disorder?
ms
Guillain-Barre syndrome, rumored to be a consequence of the swine flu shots
in the 1970's, does what to the patient's nervous system?
peripheral nerve myelin damage
What is kinesin used for?
axonal transport along microtubules
Why is saltatory conduction in the vertebrate even faster than conduction
in giant invertebrate axons?
because action potential jumps from node to node
What do all the dense lines seen in myelin in the electron microscope signify?
many membrane layers
Why might the leg of a person who had suffered debilitating polio be spindly?
nerve has trophic effect on muscle
Membrane has high resistance and high capacitance. Why do multiple layers
of membrane in myelin decrease current flow through the part of the axon
ensheathed in myelin?
resistance in series adds, capacitance in series adds inversely
If injected into the eye, radioactive proline, an amino acid, gets incorporated
into proteins. Radioactivity can be seen in area 17 by autoradiography.
How would kinesin be involved?
kinesin is like the railroad car on microtubules that go down the axons
In addition to the endothelium, a process of what cell separates the blood
from the cerebrospinal fluid.
astrocyte
What is saltatory conduction and why is it advantageous?
action potential jumps from one node of Ranvier to the next, speeds action
potential
What specific cellular component in what specific part of the nervous system
is damaged in multiple sclerosis (MS)?
myelin, CNS
In addition to the insulation provided by the multiple membrane layers of
myelin, there is a concentration of what type of molecule at the node of
Ranvier of the axon?
channels
"Postsynaptic density" - what technique and "staining"
affords us the resolution to see this as a "density?"
Transmission electron microscopy where density is seek as electron density
of heavy metals
Describe the nature of the connection of a spinal motor neuron to the muscle
cells.
credit for any or some of the following: big synapse called neuromuscular
junction, excitatory only, acetylcholine, nicotinic channel, ionotropic
What is the function of kinesin and dynein in the axon?
axonal transport (anterograde and retrograde respectively)
In addition to the endothelial cell, what separates the blood plasma from
that privileged compartment, the cerebrospinal fluid (CSF)?
"foot" of astroglial cell
In salutatory conduction, the action potential jumps from one (what?) to
the next (same thing)?
node of Ranvier
Membrane has high resistance and capacitance. Multiple membrane layers in
myelin have high resistance to make an insulator. Current leaks through
membrane capacitance. How come multiple membrane layers don't leak huge
amounts of current through the capacitance?
capacitance adds reciprocally
Membrane layers fuse so tightly in myelin that electron dense lines from
adjacent membrane layers fuse. How can there be two distinct fused appearances,
major and minor dense lines?
major dense line where cytoplasm squeezed out, minor - outsides of the membranes
fuse.
Polio causes paralysis because the virus specifically and primarily damages
what kind of cell?
Schwann cell
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This page was last updated 1/22/08
Bioelectric potentials, Ion pumps
Purves et al., Chapter 2 , also pp. 69-73, Figures from Chapter 4
Personal Reflection
I was first exposed to some of this material as a senior in 1969. Tom Ebrey
had a background in physics. He was young, and since he is still living,
but retired, I was happy to lunch with him in July, 2007 where he lives
(Seattle) since we go there now and then to see my son and his family. see:
R Crouch et al, A tribute to Thomas Ebrey, Photochem Photobiol, vol 82,
2006.
Overview
Excitable membrane has resting and action potentials
Ions are dissolved in water and are pumped using ATP -> ADP for energy
These ion gradients establish "batteries" as ions can flow through
channels
Other than channels and pumps, membranes do not pass ions well
For resting potential, Potassium (K+) channels dominate
For action potential, Sodium (Na+) channels open (activate) then close (inactivate)
Toward the end, a different type of K+ channels open (activate) then close
(passively, they do not inactivate)
Action potentials are all-or-none big depolarizations
Synaptic (graded) and sensory (generator) potentials are smaller.
They can be of variable size and can be depolarizing or hyperpolarizing.
Electrophysiology
I use a Narishige PD-5 (Tokyo) horizontal puller
with controls for an early magnet, a heater, and a late (stronger magnet).
The heater glows red
while the first magnet pulls gently.
A microswitch with
a shim detects the melt and the early pull to kick in the harder pull.
After the second pull, two electrodes
are made.
Over the history of micropipettes, many tricks have been developed to get
the very narrow tip to fill. Currently, a capillary tube with an inner
filament has magic filling properties.
First you back fill the
butt end a little with a spinal tap needle.
The electrolyte (I use saturated NaCl for ERGs) is carried to the tip.
Then, you can finish back filling the elecrode with the syringe.
If equipment is dumping current into ground in various locations, then there
is a circuit with voltage differences despite the infinitesimal resistance
through ground. The result is ground loop noise. Thus it is wise to hook
all grounds to one central ground
tree. I hook this to water pipe ground with a big braided wire and bypass
all the equipment grounds, connecting to the tree instead.
In the set-up, a dissecting
microscope can be swung into position. The probe from the amplifier is in
the Faraday cage (painted flat black) near the fly. A micromanipulator allows
the electrode to be advanced toward the eye. The cage should not be cluttered
by electrically noisy stuff, but a microscope illuminator is necessary.
A hydraulic microdrive
(Kopf) [stepping motor driving water syringe on left and controller on rignt]
driving a slave syringe
helps to get the electrode into the eye.
An electrometer serves
as the differential preamplifier
In the old days, this could feed into a polygraph, a penwriter
that graphs voltage as a function of time, limited for speed by the momentum
of the pen
Also somewhat outdated is the oscilloscope
A permanent record can be made with a camera,
and the most famous is the Grass camera
Nowadays, the computer
is used for an oscilloscope. Here is a PowerBase 180 from Power Computing
(Mac work-alike) feeding into an Optiquest monitor using the PowerLab 410
from AD Instruments as the interface
Fig. 2.2 A
Insertion of stimulating and recording microelectrodes
Fig. 2.2 B
Voltage as a function of time ("graph") - resting and action potentials
Depending on direction of stimulation, passive potentials are depolarizing
or hyperpolarizing
Threshold to trigger action potential is shown
Square wave (stimulus) leads to exponential curve (recording) because of
capacitance
Fig 2.1C
shows action potential again (unconfounded with other information) from
axon of spinal motor neuron
Fig 2.1 A&B
shows sensory stimulation (Pacinian corpuscle, touch receptor) and synaptic
potential in dendrite to show these are smaller (graded) potentials
History
1791 Luigi Galvani (Italy) (of Glvanometer fame) - nerve muscle electricity
in frog
1850 Herman von Helmholtz - speed of conduction (40 m/s)
Fig. 2.3
Walther Hermann Nernst (Germany) (1864-1941) 1920 Nobel
in Chemistry
Nernst equation says that ion gradient is equal and opposite to voltage
difference
1902 (paper) Julius Bernstein apply Nernst equation, he thought that K+
permeability was lost during the action potential, while, in fact, the Na+permeability
increases (he should have noticed this in his data)
Fig. Box A squid giant axons
1939 K. C. Cole and H. J. Curtis (US) introduced use of squid and showed
that membrane resistance decreases during passage of action potential
Invertebrates do not have myelin to speed the velocity of propagation of
the action potential.
Theoretically, this velocity increases with the radius, and so invertebrates
use giant axons when fast action potentials are needed.
Squid uses quick mantle contraction and jet propulsion through siphon in
escape response.
TRANSPARENCY (from R. D. Keynes, The nerve impulse and the squid, Scientific
American, December, 1958).
Fig. 2.6B
1950's Sir Alan L. Hodgkin & Sir Andrew F. Huxley (Great Britain)
1963 Nobel
Prize in Physiology and Medicine for "ionic mechanisms...excitation
inhibition...nerve cell membrane"
In general, They showed what was stated above:
For action potential, Na+ channels open then close, K+ channels open (then
close)
Fig. Chapter 4 Box A
Erwin Neher & Bert Sackmann (Germany) for patch clamp
Nobel
Prize in 1991 "incredibly small electric currents that pass through
an ion channel "
This electrode technique records from single channels which are distinct
molecular entities.
Membranes
Fig. 4.4A
Membranes (shows ion channel in membrane)
Fluid mosaic, two layers of lipids such as polar phospholipids with proteins
embedded
some points not emphasized in text but recalled from cell biology:
-imbalance of lipids, inositol lipids on inside, signalling
-glycolipids on outside (like gangliosides)
proteins span membrane - based on hydrophobic alpha helix
Voltage gated Na+ channel for action potential
Electrical concepts
Here is a pdf of
the transparency I'm showing you
TRANSPARENCY Circuits (equivalent circuits)
Battery, anode:+, anions:-, Cathode:-, cations:+
Current = i (Amps), defined as + to - (Benjamin Franklin)
Potential (potential difference): V or E (Volts)
(1) Battery (source of electromotive force, EMF)
(2) Current flow through a resistor
battery and resistor in circuit
E = IR (Ohm's law), R in units of Ohms, W
G is conductance, 1/R, "mho" = Siemens (S)
I = gV
Fig. 2.2 B
again, note delay in depolarizing or hyperpolarizing membrane
Membrane capacitance (not emphasized in book)
Thus, this is a low (frequency) pass (high cut-off) filter
Typically, capacitance adds delays
There are also high pass filters
Sodium - potassium "pump"
Fig. 2.3
shows elementary properties of pump
Fig. 4.10A
Na+-K+-ATPase
Uses 1/3 (2/3 if high electrical activity) of cell
Fig. 4.11B
"Electrogenic" - imbalance of 3 Na+ - 2 K+ cause current to flow,
contribute a few mV
Calculation to show only a few mV
Here's a pdf
of the calculations
Fig. 4.13AB
(molecular structure)
10 membrane spans
homologies with Ca++ pump in sarcoplasmic reticulum
homologies with bacterial K+-ATPase
Ouabain binds to pump and blocks it
From the plant digitalis purpurea (purple finger) [foxglove], we get digitalis,
another cardiac glycoside.
They look like a steroid bound to a few sugar groups with glycoside bonds.
In myocardial cells (heart muscle cells), blocking the Na+ pump slows a
Ca2+/Na+ exchanger, increasing intracellular Ca2+ for stronger heart contractility
in some sisorders.
Fig. 4.11A
classic experiment by Hodgkin and Keynes (1955)
Fire off a zillion action potentials in radioactivce sodium to preload
Measure efflux
note that K+ (out) is needed for it to work
DNP (dinitrophenol) blocks ATP synthesis - pump slows
Derivation of Nernst potential
Here's a pdf of the
transparency I'm showing you
Assume two compartments in communication
(ions like K+ or Na+ dissolved in each)
Free energy (of each system) = RT ln Ci + ziF(Potential)
RT ln Ci is chemical energy
ziF(Potential) is electrical energy
F is absolute potential, C is concentration, i is given ion, e.g. K+ or
Na+, z is valence, ln is natural (to be base e) logarythm
T is tempreature in degrees Kelvin
R = 8.31 Joules/moleoK
F = 9.65 x 104 Coulombs/mole
[ = 6.02 x 1023 ions/mole x 1.6 x 10-19 Coulombs/ion ]
Assume equilibrium which means
(1) no flux
(2) electrical and chemical gradients equal and opposite
(3) energies of two compartments the same
Simple algebra and the fact that log10 = 2.3 x ln gives:
EK+ = 58 log [K+]out / [K+]in
Table 2:1
ion gradients for mammalian neuron:
K+ in 140, K+ out 5
Na+ in 5-15, Na+ out 145
Fig. 2.4 C
shows dependence on external K+
Fig. 2.7 AB
also shows this
Here's a pdf of
the transparency I'm showing you
Goldman equation
David Goldman, 1943
assume constant field
Vm = 58 log PK[K+]out + PNa[Na+]out + PCl[Cl-]in
PK[K+]in + PNa[Na+]in + PCl[Cl-]out
Cole and Curtis use AC bridge to show resistance of membrane decreases as
action potential goes by
Kirchoff's laws
Such a membrane model seems to suggest a confusing circuitry, simplified
by several simple concepts.
Kirchoff's first law: at any junction, sum of currents is zero.
Kirchoff's second law: sum of changes in potential around loop is zero.
There is a pdf
to illustrate a problem and its solution using Kirchoff's laws.
The solution involves 3 equations with 3 unknowns (high school algebra)
[or determinants, slightly more advanced high school algebra].
Exam questions from 2005 - 2007 that apply to this outline
Hodgkin and Keynes found that removing extracellular K+ decreased the Na+
efflux from the "sodium pump." Why would this be the case?
even though extracellular potassiun is low, the Na+-K+ATP needs to pump
K+ to pump Na+
Paving the way for the Nobel Prize winning Hodgkin and Huxley work, what
could you conclude from the Cole and Curtis finding that the AC bridge went
out of balance as the
action potential goes by?
conductance increased
The time constant (=RC) describes the properties of what kind of filter
placed before the input of a differential amplifier?
low (or high) pass (or cut-off)
Faraday's constant is the charge of a mole of ions, 9.65 x 104 coulombs/mole
= Avagadro's number x the elementary charge (charge of a single ion). What
would be the units of
the elementary charge?
coulombs per ion
An appropriately low dose of the cardiac glycoside digitalis would improve
myocardial contractility by blocking what?
sodium pump directly, sodium calcium exchange indirectly
The equilibrium assumption in the derivation of the Nernst equation means
that what two gradients are equal and opposite?
electrical and chemical
Why is the "sodium pump" electrogenic?
because of the imbalance (2K+/3Na+)
If I were on the ordinate (Y axis) and V were on tha abscissa (X axis),
what electrical term is used to describe the slope of the line?
conductance (g)
How do you use the patch clamp method to determine the properties of a channel
gated by intracellular ligands like cAMP or cGMP?
get the channel, break off that hunk of membrane, then you can dip the inside
of the channel
In the numerator of the Goldman equation, we find intracellular potassium
and sodium but extracellular chloride. Why the difference?
Cl is -, others are +
On an oscilloscope (polygraph or computer), an action potential is a graph
of what as a function of what?
voltage, time
In the circuit diagram model for the Goldman equation, potentiometers are
used instead of resistors. Why?
resistance is variable
Why does a glass micropipette have high resistance?
it is so small, a narrow path of electrolyte
In contrast with "all-or-none" give the general term for those
smaller potentials of variable size that can be either depolarizing or hyperpolarizing.
(One is for sensory receptor potentials the other for synaptic potentials.)
generator-sensory, graded-synaptic
Describe the technique developed by the Nobel Prize winners Neher and Sackmann
that allowed the measurement of currents through single channels.
patch clamp puts the tip of an electrode up against a channel
The action potential is all-or-none in part because you cannot trigger one
spike on top of another. In other words, there is a refractory period. What
property of the sodium channel is responsible?
inactivation
What molecule has an ouabain binding site?
the Na+-K+-ATPase (sodium pump)
I said, "capacitance adds delays." Draw the graphs for a square
wave of current injection and the corresponding hyperpolarization to show
the low pass filtering of membrane capacitance.
look on p 61
What imbalance makes ATPase electrogenic?
3 Na+/ 2 K+
Faraday's constant, the charge of a mole of ions in Coulombs per mole, is
used to solve for which specific component of energy in the derivation of
the Nernst equation?
electrical component
Why didn't the efflux of radioactive Na+ go to zero immediately when Hodgkin
and Keynes blocked ATP synthesis with DNP (dinitrophenol)?
the pump keeps working until the ATP runs out
What factors are applied to the concentrations of Na+ and K+ to allow the
Goldman equation to account for both resting and action potentials?
relative permeabilities (conductances)
After being open, sodium channels have something, and the word "close"
does not fully convey the meaning of (what is the correct word)?
inactivate
"Other than channels and pumps, membranes do not pass ions well."
Why not?
The center of the membrane is hydrophobic
In contrast with the term "all-or-none," what does the term "graded"
signify in describing membrane potentials?
They can be of varying size
n a 1902 paper, Bernstein, applying the principles learned from Nernst,
proposed that K+ permeability was lost during the action potential. In what
way was this wrong? In what way was it insightful?
Wrong, K+ permeability was not lost, right - relative K+ permeability less
because that of Na+ is more
After assuming that the energies of two compartments are equal, algebra
boils the Nernst equation down to saying that the membrane voltage is equal
and opposite to what?
chemical gradient
I told a story about how capacitors hold a charge (that can shock a person
when they discharge). How did that story relate to the passive voltage response
of the membrane at the end of stimulation of the membrane by a square wave
of current?
After stimulation ends abruptly, membrane voltage returns to baseline gradually
Right when ATP converts to ADP to power the sodium pump, what becomes of
the inorganic phosphate?
Before it is free, it is bound to pump molecule
Pick either word, "cardiac" or "glycoside" and tell
me why the expression applies to digitalis.
In heart muscle cells, blocks Na+ pump slows Ca2+/Na+ exchanger, increasing
intracellular Ca2+ for stronger contractility, glycoside bonds.
In Hodgkin and Keynes' classic experiment on the sodium pump, how did they
obtain numbers for the Y-axis (ordinate) that relate to sodium efflux?
measured radioactivity aftye loading axon with radioactive sodium
Why is there a direct (electrogenic), though small, contribution of the
Na+-K+-ATPase to the membrane potential?
because 3 Na+'s are pumped per 2 K+'s
"Slope = 58 mV per tenfold change in K+ gradient." Answer either
of the following: How did they do this experiment? OR Why would it be expected
to be this way?
Change extracellular potassium, cause voltage = -58 times the log (to the
base 10) of the ion gradient
What does the Goldman equation tell us beyond the Nernst equation?
takes into account pooled voltage based on sodium, potassium and chloride
(ion gradients and relative permeabilities)
When the AC (fast) Wheatstome bridge of Cole and Curtis swung out of balance,
what did that tell us about the membrane events at that moment?
resistance changed (decreased) during action potential
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The action potentials and channels lecture
Action Potentials
Purves et al., Chapters 3 & 4 (review figure from chapter 2)
Summary
Fig. 3.8
what we know about K+ and Na+ permeability during the passing of the action
potential
Na+ conductance goes up then down early
K+ conductance goes up then down but much later.
There is something wrong with this figure: K+ conductance is much higher
than Na+ conductance during the resting potential.
Bernstein knew about selective K+ permeability
Thought it was lost during the action potential (actually Na+ permeability
increases)
Cole and Curtis used the AC Wheatstone bridge to show that the resistance
decreased during the action potential
R1 & R2 divide one path, Rv (variable) and Ru divide the other
Galvanometer between two nodes
Ru = Rv x R2/R1
Now it is easy to realize that the Goldman is like the Nernst equation where
the relative permeabilities of Na+ and K+ change
Fig. 3.11
An action potential is non-decremental
Alumnus research in neuroscience
Joel Geerling, a chemistry major, took this class (and also graduated) in
2000. He went to Wash U for an MD-PhD. Related to the importance of sodium
(covered throughout this course and in this outline) is the hormone aldosterone
from the adrenal cortex and its regulation of sodium in the kidney. It is
well-known, especially by athletes, that a sodium deficiency leads to increased
sodium appetite, Joel's work, in the 4 papers referenced below, addresses
this issue at the level of the brain. They illustrate the importance of
understanding techniques such as confocal microscopy, as well as brain anatomy.
JCGeerling et al., Aldosterone target neurons in the nucleus tractus solitarius
drive sodium appetite. J. Neurosci 26, 411-417, 2006
JCGeerling et al., Aldosterone-sensitive neurons in the rat central nervous
system, J Comp Neurol, 495, 515-527, 2006
JCGeerling & ADLoewy Aldosterone-sensitive neurons in the nucleus of
the solitary tract: Bidirectional connections with the central nucleus of
the amygdala, J. Comp Neurol, 497, 646-657, 2006
JCGeerling & ADLoewy Aldosterone sensitive neurons in the nucleus of
the solitary tract: Efferent projections, J Comp Neurol 497, 223-250, 2006
Passive spread of potential along axon
Fig. 3.10 A
If there were not something very special (voltage gating that activates
Na+ channel), passive voltage spread would be decremental
Current down along the axon gets smaller because it leaks through the membrane
resistance and capacitance.
At any place along the axon, a spike would depolarize the axon to threshold
for a spike a certain distance ahead of it, and that distance depends on
the square root of the radius.
Spike at one place would also depolarize the axon behind it to threshold,
but it does not generate a retrograde action potential because of the refractory
period, explained (below) by the inactivation of the Na+ channel.
Fig. 2.2 (again)
TERMS: threshold, generator potential, all-or-none, refractory, unidirectional
NOTE also the membrane acting as a low pass filter
Fig Box 3C [first figure] shows exponential decay and space constant (lambda)
Fig Box 3C [second figure] shows exponential charging of capacitance and
time constan (tao)
Cable equation
Here's a pdf of the
transparency I'm showing you
Personal reflection. My fellow graduate student, Paul Kottler, and
I took Warren Dennis's course (Physical chemistry of cell systems) together;
we also studied for our PhD exam together. My mentor, Jerry Wasserman, had
been famous for asking a question about the speed of the action potential
and asking it each subsequent year because he was never satisfied with the
answer. We resolved to retire this question since we knew that our coverage
on the cable equation was much more than Wasserman would expect. When I
found out that I passed, I asked Wasserman how he liked my answer and he
replied that "it was ok, a little theoretical." So Paul and I
decided we had done our duty for posterity, retiring the question, by answering
it with a derivation that involved differential equations.
Summary:
(1) an action potential at one place depolarizes the membrane ahead of it
to threshold.
(2) the spread is passive.
(3) current down the axoplasm leaks out through membrane resistance and
capacitance.
(4) solving, space constant varies with square root of radius, time constant
independent of radius.
(5) that is why invertebrates use giant axons for fast propagation.
(6) myelinated axons also have faster propagation for larger axons.
Coding
frequency of action potentials, not size since they are all-or-none
sometimes action potentials come in bursts
or at beginning of depolarization because of "adaptation"
Hodgkin Huxley experiments
Fig. 3.12
Propagation of action potential (spike) shown with opening and closing of
Na+ and K+ channels drawn in
Note relative opening and closing of channels
"sodium pump" already established the ion gradients
oscilloscope essentially graphs voltage as a function of time
action potentials can also be listened to on a loud speaker
activation, inactivation, voltage gating
Fig. Box 3A
general recording "geometry" -
differential amplifier compares 2 voltages and puts out current
operational amplifier is a differential amplifier to clamp voltage
space clamp - really just do whole axon at once
Fig. 3.2
voltage clamp data
voltage clamp - change voltage then pump and monitor current needed to keep
it there
I - t curves
Fig. 3.3
divide into early and late components as I - V curve
Ohm's law: E=IR, thus, the axes of an I-V curve are reversed and the slope
is
conductance = 1/R in units of Siemens (formerly "mho")
NOTE: iNa = gNa(V-VNa) - driving potential
Fig. 3.4
experiment with low Na+ to show early current is Na+
early fast sodium tetrodotoxin (TTX) sensitive (see box C, Chapter 4, on
toxins)
TTX from puffer fish, puffer fish is a delicacy in Japan, but careful preparation
is importantto prepare sushi, best if enough TTX left to make mouth numb
saxitoxin from dinoflagellates (red-tides are "blooms" and filter
feeding shellfish can become poisonous
Other experiments (e.g. dose of TTX) show few sodium channels, works only
if applied to outside of axon
late slow potassium TEA (tetraethyl ammonium) sensitive
Channels
Fig. 4.3
In summary, resting potential is based on predominant K+ permeability
then Na+ channels activate
then Na+ channels inactivate
then a late K+ channel activates
GENERALIZATION - action potential is based on Na+ and K+
there are MANY other channel types
Figures Box 3B
for 20 years they have been studied by "heterologous expression"
in cells like Xenopus oocytes
inject exogenous mRNA into clawed African frog egg
Channels are at a low "concentration" (except in post-synaptic
membrane).
It takes little tetrodotoxin to block action potential so they are proteins
that are not highly expressed.
Thus, channel mutants might be lethal, so they used tricks to get genes
like conditional mutants (like temperature sensitive with permissive and
restrictive temperatures)
Fig. 4.5 ABC
KV2.1 (A) is like "delayed rectifyer" K+ channel of action potential.
"Rectifier" means that it only allows current in one direction.
KV4.1 and HERG have inactivation.
One famous conditional channel mutant in Drosophila, ether-a-go-go, shakes
under ether anesthesia. A hunan homologue was found, HERG = human ether-a-go-go-related-gene.
HERG inactivates so quickly that it only opens after voltage is over. Contributes
to long action potential in cardiac muscle. Long QT syndrome is sometimes
mutation of HERG, QRS in EKG (electrocardiogram)
is ventricular depolarization, T is repolarization.
A lot of work was done with KV4.1 (B)
Fig. 4.6C
K+, A-type conductance, not at all like K+ channel of action potential
sea slug Anisodoris, Drosophila fruit fly - Shaker mutant
Tetramer makes channel, each component crosses membrane 6 times with hydrophobic
domains, S1-S6, inactivation is "stopper" on chain at N-terminal,
voltage gating is S4 with + charged arginines or lysines every 3 or 4 amino
acids, rotates and moves. Pore is between S5 and S6, not so hydrophobic.
Fig. 4.6G
This figure shows a 12-transmembrane protein for the Cl- channel
A famous Cl- channel is the cystic fibrosis transmembrane conductance regulator
(CFTR)
cystic fibrosis is most common genetic disorder in Caucasians (1/2000),
lungs fill up with thick mucus. One presumes the channel is two components.
Fig. 4.6A
Sodium channel, now diverse (human 10 genes)
electric eel Electrophorus electricus 600 V
Huge - 1820 amino acids - "pseudotetramer"
S4 - gating - positively charged (basic) arginine (R) or lysine (K)
Fig. 4.7
rotation
Pore between 5 & 6 (not hydrophobic)
Fig. 4.1B
low current (1-2 pA)
low conductance - 10 pS
stopper to inactivate.
There are different types of Na+ channels, and some are targets of local
anesthetics benzocaine and lidocaine.
Potassium channels (lots of them, 100)
Leak (resting potential) 20 pS
Delayed rectifier (repolarization of action potential) 10 pS
Anomalous rectifier - maintain depolarization - cardiac, fertilization
HERG human ether-a-go-go related gene
Calcium channels
16 genes
Ca2+ regulation by parathormone, calcitonin and vitamin D important
Ca2+ channel in synaptic terminal vesicle release - very important, also
many others
Ca2+ channel is receptor for IP3 (inositol trisphosphate "second"
messenger) on smooth endoplasmic reticulum
Ca2+ channel in muscle sarcoplasmic reticulum
Ca2+ channel in t- (transverse-) tubule in muscle
Box 4C
Toxins
Tetrodotoxin puffer fish (saxitoxin dinoflagellates) block Na+ channel
scorpions
and many others
Fig. Box 4D
genetic diseases of channels
myotonia (stiffness from too much excitation) from Cl- channel defect
Fig. Box 4D
paralysis from Ca2+ channel defect
CSNB from Ca2+ defect Congenital (i.e. genetic) stationary (as opposed to
degeneration) night blindness (would affect rods)
Fig. Box 4D
myotonia, paralysis or stiffness from Na+ channel
Long QT syndrome from Na+ or K+ channel defects EKG (electrocardiogram)
has PQRST waves, P from atrial depolarization, QRS from ventricualr depolarization
and T from ventricular repolarization
K+ channel from HERG = human ether-a-go-go(EAG) related gene EAG - Drosophila
twitch under ether anesthesia
Fig. 4.8
Structural studies on bacterial K+ channel - it takes a lot of protein to
do X-ran crystallography
Fig. 4.8
selectivity by pore size
interesting that non-hydrated ion passes.
Hydrated - size is inverse
Li > Na > K > Rb > Cs (lyotropic series)
Fig. 4.6
There are a lot of configurations of channels
Exam questions from 2005 - 2007 relating to this outline
How did the electric eel Electrophorus electricus assist in the isolation
of a channel?
sufficient concentration of sodium channel to allow characterization
In theory, and in data, what is the direction and amount of Na+ current
when the voltage in the axon is clamped to the Na+ equilibrium potential?
none
Paving the way for the Nobel Prize winning Hodgkin and Huxley work, what
could you conclude from the Cole and Curtis finding that the AC bridge went
out of balance as the
action potential goes by?
conductance increased
In terms of amino acid sequence, how does the S4 of the voltage-gated Na+
channel differ from the typical transmembrane alpha helix?
charged arginines or lysines every 3 or 4 amino acids
To hold the voltage of a squid giant axon at a clamped level of 0 mV, Hodgkin
and Huxley had to pump current out through the membrane at 0.5 ms (fairly
early) to compensate for
what?
sodium current
What does tetrodotoxin block?
the sodium channel
"Long QT syndrome can be caused by a mutation of HERG." Translate.
genetic long myocardial action potential
How does the space constant of an axon relate to the axon's size?
with square root of radius
Some potassium channels do show inactivation. What part of the molecule
is responsible?
stopper on the N-erminus
CSNB is a channelopathy. S=stationary (not progressive degeneration). NB=night
blindness (affecting rod photoreceptors). Why is the term C=congenital applied?
it's genetic
An action potential depolarizes the axon ahead of it to threshold, and that
is why the action potential propagates. It would also depolarize the axon
behind it. Why does it not cause a
backward action potential?
refractory potential, inactivation
Selecting for conditional channel mutants, like temperature sensitive mutants,
has been especially useful in Drosophila. Why not just isolate regular mutants?
they might be lethal
Why would two resistors in series connected to a battery be called a Voltage
divider?
Two sources of voltage (Ohm's law) E=IR, E = IR1 + IR2, used in Wheatstone
bridge
In discussing the passive properties (i.e. without an action potential),
the current gets smaller with distance from the stimulus going along the
axoplasm (down the inside of the axon). Why does it get smaller?
along the way, it is lost through the membrane (the membrane's resistance
and capacitance)
The Shaker K+ channel is a tetramer of proteins that each cross the membrane
6 times. Why is the Electrophorus Na+ channel called a pseudotetramer
instead?
because one huge molecule has 4 repeated domains each the size of one shaker
channel protein
When (or why) is there a negative conductance region in the I-V curve in
Voltage-clamp data?
early, when Na+ channels activate then inactivate
What would be the cause of death if you ate a puffer fish?
Na+ channel block, no action potentials
What does an alpha helix, namely S4, with positively charged (basic) amino
acids [arginine (R) or lysine (K)] every 3 or 4 amino acids do for the action
potential's sodium channel?
it detects Voltage to gate the activation of the channel
Cole and Curtis already knew that the conductance went up as the action
potential went by. Hodgkin and Huxley went a bit further. Which conductance(s)
went up?
Na+ and K+
Give the name of at least one "channelopathy" (genetic disease
resulting from a mutation affecting a channel protein).
paralysis, myotonia, long QT syndrome, congenital stationary night blindness
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Synapses
Purves et al. Chapter 5
Major point
Cell theory (cells being separated) implies that cells must communicate
with each other through extracellular connections and most communication
is through chemical messages
- "synapse" - = "clasp" (sherrington)
Fig. 5.1B
Vesicles, spine, receptors (the ionotropic type, i.e. channels) are shown
Alumna
Johnnie Moore took this course in 2002. She published this paper: Moore
et al., Stable gene silencing of synaptotagmin I in rat PC12 cells inhibits
Ca 2+-evoked release of catecholamine, Am J. Physiol Cell Physiol 291, 270-281,
2006
Topics to discuss:
confocal
synaptotagmin
NGF
calcium
PC
"Electrical synapses"
Fig 5.1A
Gap junction is an exception to the above generalization in that cells are
coupled electrically with cytoplasmic continuities (small ones).
Gap junctions are used in crayfish escape,
"Landmark" paper EJFurshpan and DDPotter, Mechanism of
nerve-impulse transmission at a crayfish synapse, Nature 180, 342, 1957
and J. Physiol. 145, 289, 1959. "Landmarks" was a department in
The Journal of NIH Research, includes interviews. (ref=vol 8, Oct 1996,
51-57
They are also used to connect myocardial cells electrically at intercalated
disk.
Conductance is high - 120 pS.
Fig 5.2A
Gap junction is patch of hexamers forming big channel in register with adjacent
cell.
Proteins, called connexins, are very diverse.
They are often named with a number that represents the molecular weight.
Recent paper CDLandisman & BWConners, Long-term modulation of
electrical synapses in the mammalian thalamus, Science 310, 1809-1813, 2005.
There are gap junctions with connexin36 (Cx36) in thalamic reticular nucleus
(TRN). There are chemical synapses using metabotropic glutamate receptors
(mGluRs) from neocortex. Activating this corticothalamic path causes long-term
decrease in electrical synapse strength. This is like long term depression,
a model for learning at the level of the chemical synapse.(Each item of
terminology that might be unfamiliar to you now will be covered later.)
Pore is big enough to give cytoplasmic continuity for medium sized molecules
(dyes).
In addition to electrical coupling, there can be communication by molecules.
In EM, membranes appear very close but not fused
Extracellular tracers (heavy metal Lanthanum) proves there is extracellular
space.
History
In 1906 Sir Charles S. Sherrington (England) published Integrative Action
of the Nervous System and later (1932) won the Nobel
prize for "functions of neurons." He coined the term "synapse."
In studies of the spinal reflex, he determined that the spinal motor neuron
was the "final common pathway" (for integrative action of the
nervous system). Spinal reflexes were studied in spinal animals in which
the spinal cord was transected to prevent descending cortical influence.
There are no inhibitory neuromuscular junctions in vertebrates, so whether
the spinal motor neuron fires, based on summed inhibitory and excitatory
influences, is the last chance to integrate neural influences.
Fig. 5.4
1926 Otto Loewi (Austria) experiment he dreamed, stimulate vagus (10th cranial
nerve, parasympathetic), take substance and show that it slows a heart in
another dish, vagus substance = acetylcholine (ACh) a monamine transmitter.
1930's Sir Henry H. Dale (England) acetylcholine
share 1936 Nobel
"chemical transmission of nerve impulses"
Fig. 5.21AB
Sir John C. Eccles 1963 Nobel
(with Hodgkin & Huxley) EPSP & IPSP
Excitatory or Inhibitory PostSynaptic Potentials (Eccles, using spinal motor
neurons)
Excitatory and Inhibitory integrate in cell, and axon hillock "decides"
whether to fire.
Fig. 5.20A
glutamate is the excitatory transmitter
EPSP - depolarize (unless clamped positive to reversal potential)
increase sodium and potassium conductance
inferred because reversal potential is near zero (in voltage clamp)
Fig 5.20BC
GABA (gamma amino butyric acid) is the inhibitory transmitter
IPSP - hyperpolarize (unless clamped negative to reversal potential)
increase potassium and chloride conductance
inferred because reversal potential negative to resting potential (in voltage
clamp)
and by changing Cl- gradient by using ion specific electrodes to inject
Cl-
1970 Nobel
Sir Bernard Katz (England) Ulf von Euler (Sweden) Julius Axelrod (US) "humoral
transmitters...nerve terminals....storage release inactivation"
Fig. 5.7A
classic experiment by Katz showing that the transmission at the neuromuscular
junction is "quantal." Quantum is one vesicle. EPP (end plate
potential) is reduced to meep's (miniature end plate potentials, 0.4 mV)
by lowering extracellular Ca2+ ion, and nerve stimulation elicits responses
the size of 0, 1, 2, or 3 meep's according to the Poisson distribution.
"end plate" potential is big and effective in generating muscle
action potential. Usually 200 vesicles give 40 mV potential.
Fig. 5.8 A
Here is a classic pictures, work by Hueser and Reese, of vesicle release
at the neuromuscular junction, a freeze
fracture electron micrograph
also a transmission electon micrograph
(Heuser) where the vesicle release is called an omega figure because it
is shaped like the Greek letter.
Just to put into perspective the degree to which much of this information
is background,
TRANSPARENCY shows the version of this picture the Biology Department teaches
to freshmen.
Specifics shown in this figure:
Ca2+ enters presynaptic terminal upon arrival of the action potential.
The receptor shown is a channel passing Na+ (this situation can vary).
Neurotransmitter is broken down (true for acetylcholine, but this situation
also varies).
Fig. 5.3
Chemical synapses
Presynaptic membrane, cleft, Postsynaptic membrane (intracellular density
seen in EM [electron microscopy]), vesicle
Specifics in this figure
Note that the post-synaptic membrane is up on a spine.
Membrane is recycled, and endocytotic pits and vesicles are coated (with
clathrin); coated pit
from my work another
(not related to synapses).
Fig 5.13C
There is a protein called dynamin that helps pinch off vesicles. It is the
product of the temperature sensitive Drosophila paralytic mutant called
shibire. At restrictive temperature, there is a block
in endocytosis of vesicles (another view).
vesicles and T-shaped ribbons in Drosophila
Here is a transmission electron micrograph of a synapse
Vertebrate - inputs to cell or dendrite (spine)
Invertebrate - cell is usually away from action surround "neuropil(e)."
Here is a picture from
my work on Drosophila, retina (compound eye is off top, cartridges of synaptic
connections are at bottom, cell bodies of post-synaptic neurons are between.
Vesicle release
General: vesicles are interesting, transmitter is very concentrated, there
are pumps to move transmitter "up hill" (against gradient) into
vesicle, sometimes part of synthesis is in vesicle.
Fig. (not in the book anymore)
very modern, interesting and detailed
also, interesting Box C on toxins that affect neurotransmitter release
there are vesicle membrane proteins, target (presynaptic) membrane proteins,
and cytoplasmic proteins
Ca2+ in through Q or N type voltage gated channel
(N stands for "neither," as opposed to T=transient or L=long lasting,
the N channel is blocked by omega toxin from Conus [snail genus])
Vesicle proteins:
Synaptobrevin / VAMP (vesicle-associated membrane protein) = v-SNARE (SNAP
receptor)
Botulinum and Tetanus toxin (clostridial toxins) are proteases which cleave
synaptobrevin
Botulism (Clostridium botulinum) anaerobic, improper canning (need to heat
to kill spores) - block release
When I ws 10, in the Cold War, we discussed, at the dining room table, how
1 teaspoon in the reservoir would kill the city. Now. 45 years later, people
take it (injected) to get rid of face wrinkles.
Tetany is term for sustained muscle contraction based on twitches adding
up.
Tetanus toxin cleaves synaptobrevin in inhibitory interneurons.
The disease is contracted in deep (because it is an anaerobic bacterium)
dirty puncture wounds.
You would die with muscles contracted, called "lock-jaw."
There is a vaccine and boosters every 10 years are suggested.
Synaptotagmin - binds calcium
synapsins get phosphorylated (by CaM Kinase II and PKA) interact with actin
rhabphilin receptor
Target membrane proteins:
Syntaxin = t-SNARE = unc-18 (uncoordinated C. elegans roundworm mutant)
Neurexin - black widow spider venom (alpha Latrotoxin) causes too much release
Neuroexins bind to synaptotagmin
Cytoplasmic:
NSF - N-ethylmaleimide sensitive factor (ATPase activity when complex dispersed)
SNAP - soluable NSF associated protein
Rab3 (like ras, small GTP binding protein) (lots of rab's, specific for
transport)
rabphillin
Summary:
Fig. 5.14 AB
SNAREs and SNAP (docking)
In addition to SNAREs and SNAP, Ca binding synaptotagmin is for fusion
Fig. Box 5C
BoTX and TeTX sites.
Test questions from 2005 -2007 that relate to this outline
Why do they refer to "omega figures" in the ultrastructure of
synapses?
vesicles in the process of release are shaped like Greek letter omega
What kind of synapse involves opening of a chloride channel?
inhibitory
Suppose you voltage clamp a postsynaptic neuron to a level negative to the
reversal potential. What would you record (postsynaptically) if you activated
a cell making a GABAergic
synapse?
in this case it would depolarize
Name a protein involved in recycling of synaptic vesicle membrane.
clathrin, dynamin
What is the quantum of transmission that Katz found to elicit a miniature
end plate potential of 0.4 mV?
vesicle
Compared with the conductance of a voltage-gated ion channel, what is the
conductance of a one gap junction channel?
huge
What happens to the conductance of the postsynaptic menbrane during the
EPSP?
it increases
What is a connexin used for?
gap junction
How does Ca2+ get into the cell to affect vesicle release?
through a calcium channel
What do the clostridial toxins from anaerobic bacteria do?
cleave Synaptobrevin / VAMP (vesicle-associated membrane protein) = v-SNARE,
inhibit vesicle release
Katz was interested in the end plate potential. Where is the end plate?
the "post-synaptic membrane" of the muscle cell
Two SNAREs hook onto eachother, v-SNARE and t-SNARE. What are v- and t-?
vesicle and "target" (presynaptic membrane)
What happens to the end plate potential when extracellular Ca2+ is decreased?
gets small
Why do tetanus and botulinum toxins have opposite effects on motor activity?
both inhibit vesicle release, tetanus is in inhibitory interneurons
What would not happen at the restrictive temperature in a temperature sensitive
mutation affecting the protein dynamin?
coated pits would not pinch off to vesicles
Why did Sherrington consider the spinal motor neuron rather than the muscle
cell itself to be the "final common pathway" of "the integrative
action of the nervous system?"
because it receives + and - inputs while the muscle only gets + input
What happens to the conductance at the postsynaptic ionotropic receptors
for K+ and Cl- for the IPSP?
they go up
Not just any old Ca2+ channel would work on the presynaptic membrane. It
has to be voltage gated. Why?
to detect the arrival of the action potential
What are connexin proteins, such as Cx36, used for?
gap junctions
With extremely low extracellular Ca2+, why would the potential recorded
at the end plate be several different sizes for several different nerve
stimulations?
because you might get o, 1, 2, ... miniature end plate potentials
What does parasympathetic output via the vagus do to the heart rate?
slows it
The toxin from Clostridium botulinum (BoTX) cleaves an important
protein. Precisely where is this protein localized?
on the vesicle
Why are vesicles in the process of release sometimes called omega figures?
a TEM of it is shaped like the Greek letter
Electrical "synapses" use what membrane specialization in common
with heart muscle cells?
gap junctions with connexons made up of connexin protein
What happens to the conductance of the postsynaptic membrane when GABA (gamma
amino butyric acid) elicits an IPSP (inhibitory postsynaptic potential)?
increases (for potassium and chloride)
"Activating the corticothalamic path causes long-term decrease in electrical
synapse strength." These electrical synapses are made of what protein?
connexin
Why did the Nobel prize winning Sir Charles Sherrington refer to the vertebrate
spinal motor neuron as "the final common pathway in the integrative
action of the nervous system?"
there can be no integration (of + & - inputs) further out since each
muscle cell has only (one) + connection
Graded depolarizations and hyperpolarizations on the dendrites and cell
body pool. As a result, an action potential is initiated (where)?
Axon hillock
Determining reversal potentials was instrumental in establishing the conductances
mediating the EPSP and IPSP (excitatory and inhibitory postsynaptic potentials).
What was done, in addition to Voltage clamping and recording from the postsynaptic
membrane, to determine the reversal potentials?
stimulate the presynaptic neuron
With very low Ca2+, upon stimulating the motor neuron's axon, the end plate
potential (EPP) was usually 0.4, 0.8, 1.2, etc mV. What other size was observed?
zero
Recycling of vesicle membrane begins with a clathrin coated pit. A mutation
of what protein prevents the pit to pinch off to a vesicle?
dynamin (the shibire gene product)
There are synaptic connections to the dendrites and cell bodies of vertebrates.
How is the situation strikingly different for invertebrates?
cell bodies are on outside of neuropil, away from where connections are
If heat resistant bacterial endospores survive improper canning, by what
mechanism would eating those tomatoes affect transmitter action?
bacterial botulism toxin would cleave synaptobrevin (v-SNARE)
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This page was last updated 1/31/08
The neurotransmitters and neuromodulators lecture
Neurotransmitters
Purves et al., Chapter 6 and selections from Chapters 5, 17 and 21 (for
autonomic nervous system)
Sylvius (there are many places where you might want to look up the structures
discussed)
This outline will focus on transmitters. Although transmitter receptors
will be mentioned, they will be covered in more detail on the next outline.
Alumna
Michelle Lugus (nee Li) took this course in 2006. I am showing you one of
her papers, Li et al., Electroanalysis 17, 1171-1180, 2005. A microchip-based
system for imobilizing PC 12 cells and amperometrically detecting catecholamines
released after stimulation with calcium.
Topics to discuss:
PC 12 cells
microchip
why calcium
Background
Synaptosomes
After gentle homogenization, pre- and post-synaptic membranes stick together,
and membranes seal back up; all the chemicals of the synapse can thus be
found in one centrifuge tube layer.
Figure
Box A (Chapter 5)
criteria used to be real stringent
now (1) presence, (2) release and (3) receptors
They used to use the expression "putative neurotransmitter" a
lot to cast doubt as to the universal acceptance that a substance was qualified.
Pharmacology was pivotal in criteria, and it still is in discussing chemical
transmission.
agonist - a drug that mimics the neurotransmitter
antagonist - a drug that blocks the neurotransmitter
Types of molecules
Table 6.1
Fig 6.1
Chemical synaptic transmitter substances:
Monamines (acetylcholine, catecholamines, serotonin, histamine, octopamine)
Amino Acids (GABA [gamma amino butyric acid], glutamate, glycine)
Figure 6.15
Peptides (many)
gasses like Nitric Oxide (NO), see below
Purines - ATP (and AMP and adenosine) excitatory transmitters (not much
to say)
endocanabinoids (see below)
General aspects about synthesis
Fig. 5.5A
synthesis for small molecules in terminal
enzymes transported by slow axonal transport
Fig 5.5C
peptides are synthesized as pre-propeptides in rough endoplasmic reticulum
signal sequence (for secretion) is removed
Propeptide is processed in Golgi apparatus, put in vesicles, fast axonal
transport using ATP and kinesin.
Fig. 6.14 AB
Further processing, especially cleavage (common for many peptide transmitters
and hormones)
vesicles
Fig. 5.5 B
40 nm (small) electron lucent vesicles and just a few large dense core
Fig. 5.5 D
somewhat larger dense core are catecholamines or peptides
100 nm diameter granules are secretory
Importantly, transporters concentrate transmitters into vesicles
General
Fig. 5.1.B
Here, I show a typical synapse figure (again).
Receptors in this figure are channels
Fig. 5.23 A
This kind of transmission (channels) is called ionotropic.
For Acetylcholine (cholinergic transmission), the nicotinic receptor is
an example.
Nicotine is an agonist (though it has some properties of an antagonist).
Fig. 5.23B
There is another kind of receptor, the G-protein-coupled receptor.
For cholinergic transmission, the muscarinic receptor is an example
Monamines
Fig. 5.4
Loewi 1936 Nobel
Prize (already covered)
Reportedly, he thought of this experiment in a dream
vagus-stuff slows heart (10th cranial nerve, parasympathetic)
Acetylcholine
Fig. 6.2
Aceylcholine metabolism
Dale 1936 Nobel
"cholinergic" ("-ergic" used universally)
unique in that amino acid not involved
Dietary choline -reuptake or uptake (transporter is Na+ dependent) ->
intraneural choline
-Choline-O-acetyltransferase-> H3-CO-O-CH2-N+-(CH3)3
Acetyl Co-A is acetate donor
Acetylcholinesterase blocked by malathion and neostigmine
organophosphates, nerve gas, etc
Catecholamines
Fig. 6.10
Adrenergic
Landmark paper
(1970 Nobel
Prize) Julius Axelrod, Noradrenalin: Fate and control of its biosynthesis,
Science 173, 598-606, 1971. Science publishes Nobel Prize papers.
Reflection, I saw Axelrod (twice) and he gave great talks, in an
easy-going manner, said everything that was known.
tyrosine hydroxylase - rate limiting and regulated by end-product inhibition
calcium activates
it is DOPA quinones which polymerase to make melanin
substantia nigra is pale in Parkinson's disease => synthesis overlap
DOPA decarboxylase - gets rid of l vs. d
in insects, dopamine quinones "tan the hide"
dopamine beta hydroxylase - adds optical asymetry back again
interestingly, within vesicle
ATP is released with NE, ATPase turns to adenosine
Important agonists and antagonists and other drugs
PNMT (phentolamine N-methyltraansferase)
interestingly, in cytosol, necessitating transport out then in vesicle
Table 6.1
"Metabolism"
Most removal is by transporters, but there is breakdown
MAO - monamine oxidase intracellular, inhibitors (MAOI's) are antidepressants
on outer mitochondrial membrane
COMT - catechol O-methyltransferase extracellular, but there are no inhibitors)
but reuptake most important
Autonomic n.s.
Motor system for smooth muscle and glands, covered here because of acetylcholine
and norepinephrine involvement
Part of Fig. 21.1
Parasympathetic, cranio-sacral, ACh (nicotinic and muscarinic), ganglion
near target
Part of Fig. 21.1
Sympathetic, thoraco-lumbar, ACh (nicotinic) then NE, ganglion near spinal
cord
Many targets are "push-pull" like heart
Some are unique like arterioles (sympathetic only) -- close in peripheral
vascular beds (make hands cold), open in muscle (hyperemia).
Fig. 21.2 A
arrangement of sympathetic output from lateral horn neuron -> white ramus
-> sympathetic ganglion -> gray ramus
Fig. 21.3 B
Simpler for parasympathetic, i.e. from brain stem nucleus...
or ...
Fig. 21.3 C
lateral horn in sacral cord to parasympathetic ganglion
Fig. 21.4 A
called "enteric" for gut. Contribution of neural network (plexus)
to circular and longitudinal muscles to mediate peristalsis. Parasympathetic
allows digestion, sympathetic puts it on hold. Atropine (I'll talk more
about atropine in next outline) blocks muscarinic synapses and is in anti-diarrhea
medications to slow motility.
Fig. 21.8
heart as an example. Automaticity at SA and AV nodes (spread from myocardial
cell to next myocardial cell). Sympathetic speeds heart, parasympathetic
(via vagus, X) slows, and relaxed heart rate is slower than automatic rate.
Male sexual function as an example.
Fig. 21.9
Important aspect of quality of life
Robert F. Furchgott, Louis J. Ignarro, Ferid Murad Nobel
1998 "for their discoveries concerning nitric oxide as a signalling
molecule in the cardiovascular system"
A few years ago, I wrote, "This is the only place where parasympathetic
affects arterioles, dilating them in corpus cavernosum for erection. Sympathetic
contributes to ejaculation."
Then I read a paper by Ignarro and then his Nobel "speech." Actually,
for erection (relaxing arteriole smooth muscle), adrenergic (via alpha 1
receptors) contracts smooth muscle, cholinergic (via muscarinic receptors)
inhibits adrenergic-induced-contraction (resulting in relaxation); more
than cholinergic and adrenergic, a little mentioned autonomic component,
the NANC (nonadrenergic noncholinergic) system, mediates relaxation.
In the 2003 movie Something's
gotta give, Jack Nicholson has a heart attack while having sex, and
the docs ask if he is on Viagra as they are about to give him nitroglycerine.
(also listed in advertisements for ED (erectile dysfunction) medications
because of interaction and resulting low blood pressure)
People take nitroglycerine for angina (chest pain), and it releases NO (nitric
oxide) and relaxes the coronary arteries
Nitric Oxide (NO), made by endothelial nitric oxide synthase (eNOS), unusual
in that it diffuses across "postsynaptic" membrane to affect guanylyl
cyclase (GC) involved in making cGMP.
NO was endothelial derived relaxation factor (EDRF), mediator of parasympathetic
nervous system's dilation of arterioles in corpus cavernosum. Viagra (sildenafil)
inhibits the PDE that breaks down cGMP
Serotonin
Fig. 6.13 B
Serotonin = 5-HT (5-hydroxy tryptamine)
tryptophan hydroxylase
l-aromatic amino acid (5-HTP) decarboxylase
Serotonin from Raphe nucleus ispread widely and involved in sleep (discussed
later in the semester). Tryptophan in turkey blamed for sleepyness after
Thanksgiving dinner.
Alumnus interview
relates to SSRIs
SSRIs (selective serotonin reuptake inhibitor)
Prozac (fluoxetine)
Paxil (paroxetine)
Zoloft (sertraline)
There is new controversy about whether these increase the incidence of suicide,
now that they are given to teenagers, but there was also controversy overr
a decade ago. The other side of the argument is that it is given to depressed
people.
LSD (lysergic acid diethylamide) agonist of 5HT receptors in Raphe, cause
decreased output to brain (as in sleep).
People used to take tryptophan, but bad
batch caused eosinophilic-myalgia syndrome so FDA banned it in 1990.
The melatonin story
2 more steps after 5-HT to make melatonin (sleep promoting hormone, higher
at night) in pineal
N-acetyltransferase (regulated) and hydroxy indole O-methyl transferase.
High at night, low during day, relates to biorhythms, see lecture
later in the semester.
In animals where light can reach the pineal, it has photoreceptors.
For us, eye to suprachiasmatic nucleus of hypothalamus to pineal.
N-acetyltransferase is rate limiting step.
Melatonin sales went wild in mid-1990's after books stated that melatonin
was a "wonder," "miracle" or keeps you young.
Thought to restore sleep cycle after jet lag.
Melatonin controls reproductive cycle in seasonally reproductive species.
Here is the diagram
used in the Mizzou Physio lab on endocrinology.
Testes of short-day
hamsters are smaller than long-day hamsters (Mizzou Physio Lab)
Melatonin was used at high doses for birth control by women in Holland
Amino acid transmitters
Fig. 6.6
Glutamate
Central excitatory - like inputs to hippocampus - maybe half of CNS synapses
Synthesis is simple from glutamine (from nearby glia) by glutaminase.
Prof Bode in my department
has a special interest in glutamine transport.
Affected by many toxins, for instance poison from mussels - domoic acid,
and plants (Box 6B).
Involvement in ALS (Amyotrophic lateral sclerosis [Lou Gehrig's] ALS) and
possibly Alzheimers.
Excitotoxicity - Box 6C - too much glutamate causes a cycle of Ca2+ influx.
May be involved in ischemia - induced injury.
Fig. 6.8 A
GABA (gamma amino butyric acid)
really important inhibitory neurotransmitter
synthesis GAD glutamic acid decarboxylase
made in a shunt in the TCA (Kreb's) cycle, present in brain
There is a lot of GABA in the brain, mostly local circuits, but also Purkinje
output.
Incidentally, a natural breakdown product of GABA is gamma hydroxy butyrate
(GHB), the date rape drug.
Fig. 6.8 B
Glycine is the other major inhibitory transmitter
transporter mutation causes hyperglycenemia - neonatal seizures, lethargy,
retardation
synthesis by serine hydroxymethyltransferase
a lot in the spinal cord
strychnine blocks
Histamine
Fig. 6.13 B
Histamine is a transmitter (in addition to being a mediator of inflamation
from mast cells)
antihistamines that cross BBB make you sleepy
Chemical neuroanatomy
Fig. 6.11 AB
Fig. 6.12 B
1960's technique of histochemical fluorescence allowed chemical anatomy
-
Expose sections to vapor of paraformaldehyde
neurotransmitters have widespread effects but come from defined locations
Dopamine from substantia nigra
Norepinephrine from locus coeruleus
Serotonin from Raphe
Parkinson's
(mentioned here because of dopamine)
Miclelle Li, graduate student in 2006 class, gave a presentation
on Parkinson's
Fig. 17.9B
degeneration of substantia nigra (left) relative to control (right)
Box B in Chapter 17
1817 Shaky palsey
Degenerate dopaminergic input to striatum from substantia nigra
Cells that survive have inclusions called Lewy bodies.
Aflicted have bradykinesia, akinesia, rigitystilted gait, tremors, walk
in shuffle, stone (expressionless) face, loss of affect.
1% of people over 50 years old
Lateral hypothalamic lesions make thin rat and some motivational defects,
dopamine in medial forebrain bundle toward basal ganglia.
Dopaminergic neurons degenerate, animal model - 6-OHDA uptake makes peroxide,
cells die.
Cannot give dopamine because it coes not cross the blood brain barrier.
Give l-DOPA (in large doses because l-AAAdeCOOHase is everywhere); give
decarboxylase inhibitor carbidopa. Jill Smith, Ph.D. 2005, in Dr. Fisher's
lab (Bio, SLU) worked on this.
Extrapyramidal motor syndrome also comes from long term administration of
antipsychotic phenothiozines such as chlorpromazine (brand name Thorazine).
(Chronic use of these drugs also cause a corioretinopathy.)
There was a bad batch of street drugs with an impurity called MPTP which
gave its users a Parkinson's like disease.
The commonly used insecticide rotenone, and other insecticides, are like
MPTP.
There had been some experimental cell transplant therapies - controversal.
Arvid Carlsson made contributions here and shared 2000 Nobel
Prize in Physiology and Medicine.
Several famous people have Parkinson's - the late Pope, Mohammad Ali, Michael
J Fox.
Mostly it is "sporatic" (not genetic), but familial cases have
been interesting.
Alpha-synuclein, Parkin and DJ-1.
Psychiatry
Personal reflection. I took abnormal psychology when I was an undergraduate
at Columbia College in New York in the 1960's. We were sent up the the Psychiatric
Institute at Columbia Physicians and Surgeons to see a psychiatrist interview
patients for two classes. That part of New York is hilly, and the ground
floor of PI was the 9th floor. An odd coincidence was that we had all read
Dante's Inferno recently in literature humanities. The first patient was
an 18 yr old kid who played chess instead of basketball who was being fed
a shovel full of chlorpromazine every day. After he left the room, the doctor
asked the class what was wrong with the kid and we all looked in the pony
for the abnormal psych text and said things like "paranoid neurotic"
etc., and the doctor said "you guys are far too cerebral, this kid's
a schmuck, he has the schmuck syndrome." The next week we saw a person
more normal than any of us who seemed to think an appeal to the class was
his only means of escape. We were all happy to get out of the PI without
being sent down to one of the lower floors (Dante's inner circles) and chained
to the wall.
Alumnus interview
relates to Psychiatry
Box E biogenic amines and psychiatric disorders.
Psychosis - severe.
Neuroses not so severe.
Schizophrenia (dementia praecox= early loss of intelligence) (paranoid,
catatonic, etc.), real thought disorders, progressive and degenerative,
used to be the cause of more "hospitalization" than everything
else put together.
They were called "insane asylums" (These were the days before
political correctness.)
Borris Karloff old movie "Bedlam" is about insane asylum.
It is popular to mistrust psychiatry, for instance the movie "One flew
over the cuckoo's nest" with Jack Nicholson (1975), but people with
schizophrenia are really crazy without a doubt.
Reserpine storage blocker, used for hypertension (for NE [andDA, 5HT]) for
psychosis; 1950s - revolutionized psychiatry (nowadays, the disparaging
phrase is "went off his or her meds").
There was a 1960s radio advertizing slogan "mental illness [again before
political correctness] is no longer hopeless" (that kids used to say
to each other).
There was a book, D.W.Woolley, The biochemical bases of psychoses (subtitle
- the serotonin hypothesis about mental diseases (New York, Jhhn Wiley and
Sons, Inc., 1962), and the understanding that LSD affected serotoninergic
transmission fit in.
It seems every time a neurotransmitter was characterized, there was a band
wagon of attributing everything to it, a catecholamine (norepinephrine)
theory of affective disorders (partly attributed to Stein (J. J. Schildkraut
and S. S. Kety, Biogenic amines and emotions, Science, 156, 21-30, 1967),
and this fit in with the idea that amphetamine caused psychosis (Amphetamine
stimulates NE release); this is before dopamine was appreciated as a transmitter.
Methedrine (speed, drug of abuse, MO (Jefferson Co famous for manufacture,
explosions, fires), dexedrine (once used as a diet pill, recently, oddly,
used for ADHD [attention
deficit hyperactivity disorder]) [works on explorer, not netscape], and
benzedrine (mild uppers, abused by students cramming for exams); now ritalin
used for ADHD; I repeat that is it odd that stimulants would help hyperactivity;
it is also controversial and troublesome how many kids are given such drugs.
(Later in the semester, we will talk about "amphetamine and cocaine
regulated transcription factor."
Now thought to be over-activation in dopamine pathway.
Dopamine receptor blockers (antagonist) - haloperidol, chlorpromazine are
antipsychotics.
Chronic chlorpromazine treatment causes chorioretinopathy and Parkinson's
tremors.
Incidentally, a controversal 1971 book (D. Rosenthal, Genetics of psychopathology,
New York, McGraw-Hill Book Co) suggested an underlying genetic predisposition
for schizophrenia, now widely believed.
Depression, unipolar, bipolar ("manic depression is a frustrating mess"
- Jimi Hendrix)), involutional melancholy (in elderly) - great suffering.
Bipolar seems to run in families, treated with lithium salt, my theory is
that, since Li+ can replace Na+ for the action potential but not in the
Na+ pump, action potentials would be smaller.
Unipolar Tricyclic antidepressants (desipramine) blocks NE (and other) reuptake.
SSRI's covered above.
Antidepressants MAOI's (phenylzine)
After electroconvulsive shock (ECS), patients seem much happier; sounds
barbaric, but still used and, with correct control medications, it is not
cruel; Interestingly, there is a memory loss for the time before the shock,
and ECS fits in with the idea that correctly reverberating neural circuits
are important for memory consolidation.
Anxiety - Tranquillizers - benzodiazepines (chlordiazepoxide = Librium,
diazepam = Valium) enhance GABA-A receptors
Treat panic with MAOI's, also serotonin receptor blockers, also benzodiazepine
alprazolam (Xanax).
Peptides
substance P - 11 amino acids known for 60 years, named after "powder"
involved in pain
Landmark paper CBPert and SHSnyder, Opiate receptor: Demonstration
in nervous tissue, Science 179, 1011, 1973, see also J NIH Res 2, 73-79,
1990
Tritiated naloxone, opiate antagonist, binds to places in the brain and
is displaced by opiates in parallel with their strength.
Table 6.2
Solomon Snyder discovery of opiate receptors - binding studies
(While you have receptors but do not know what the ligand is [yet], these
are called "orphan receptors."
then discovery of endogenous opiates (enkephalins, endorphins dynorphins)
met-enkephalin and leu-enkephalin, 5 amino acids
beta-endorphin 31 amino acids
cleaved from pro-opiomelanocortin or proenkephalin precursor
Marijuana
Fig. 6.16
Fig. 6.17
Box G
Cannabis sativa
Recent paper R. A. Nicoll and B. E. Alger, The brain's own marijuana,
Scientific American, pp 68-75, Dec 2004.
BoxG
THC used to treat anxiety, pain, nausea, obesity, glaucoma.
BoxF
Affects hypothalamus, basal ganglia, amygdala, brain stem, cortex, hippocampus,
cerebellum.
A. C. Howlett, 1988, SLU, receptor CB1, later CB2 was found.
G protein coupled receptors.
Presynaptic CB1 prevents GABA release to block glutamate excitation
Fig 6.16A
Anandamide
Fig. 6.16B
2-arachidonoyl glycerol (2-AG)
Fig. 6.16C
2-AG released from postsynaptic cell
Test questions from 2005 - 2007 relating to this outline
What is the common precursor for dopamine and melanin?
l-DOPA
In presenting the synthesis of glutamate, what cell is the source of the
precursor, glutamine?
glia
SSRIs (selective serotonin reuptake inhibitors) are used to treat what disorder?
depression
What is the source (location) of serotonin that is spread widely through
the brain?
Raphe nucleus
l-aromatic acid decarboxylase, used to convert 5-HTP to 5-HT, also makes
what other neurotransmitter?
dopamine
In which part of the nervous system is glycine widely used?
spinal cord
Where are the enzymes for norepinephrine synthesis?
in the terminal
The benzodiazepine tranquillizers (chlordiazepoxide = Librium, diazepam
= Valium) affect transmission with what transmitter?
GABA
At the autonomic ganglia, what is the transmitter?
acetylcholine
From what transmitter is melatonin synthesized in the pineal?
serotonin
What transmitter is most closely related to the date rape drug?
GABA
How is POMT (proopiomenanocortin) processed to yield b-endorphin?
cleved
What transmitter from the sympathetic nervous system would speed the heart
beat?
NE
What class of molecules serves as the precursor for endocannabinoids?
membrane phospholipids
What does NO=nitric oxide do to arteriole smooth muscle?
relax
On the news this week is the case of a defendent blaming the murder on Zoloft
(the Zoloft defense). Why would he have Zoloft in his system?
for depression
"Thoraco-lumbar" is another term for what component of the nervous
system?
sympathetic
Name two monamines synthesized from amino acids.
dopamine, norepinephrine, epinephrine, serotonin, histamine
Tell me about the vesicles for endocannabinoid transmission.
there are none
How is GABA different from the 20 amino acids coded in the genetic code
and used as the building blocks of proteins?
NH2 and COOH are on different carbons
What is the difference in how acetylcholine and norepinephrine are cleared
from the synaptic cleft?
ACh broken down, NE reuptaken
Dopamine beta-hydroxylase converts dopamine to norepinephrine. Discuss optical
isomerization (l- vs. d-) for precursor and product.
dopamine lacks a carbon with 4 separate groups while there could be l- and
d-NE (it is l- that we use)
The garden tomatoes were not cooked enough before being "canned"
in mason jars. What would happen to your muscle contractions if you eat
them?
botulism would block muscle activation by nerve vesicles
In addition to cranial nerves, what other nerves make up the parasympathetic
nervous system?
sacral
"The parasympathetic nervous system dilates arterioles in the corpus
cavernosum, mediating erection." Give either of the reasons that this
statement is not the whole truth according to more modern research.
the parasympathetic ns actually works by inhibiting the sympathetic. Also,
the NANC (non adrenergic non cholinergic)ns is predominant.
What would sympathetic activation do to the blood flow in muscle?
increase it, hyperemia, "pumpitude"
How would you get beta-endorphin from proopiomelanocortin?
proteins are chopped down to make peptide transmitters
"Muscarine is an agonist for the cholinergic receptor." Translate.
muscarine is a drug that would activate one type of synapse for acetylcholine
Refering to schizophrenia, in interview, Bob said "receptor subtypes
are very important. Block them all ... and you can get a Parkinson like
movement disorder. Block only certain subtypes ... and you get relief of
symptoms without the movement disorders." Receptors for what transmitter?
dopamine
How do sodium channel and sodium pump respond when lithium ions are substituted
for sodium ions?
lithium goes in through sodium channels but is not pumped out by sodium
pump
What pineal hormone is implicated in the differing testes of long- vs. short-day
hamsters?
melatonin
Talk about the regulation of release (vesicles?) for nitric oxide (NO).
made on demand by eNOS (endothelial nitric oxide synthase) and diffuses
directly across 2 membranes into the "postsynaptic cell" to stimulate
GC (guanylyl cyclase)
Excitotoxicity, and too great an influx of calcium ions, is caused by overstimulation
of synapses for what transmitter?
glutamate
What is the standard treatment to increase dopamine in the striatum in Parkinson's
syndrome patients with low dopamine from degeneration of dopaminergic neurons?
feed them l-DOPA
Histochemical fluorescence demonstrated a place in the brain that spreads
norepinephrine throughout the brain. What is the name of this place?
locus coeruleus
Ritalin is given for ADHD which stands for what?
attention deficit hyperactivity disorder
What type of molecule is arachidonic acid and how is it related to endocannabinoids?
fatty acid, it is the major portion of the molecule
How does epinephrine differ from norepinephrine?
NE is sympathetic neurotransmitter, PNMT converts NE to E which is hormone
from adrenal medulla
Before it was shown to be nitric oxide (NO), it was called "endothelial
derived relaxation factor (EDRF)." What did it relax?
arteriole smooth muscle
Title of a published paper: "Localization of cholecystokinin to cells
of the retina." What is a gut hormone doing in that part of the nervous
system?
originally identified as a gut hormone, it has different functions in different
places
Met-enkephalin and Leu-enkephalin are chopped out of what kind of molecule?
larger protein precursor
A neurotransmitter activates a G-protein-coupled receptor, and that signals
to (what is next in the cascade)?
duh! G protein (the heterotrimeric kind)
Say something about l- vs d- in the synthesis of catecholamines.
start w/ l-aa. lose when DOPA to Dopamine. Back to l- when dopamine goes
to epinephrine
"End-product inhibition regulates synthesis by controlling the rate-limiting
enzyme." If norepinephrine is the end product, what is the rate-limiting
enzyme?
tyrosine hydroxylase
By what mechanism would monamineoxidase (MAO) inhibitors relieve depression?
increase presence of norepinephrine
A hormone that is formed from serotonin by two additional enzymatic steps
is produced in what brain structure?
pineal
While glycine is an inhibitory transmitter of the spinal cord, what is the
main inhibitory transmitter in the brain?
GABA
Transporters in what two cell areas terminate the action of glutamate?
nerve terminal and glial cell
What would Prozac, Paxil or Zoloft do the the concentration of what transmitter
in the synaptic cleft?
increase serotonin
When more acetylcholine is needed, vesicles are released. How is the "transmitter"
NO (nitric oxide) increased when it is needed?
turn on endothelial nitric oxide synthase (eNOS)
What does output from a famous cranial nerve do to heart rate?
vagus slows heart
Where is the chain of sympathetic ganglia?
near spinal cord, on each side, in thoracolumbar area
Chronic chlorpromazine administration causes "extrapyramidal motor
syndrome" which is like what named disease?
Parkinson's disease
Theories that defects in serotonin and norepinephrine metabolism cause schizophrenia
were replaced with the current explanation involving what transmitter?
dopamine
What ion has long been used to treat manic-depression?
lithium
"Naloxone, an antagonist, displaced certain narcotic analgesics in
brain binding." This finding led to the isolation of what kind of receptor?
the opiate receptor
In the synthesis of anandamide and 2-arachidonylglycerol (2-AG), answer
one: either What class of molecules are the original precursors? OR What
kinds of enzymes are used?
membrane phospholipids (phosphatidylethanolamine or phosphadidyl inositol),
phospholipases
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This page was last updated 2/7/08
Alumnus e-interview
Robert Marietta, MD (SLU-2000) was a Med-Scholar 1992-1996. He did several
courses from me including this course. He completed a Navy residency in
Psychiatry, and is now serving in Okinawa.
Q: Prozac and related drugs have revolutionized the treatment
of
depression. From the outset and recently, they have been implicated,
by
their detractors, in suicide and homicide. How do you address
these issues?
A: People with depression have a higher incidence of suicide
than
people without depression. Is suicide caused by depression, caused
by
the drug or both? If you look at the rate of suicide for the
entire US
population over time you will see that it dropped around the time
anti-depressants came on the market. The current consensus in
psychiatry is that anti-depressants are safe, effective and reduce
suicide when used appropriately. Just as a drug could make someone
feel
better it could also make them feel "too good", more agitated
or
irritable. This is especially true in the case of a bipolar patient
presenting in a depressed phase. An anti-depressant used alone
might
flip such a patient into a mania and result in agitation or suicidal
ideation. The way the clinician addresses this is through the
process
of informed consent. We tell patients the risks and benefits
of a drug
and let them decide if they want to take it. We warn patients
to look
out for the potential side-effects and to stop the medication and call
us if they arise.
Q: Depression, and medication for depression, is now a big issue
in
children in teenagers. What are the appropriate and ethical approaches?
A: To my knowledge there was only a single study that suggested
a small
increase in suicidal IDEATION (not the incidence of completed suicide or
suicide attempts) in children on anti-depressants. Given the
dramatic
and litigious nature of our society, the story was sensationalized and
developed a life of its own. The study was quickly debunked and
disregarded by child psychiatrists. The proper approach again
is
informed consent. To provide informed consent the pediatrician
or child
psychiatrist has to have a firm understanding of the literature
surrounding issues like this so they can competently talk about the risks.
Children are very dynamic just like the wiring in their brain. They
tend to have different and more transient symptoms than adults. For
example, a depressed child might be irritable compared with an adult who
feels sadness and decreased energy. Many symptoms in children
represent
prodomes for disorders that will occur later in life. The big
difference between the standard of care for treatment of children and
adults is that they require more frequent follow-up. It might
be
appropriate to start and adult on an anti-depressant and wait a month
for follow-up. However a child patient requires a follow-up after
the
first week of starting a medication.
Q: In the early days of treatment for hyperactivity, it seemed
odd that
an amphetamine (dexedrine) should be used. How can it have such
different effects, calming hyperactivity in youth and acting as a
stimulant in adults?
A: ADHD is divided into 2 main symptom clusters including inattention
and hyperactivity. It is possible to have inattention alone,
hyperactivity alone or a mixed presentation. Approximately half
of children with ADHD continue to have the disorder as adults. It
could very well be that these symptom clusters share a similar genetic mechanism
of action. For example, the serotonin transporter gene and dopamine
receptor. Recent neuroimaging studies like the PET scan show
that different areas of the brain light up in patients with ADHD vs. normal
controls. There might be separate areas in the brain responsible
for attention and impulse control affected by the same genes. The
"genetic load" or number of mutated genes in addition to the severity
of the mutations is important to consider. Regardless of the
precise cellular mechanisms one could see how increasing the amount of dopamine
or norepinephrine might act on both areas to improve attention because these
areas of the brain are stimulated.
Your question is a reminder that for as much as we know about medications
including what neurotransmitters they act on, we really don't know the exact
mechanism of action for how they alleviate people's symptoms. For
example, we know that norepinephrine and dopamine improve concentration. At
the same time, it might not be accurate to say ADHD is caused by a "deficiency"
of these neurotransmitters. Besides acting directly on neurons,
stimulants might increase blood flow to certain areas of the brain.
Q: Nowadays, Ritalin is widely prescribed and hyperactivity is
called ADHD. Tom Cruise, and the Church of Scientology, have been outspoken
critics. Answer them on the reality of ADHD and the usefulness of medications.
A: When neuroimaging studies suggested the possibility of differences
between ADHD and control subjects the Church of Scientology claimed that
the medications themselves were resulting in brain damage. A
follow-up study was performed that compared neuroimaging studies of patients
with ADHD on medication and control subjects with ADHD without medication. As
I recall, the results were the same or better for subjects on medication. The
fact is regardless of the cause of the disorder, stimulants are very effective
for ADHD. There are other non-stimulant medications such as buproprion
and atomoxetine that have also been proven effective for the treatment of
ADHD. Neuroimaging, genetic studies and that fact that patient's
symptoms improve by drugs affecting specific suggests that our biology plays
a significant role in ADHD. To accept the notion that ADHD doesn't
exist and that medications are harmful or ineffective means ignoring all
this scientific research. It is irresponsible and harmful for
these parties to make such unsubstantiated claims and I question their motives.
Q: Brook Shields was criticized for receiving treatment for her
post-partum depression. Answer this criticism.
A: There is a clear relationship between hormones and depression. A
disorder called premenstrual dysphoric disorder has been described in the
literature where women experience clinically significant depression at a
predictable point during their monthly cycle. Similarly, birth
control pills are known to cause depression. Pregnancy and the
post-partum period is a time when hormones are changing rapidly. There
is strong evidence for a biological etiology for post-partum depression.
If someone falls down they are experience pain. Suppose they
were doing something foolish that caused their fall. Does that
make a difference as to whether or not they deserve an effective treatment? If
we suggested withholding medication that would effectively treat the pain
that would be unethical and immoral. The same thing applies to
patients with depression. Even if a patient had a 100% psychological
etiology for depression medications could still be considered an effective
treatment. Medications might improve the new mom's mood, energy
level and sleeping pattern. This might benefit the child by improving
the mother's ability to bond with her child.
Q: Although it sounds barbaric, electroconvulsive (ECT) shock has played
a role in treatment for depression. How useful was it and is it still used?
A: At some point the clinical observation was made that patients with epilepsy
have a lower incidence of psychiatric disorders. Around 1940, someone tried
generating a seizure in a patient with severe psychiatric problems and
reported good outcomes. The problem with a seizure is that it causes
muscular contractions all over the body. In modern ECT, patients are given
a paralytic agent such as succinylcholine prior to the procedure. They are
also given an anesthetic to make them unconscious. The psychiatrist then
connects usually two leads or sometimes one lead ("unipolar")
to a machine
and generates a seizure. Unipolar ECT is used with people with dementia
and
depression to reduce the chance of memory loss. The leads are connected
to
an EEG so that the psychiatrist can make sure an adequate seizure was
generated. ECT is generally administered 1 to 3 times per week for several
weeks and then less frequent for maintenance treatment. ECT is very
effective for mood disorders such as depression and bipolar disorder. It
is
unique in that it results in a very rapid improvement of symptoms where
medications act at the cellular level and take weeks to work. I suspect
the
mechanism of action has to due with release of neurotransmitters. A
definitive mechnism of action is unknown. ECT has a unique utility for
elderly patients who can't tolerate medications. ECT can result in limited
memory loss and generally has few adverse side-effects.
Q: Any other thoughts?
A: One of the biggest areas of research in psychiatry is psychosis
because of the impact on society and costs involved. The psychotic
disorders especially schizophrenia are considered to be very much a
biological illness. Probably the number one prognostic factor
in this
disorder is compliance with medication. The neurotransmitter
in
psychosis is dopamine. The medications used for treatment of
schizophrenia block dopamine receptors. Too much dopamine or
overactive
receptors could mean psychotic symptoms like hallucinations. Cocaine
causes release of dopamine and results in psychotic symptoms sometimes.
The dopamine receptor subtypes are very important. Block them
all like
the older "typical" anti-psychotic agents and you can get tardive
dyskinesia and a Parkinson like movement disorder. Block only
certain
subtypes with the new "atypical" antipsychotics and you get relief
of
symptoms without the movement disorders. There is a newer class
now
that has partial agonist and antagonist effect on dopamine receptors:
keep them active at a low level but block the rest.
The second messenger systems lecture
Signalling
Neurotransmitter receptors and Second messenger systems
Purves et al., Chapters 6 & 7
Channels
Nicotinic receptors
Fig. 6.3 A, B, C, D
Two molecules of acetylcholine bind.
Nicotinic Acetylcholine receptor - so named because of agonist from Nicotinia
tabacum nicotine
found in vertebrate in all (sympathetic and parasympathetic) autonomic ganglia
(the first synapse, not the neuro-effector junction), muscle and other places
Torpedo - electric ray, up to 75 V (not that much) but 20 Amps.
Lots of generator potentials added up (vs. Electrophorus - lots of spikes,
used to isolate the Na+ channel of the action potential).
(There are also fish with electric sense, not just those that stun prey.)
Can be bound by alpha-bungarotoxin - from banded krait Bungarus multicinctus
(snake), 74 amino acids binds receptor irreversibly and thus causes paralysis
by blocking transmission, very useful in studies to label receptor - labeled
by 125I alpha-bungarotoxin.
5 subunits - 2 alpha, beta, gamma and delta
in neurons, 3 alpha, 2 beta (and no alpha bungarotoxin sensitivity)
Here is a transmission electron micrograph
of the neuromuscular junction. Note Schwann cell, nerve terminal and muscle
cell. The subsynaptic muscle cell membrane has invaginations and folds;
the acetylcholine receptor, on the crests, is labeled with alpha bungarotoxin
and horseradish peroxidase.
Protein subunit structure likely spans the membrane 4 times.
M2 likely lines the pore.
Nicotine is an agonist; but it seems somewhat like an antagonist because
it blocks transmission at autonomic ganglia by depolarization blockade.
There are pharmacological antagonists (curare, a plant alkaloid from Clondodendron
tomentosum).
Important for mechanisms of muscular relaxatants used in surgery (like succinylcholine).
Must relax muscles in surgery but must prove that anesthesia is adequate.
Recent paper
Beverly A Orser, Lifting the fog around anesthesia, Scientific American,
June 2007, 54-61
Obviously, analgesia (absence of pain) is paramount
Unconsciousness (hypnosis)
Immobility
Interestingly, amnesia (loss of memory)
Dentist William Morton used ether in Boston in 1846
These days, drugs that keep GABA-A channels open (benzodiazepines like Valium
also affect these)
Some additional points about nicotinic receptors:
Developmentally, when nerve-muscle junction is made, diffuse receptors cluster.
Acetylcholinesterase, by contrast, is all over the place.
Receptor molecules are very concentrated at n.m.j. crest, 20,000 - 30,000
per square micron (about as tightly packed as possible in contrast with
punctate voltage gated sodium channels).
Probably water filled pore.
All 4 subunits needed in expression systems to get functioning receptor.
10 to the 6th ACh molecules from one a.p. into n.m.j. cleft.
2.5 x 10 to the 5th channels transiently open.
400 nA n.m.j. end plate current.
1 ms open time.
10,000 Na+'s flow through each channel in this time.
Channel conductances of 25 pS
Fig Box B (Chapter 6)
Myasthenia gravis
Smaller miniature end plate potential.
Great weakness (seen in droopy eyes); here's a picture
I found on the web of the eyelid droop.
Receptors low in mysthenia gravis - autoimmunity to nicotinic receptors.
(Nervous system proteins are generally separated from immune surveillance
by blood brain barrier.)
First noted by Thomas Willis (1685, of circle of Willis fame.)
Treatment by cholinesterase inhibitors - note that action potentials are
increased by neostigmine treatment.
Involvement of thymus.
Other channels
Fig. 6.4 A B C
Glutamate (AMPA, NMDA, Kainate), GABA, glycine, setotonin, purine receptors
can be ion channels.
Keeping in mind that we already discussed ACh (nicotinic) receptors (above),
the notable ligands missing from the channel receptor list are epinephrine
and dopamine.
There is a staggering diversity of different types.
Glutamate channel agonists:
NMDA = N-methyl D-aspartate.
blocked by AP5 (2-amino-5-phosphonovalerate)
central excitatory - like inputs to hippocampus
On the basis of the reversal potential, it is inferred that the channel
is nonselective cation channel.
Fig. 6.7 A
Na+ & Ca2+
Calcium influx - excitotoxicity in injury or stroke.
Voltage, glutamate, calcium cause "vicious cycle of glutamate release."
The general involvement of Ca2+, and its role as a signal transduction "second
messenger" means that a lot of important neural processes, such as
"learning," are attributed to NMDA receptors
AMPA = alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate, also kainate
Kainate (from red alga Digenea simplex) and Quisqualate (from seed of Quisqualis
indica) are excitotoxic amino acids
reversal potential is at 0 mV so it is likely opening for K+ & Na+ channels
Fig. 6.9 B
GABA-A channel is for Cl-.
Different combinations of 5 different subunits makes for a lot of diversity.
Diazepam (Valium) and chlordiazepoxide (Librium) [tranquilizers] bind to
alpha and delta subunits - enhance GABAergic transmission.
Barbiturates [hypnotics] like phenobarbital bind to gamma subunit.
GABA-A receptors blocked by bicuculline from Dutchman's breeches and picrotoxin
from Anamerta cocculus.
Glycine receptor blocked by strychnine, alkaloid from seeds of Strychnos
nux-vomica - causes seizures.
5HT3 is also an ion channel - maybe the molecule only spans the membrane
3 times.
Ionotropic vs metabotropic receptors
1971 Nobel
Earl W. Sutherland, Jr. (US) "mechanisms of actions of hormones,"
father of signal transduction. His major contribution dealt with cAMP as
a second messenger in mediating adrenergic effects on metabolism in the
liver (which mobilizes glucose from glycogen).
personal reflection:
When I first took physiology (1969), there was an emphasis on the autonomic
n.s., hence on acetylcholine and norepinephrine.
Acetylcholine nicotinic (ionotropic) at ganglia, muscarinic (now "metabotropic")
at parasympathetic neuro-effector junction (post-ganglionic)
Adrenergic only in sympathetic neuro-effector.
Adrenergic receptors: alpha usually excitatory, e.g. arteriole constriction,
agonist nose decongestant spray like Neosynephrine (phenylephrine).
Beta usually inhibitory but it is excitatory at heart, and beta blocker
propranolol used for hypertension.
About 10 years later, people I knew were involved in showing there were
several alphas & betas.
With hindsight, it is interesting that adrenergic is metabotropic, not ionotropic
(not in Fig. 6.4 C)
Landmark paper RADixon et al. (RJLefkowitz) Cloning of the gene and
cDNA for mammalian beta-adrenergic receptor and homology with rhodopsin,
Nature 321, 75, 1986, see J NIH Res, 9, 45-52, 1997.
Fig 6.5 A
7 transmembrane domains called G protein coupled receptors.
By hydrophobicity, they all cross membrane in 7 alpha-helices.
Rhodopsin was the prototype, followed closely by the beta adrenergic receptor.
Then many neurotransmitter and hormone receptors were found.
In the early 1990's, olfactory receptors were found to be G protein coupled
receptors, and there are lots of olfactory receptors; Richard Axel and Linda
B. Buch won the 2004 Nobel
prize for this work.
In summary, there is an enormous diversity! Superfamily (>1000 in mammals).
N terminus outside cell, glycosylation
C-inside (heptahelical) -phosphorylation,
2nd and 3rd loops and C terminus for interaction with a subunit of G protein
Fig 6.5 B
Here's the example of the huge list for transmitters.
Many types mGluR1-8, NE alpha 1 & 2, beta 1 , 2, & 3, D1(AB)-D4,
GABA-B(1&2), 5-HT-1- 7, Purines 1, 2 (a&b), 3, P 2(x,y,z,t,u)
And muscarinic (1-5)
Muscarinic receptors (postganglionic parasympathetic) - muscarine - from
poisonous red mushroom (Amanita muscaria) stimulates, atropine (from deadly
nightshade) blocks (belladonna = beautiful lady). SLIDE (Hess, Scientific
American, Nov. 1975, p.111) Women are more beautiful with dilated pupils
muscarinic receptors are at parasympathetic neuro-effector junctions (incl.
smooth muscle)
Muscarinic "7TD" (G protein coupled receptor, more later).
Because Acetylcholine from Vagus (X cranial nerve) slows heart, poisoning
with organophosphate (acetylcholinesterase inhibitor such as insecticide
malation or nerve gas) would stop heart; atropine, by blocking receptor,
would save your life.
Metabotropic receptors
Fig. 7.4 ABCD
Channel, enzyme (many for development), G protein coupled receptor, intracellular
(like for steroid).
Receptor like the beta adrenergic receptor binds G protein (alpha, beta
and gamma subunits).
Signal transduction cascades
Fig. 7.5A
G protein so named because it (alpha subunit) binds GTP
AGGilman and M Rodbell, Nobel
1994
heterotrimer alpha, beta and gamma
alpha and beta are about the same size, gamma is smaller
alpha and gamma linked to membrane by fatty acid
alpha subunit affects effector and is GTPase
Fig. 7.6
cascades with different second messenger (signalling) systems (effectors)
For beta adrenergic receptor, Gs (stimulatory) activates adenylyl cyclase,
to make cAMP, which, in turn, activates protein kinase (PKA) for phosphorylation
(more below)
For glutamate, Gq (q is designation here) activates Phospholipase C (PLC)
or PLA2.
(more below)
Recent paper SKEKoekkoek et al., Cerebellar LTD and learning-dependent
timing of conditioned eyelid responses, Science 301, 1736-1739, 2003, see
also D. J. Linden, From molecules to memory in the cerebellum (Perspectives),
Science 301, 1682-1685, 2003.
LTD=Long term depression, a model for learning.
Conditioned eyelid response is a paradigm for learning.
Transgenic with a Purkinje-specific promotor was used to express a molecule
to inhibit PKC.
These mice lack LTD for this learning.
For dopamine, a Gi (inhibitory) inhibits the cAMP cascade
The phosphoinositide cascade
Fig. 7.7D
My real name is phosphatidylinositol-4,5-bisphosphate but my friends call
me PIP2 (apologies to Charles Dickens) (special membrane lipid) is cleaved
to DAG (diacyl glycerol) and IP3 (inositol trisphosphate.
IP3 causes release of Ca2+ from nonmitochondrial stores, IP3 receptor.
Ca2+ is a real wide ranging intracellular messenger.
Calcium binds to calcium binding proteins like calmodulin
DAG activates PKC (protein kinase C) [kinase is an enzyme that phosphorylates].
personal reflection:
In 1970, I took "membrane biochemistry" - lipids seemed boring,
hold proteins.
By early to mid 1980's, lipids shown to turn over and to be signaling precursors.
NorpA (no receptor potential) Drosophila have rhodopsin but lack phospholipase
C.
I did not isolate the mutant or make this discovery, but I did work on norpA.
Eventually, I did some research
on lipids and fatty acids in Drosophila with reference to phototransduction.
Fig. 7.8
How phosphorylation (by kinase) could affect protein - (activate it by binding
phosphate onto it).
Need a phosphatase to take phosphate off.
cAMP
Fig. 7.7C
cAMP mechanism
ATP -> adenylyl cyclase -> cAMP -> phosphodiesterase -> 5'AMP.
Caffeine and theophylline inhibit PDE (phosphodiesterase for cAMP), thus
potentiating the "upper" action of norepinephrine by making its
second messenger longer lasting.
Fig. 7.9 A
A-Kinase (PKA) - catalytic (C) and regulatory (R) (inhibitory) subunits.
2 cAMP's each bind 2R's, pull them off of 2C's
Fig. 7.11
CREB = cAMP response element binding protein affects gene transcription
Summary
Chapter 7 (Molecular signaling within neurons) is difficult because, following
Chapter 6 (Neurotransmitter receptors and their receptors), one would hope
it was restricted to metabotropic transmitter mechanisms, but it expands
to signal transduction in general, a broad topic indeed, and the subject
of an entire course
I have recently taught).
Exam questions form 2005 - 2007 relating to this outline
What would 125I - labeled a-bungarotoxin label?
the nicotinic receptor on muscle
What is the next in line downstream of the metabotropic glutamate receptor?
G protein
Describe, in terms of chemical structure, how cAMP interacts to activate
PKA (protein kinase A).
4 cAMPs bind 2 inhibitory subunits releasing catalytic subunits
Linda B. Buch and Richard Axel won the 2004 Nobel Prize for discovering
the nature of the olfactory receptor. What type of molecule is it?
G rotein coupled receptor
In what way is the nicotinic receptor different for muscle vs. neurons?
different subunits for pentamer
The Nobel laureate Earl Sutherland is considered the founder of signal transduction
and is associtated with identifying what "second messenger" for
adrenergic transmission?
cAMP
What is the transmitter for the NMDA (N-methyl D-aspartate) receptor?
glutamate
Why is atropine from deadly nightshade called "belladonna alkaloid."
women used pupil dilation to look beautiful
What would you give a patient with myasthenia gravis to relieve the symptoms?
neostigmine
Give the name (that relates to the pharmacological agonist) for the ionotropic
(channel) receptor for acetylcholine.
nicotinic
Inositol trisphosphate is a ligand for what kind of channel located where?
calcium on reticulum
"Atropine could save your life if your heart were stopping from Malathion
poisoning." This relates to what type specific receptor on the heart
(name should include pharmacological agonist plus neurotransmitter)?
muscarinic acetylcholine
"Transgenic mice in which a Purkinje cell-specific promotor drove expression
of a molecule that inhibits PKC lack LTD for the conditioned eye blink."
Explain the significance, including what is PKC and LTD.
This was a way to show that protein kinase C mediated long term depression,
a model of synaptic learning is a specific cell type, the Purkinje cell
A vesicle contains a pretty standard amount of acetylcholine. Then why is
the mepp (miniature end plate potential) smaller in myasthenia gravis?
there are fewer nicotinic receptors
How do you make an NMDA receptor from subunits NMDA-R1 and NMDA-R2A through
NMDA-R2D?
Lots of possibilitits since receptor is a multimer (4 or 5) mixed from that
list
The lecture and outline indicated that "the second and third loops
and C terminus are for interaction with the alpha subunit of heterotrimeric
G protein." Loops and C terminus of what type of protein, and where,
in the cell's topology, are the loops and C terminus?
G protein coupled receptor is on membrane and those places are, obviously,
on the cytoplasmic side
In the G protein signal transduction cascade, which specific molecule or
subunit has GTPase activity?
alpha subunit of heterotrimeric G protein
Where does CREB (cAMP response element binding protein) bind, and what does
it do by binding there?
promoter, affect transcription
How does caffeine have its stimulatory effects?
inhibits cAMP phosphodiesterase
In the good old days (1980's), gene cloners started with a tissue that expressed
the gene product abundantly. What was this tissue for the nicotinic receptor?
electric organ of Torpedo
Why would you use alpha-bungarotoxin labeled with radioactive iodine in
research?
label nicotinic receptor
Curare is most famous for blocking (what specific kind of receptor) in (what
specific location)?
nicotinic motor end plate
For ionotropic receptors, e.g. NMDA receptors, there are "a large number
of receptor isoforms." Why?
many possible subunits in many different conformations
Librium, Valium and barbiturates bind to subumits of (what type of receptor)
for (what transmitter)?
GABA
What drug slows the termination of cAMP activity and how?
caffeine blocks cAMP phosphodiesterase
"The beta blocker Propranolol is used to treat hypertension."
What is the neurotransmitter whose receptor is blocked and where?
norepinephrine, SA node
Why would you think, even before it had been shown, that the N-terminal
part of the G protein coupled receptor was not the part that binds the G
protein?
it must be on the outside of the membrane
Atropine causes the pupil to dilate. With that hint, tell me what part of
the nervous system, using what transmitter, causes the pupil to constrict.
parasympathetic, acetylcholine
The alpha subunit of the heterotrimeric G protein has GTPase activity. Why
is that important?
to terminate its action
IP3 causes an increase in cytosolic Ca2+. How?
bind IP3 receptor (Ca2+ channel) in smooth ER
It takes 4 cAMP molecules to activate PKA. How (biochemically) do they do
that?
2 each bind and remove 2 inhibitory subunits from 2 catalytic subunits
In the cAMP pathway, protein kinase A (PKA) can phosphorylate CREB (cAMP
response element binding protein). What type of molecule does CREB bind
to?
DNA
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The neuroanatomy lecture
Neuroanatomy
Purves et al. part of Chapter 1, Appendix, the Sylvius CD, Box A in Chapter
19 for prions, Figure from chapter 22
Resources
Here is a site I found on mouse brain
anatomy
(might not work on Netscape)
(unfortunately, some of the links are dead)
I found these pictures of stereotactic
apparatus at the Kopf Instrument site. (might not work on Netscape)
Sutures in bones are landmarks for surgery, Bregma is the anterior square
one, and Lambda is the posterior V shaped one, and here
is a picture from a site where you can buy a rat skull on a chain.
Using these landmarks, a rat brain atlas, and a drill, electrodes can be
placed into specified locations for stimulating or lesioning.
Here is a site
for sheep brain dissection.
Acknowledgements
In 1970-1971, I was assigned to be a teaching assistant (TA) in Physiological
Psychology at the University of Wiscconsin - Madison for Prof. Richard Keesey.
Without the help of the senior TA, Norm Ferguson, I do not know how I would
have survived. A few years later, Norm published "Neuropsychology Laboratory
Manual" (Norman B. L. Ferguson, San Francisco, Albion Publishing Company,
1977), with good coverage on anatomy. The slide
collection I present to you is mostly the slide collection I was given to
use as a TA. For the first time in recent years, a student dissection of
the sheep brain is being incorporated into this course. The dissection
guide, which we will follow, and the glossary
of neuroanatomical terms, which is entertaining and informative, is from
the course I TAed. This lab was prepared and added to the Neuro curriculum
for Spring 2005 mostly from the efforts of Christine Zelle, Lab coordinator
for upper division biology labs. 2006 revisions included (1) labeling the
slides, (2) simplifying the dissection guide from its original version,
and (3) hyperlinking to slides from the guide; some of these revisions were
suggested by 2005 students in their course assessment.
The Prion Lecture
Chapter 18 Box A
Prion diseases - this is in the cerebellum chapter because cerebellar ataxia
is one of the characteristics of the diseases; I put it here as a warning
for obvious reasons.
Creutzfeldt - Jakob Disease (CJD) "Spongiform" (brain turns to
sponge) degeneration.
There were seemingly esoteric* cases of spongiform encephalitis.
* for instance afflicting Jews in Lybia who thought raw sheep eyeballs were
a delicacy.
Kuru was a disease in New Guinea among cannibals.
D. Carleton Gadjusek (1976 Nobel
Prize) thought it was a slow virus.
Scrapie in sheep so named because they roll around with intense itching.
Personal reflection. Since we did a sheep brain dissection in physiological
psychology lab at Hopkins, I wondered if rubber gloves were necessary. Since
Baltimore was close to Bethesda, I called. Gadjusek was away, studying some
remote tribe, but I spoke with his coworker (Gibbs) who thought formaldehyde
might not kill the virus. Then I got on their mailing list and, once a month
or so, got an inch thich envelope full of case studies of diseases in far
away places. I had to move to Missouri (in 1979) to make it stop.
Stanley Pruisinger 1980's proposes "prion" (protenaceous infectious
particle).
That a disease could be transmitted without virus or bactera was heresy
at the time.
But he had strong evidence and won the 1997 Nobel
Prize.
Normal protein (PrP-C [control]) is altered by altered form (PrP-Sc [scrapie])
In the 1990s when the term "mad cow disease," was applied to observations
in Britain, it seemed like a joke.
Now "BSE" (bovine spongiform encephalitis) is no laughing matter.
In meat industry, having matter from other animals in the feed is really
bad.
Can disease spread from animal to animal? (probably)
Can disease spread from animal to human? (probably)
Cases in Canida, mainland Europe, and even in the US are in the news.
Should "downers" ("cows" that have dropped to the ground)
be slaughtered for food?
How is it that meat from one downer can be sold in many different states
and, only later, the announcement is made that it had BSE?
To supplement the above material, please view the 2006
graduate student presentation on prions.
Background
big area of cerebral cortex (2.2 square meters) from folding into sulci
and gyri
Fig. 1.6 FG
cellular cytoarchitecture - 2 mm thick cerebral cortex
6 layers, top (I) = molecular (without cells)
Brodman made areas (from cytoarchitecture), famous:
4 motor
17 vision
Fig. A1 [A,B] (Appendix)
Review (already covered in first lecture) and terminology:
Rostral - caudal
Medial - lateral
Ipsilateral - contralateral
Sagittal - coronal - horizontal
also:
gray matter, cortex, nucleus and ganglion
substantia (ex. substantia nigra) like nucleus but less distinct
locus (l. coeruleus) small distinct group
nerve, white matter, tract
bundle (medial forebrain bundle) go together but unrelated
capsule (internal c.) cerebrum - brainstem connection
commisure - one side to another
lemniscus (medial l.) - like ribbon
Fig. A10
Overall external anatomy viewed laterally
Shows brains of mammals (cortex = "bark")
cerebrum senses - hemisphere controls contralateral
cerebellum (little brain) - hemisphere controls ipsilateral
Landmarks:
Central Sulcus divides
postcentral gyrus (primary sensory projection)
17 vision
precentral gyrus (primary motor area) Brodman made area 4 motor
Lateral (Sylvian) fissure
Brainstem
Fig. A3
frontal lobe - planning behavior
parietal lobe - attending to stimuli
temporal lobe - recognition
occipital lobe - visual analysis
Figure, (not in book anymore, but relates to Fig. 22.5)
Developmental introduction to neuroanatomy
(there is also a development chapter, chapter 21)
Prosencephalon
Mesencephalon
Rhombencephalon
Each of the above develops further. note (especially):
Telencephalon -olfactory bulbs, cerebral cortex, basal ganglia, hippocampus,
etc.
Diencephalon is thalamus (sensory & motor "relay") and hypothalamus
(visceral function)
Mesencephalon - tectum -> superior and inferior colliculi (vision and
audition respectively)
Metencephalon - cerebellum, pons
Myelencephalon - medulla - auditory, somatic, gustatory
Table A2 (appendix)
and
Fig. A7 (appendix)
and figure
from sheep brain dissection
another figure
from sheep
yet another
ventral view of brain
cranial nerves.(some are tracts)
sensory vs. motor, somatic vs. visceral (autonomic)
I olfactory
II optic
III occulomotor - goes to 4 external eye muscles, pupil, accomodation, eyelids
IV trochlear - to superior oblique muscle
V trigeminal - somatic from face, chewing
VI abducens - to external rectus muscle of eye
VII facial - facial muscles, lacrimal and salivary glands, taste
VIII auditory / vestibular
IX glossopharyngeal - taste from back of tongue, sense from pharynx, carotid
baroreceptors
X vagus - autonomic, sensation, vocal cords, swallowing
XI accessory - shoulder & neck muscles
XII hypoglossal - tongue movements
some other ventral landmarks:
pyramids- of pyramidal (corticospinal tract) (decussation is caudal to this)
(vs. extrapyramidal)
mammallary body, pons, inferior olive (motor control), rhinal fissure, etc
optic nerve, chiasm and tract
cerebral peduncles - axons between brainstem and cortex
Fig. A14
neocortex (found only in mammals),
hippocampus (archipallium) (one cell layer) (seahorse shaped)
and olfactory cortex
Fig A12
human midsagittal
sheep
close up
tract dissection
thalamus, hypothalamus, midbrain, pons, medulla
(subthalamus is between, concerned with motor function)
corpus callosum, anterior commisure, cingulate sulcus and gyrus, etc.
optic chiasm, infundibular stalk, pituitary, mammallary body, pineal, colliculi,
etc.
some of these are in limbic system (chapter 29)
Fig. A8
sheep
dorsal view of midbrain and brainstem
Cerebellum has 3 peduncles
superior and inferior colliculi
many important nuclei, principally of cranial nerves, are drawn in
Fig. A14A
coronal section
this view is especially good for the basal ganglia and internal capsule
striatum = caudate + putamen
sheep
horizintal section
Prep for dissection
A
B
C
D
E
F
G
Fig. A2A
spinal cord - cervical thoracic lumbar and sacral nerves
Cauda equina branches out toward bottom
Fig. A19
meninges (as in meningitis)
(1) dura (2) arachnoid (3) pia
subarachnoid space has cerebrospinal fluid (CSF)
So do ventricals.
sheep
Fig. A21
ventricles
the CSF is "isolated" by the blood-brain-barrier (BBB)
and is secreted by the choroid plexus
Exam questions from 2005 - 2007 relating to this outline (plus dissection
guide and slides)
For 1-16, refer to Figs 1st
p, 2nd p,
3rd p, 4th
p,
1. The name of this bulge.
pons
2. The name of this blood vessel feeding the circle of Willis.
internal carotid artery
3. The name of this ventricle.
3rd
4. The name of this nucleus. Its function. (two points)
caudate, motor (extrapyramidal
5. The name of this tract.
fornix
6. What big tract is being ripped here?
internal capsule
7. The name of this structure.
hippocampus
8. What part of the thalamus is this?
lateral geniculate
9. The name of this whole tract that is teased into 3 components on the
other side.
cerebellar peduncle
10. Name one of the two nuclei that form this lens-shaped nucleus.
ptuamen, glogus pallidus
11. The name of this bulge. The name of the equivalent structure in the
frog. (2 points)
superior colliculus, optic tectum
12. The name of this big bundle of cross over axons.
corpus callosum
13. The name of this bulge. Its function. (2 points)
precentral gyrus, motor
14. The name of this major subdivision of the brain.
cerebellum
15. The name of this small bundle of cross over axons.
anterior commisure
16. The name of this major subdivision of the brain.
medulla
Using a stereotaxic atlas of the rat brain and a stereotaxic apparatus,
what do you measure from on the rat's head to find a defined brain location
like the ventromedial nucleus of the
hypothalamus?
bone sutures bregma and lambda
Why do they call part of the basal ganglia the "striatum?"
brances off the internal capsule make these nuclei look striped
Only one of the cranial nerves for eye movements is also part of the parasympathetic
nervous system. Which?
occulomotor (III)
When you remove the cerebellum, you are looking at the floor of which ventricle?
4th
The hippocampus looks white because of axons of the fimbria that form what
major tract?
fornix
Among the meninges (brain membranes), which is the toughest?
dura mater
When Stanley Pruisinger, who eventually won a Nobel Prize, proposed the
prion theory for spongiform encephalitis, how was he disagreeing with the
Nobel Prize winning work
of D. Carleton Gadjusek?
SP said a protein could be infectious while DCG thought more traditionally
that it was a virus (a slow one)
For questions # 1 - 4, refer to this
figure.
1. This gray matter. Note that it is covered with white matter. Also note
its location between the white matter of the cerebral cortex and the thalamus.
hippocampus
2. This thin midsagittal structure blocks your view into the lateral ventricle
and the head of the caudate nucleus.
septum pellucidum
3. Part of the mesencephalon, this part of the lamina quadrigemina is a
visual area related to the optic tectum of the frog.
superior colliculus
4. This bulge, white matter, leads to the brachium pontis of the cerebellar
pecuncle. On the ventral view of the brain, it blocks your view of the pyramidal
tract.
pons
for 5-8, see this
figure
5. If you started cutting into the longitudinal fissure, what is the first
white matter you would cut?
corpus callosum
6. This visual structure blocks your view to the supraoptic nucleus of the
hypothalamus.
optic chiasm
7, Many of the brains we had for dissection showed this ribbon-shaped cranial
nerve.
oculomotor nerve (III)
8. This tract is named for its connection from the thalamus to what specific
portion of the hypothalamus, a body which would be conspicuous on the ventral
view.
mammillary body
for 9-12, see this
figure
9. This portion of the cerebellar peduncle has axons that are seen in what
ventral structure?
pons
10. What commisure is here? (The arrow does not point to the corpus callosum.)
hippocampal commisure
11. What major subdivision of the brain is this?
cerebellum
12. Why is the hippocampus white?
its output axons, the fimbria, are on the surface
"Each picture in a stereotactic atlas of the rat brain is a coronal
section with its distance anterior or posterior of bregma indicated."
Translate.
coronal is dorsal-ventral, lateral-contralateral plane, and bregma is a
landmark on the sutures of the bones
Why did I decide to tell the prion story in the neuroanatomy lecture before
the brain dissection?
to give you a cautious appreciation for how contact with neural tissue,
in the case of scrapie, might be dangerous
The pons covers up a white matter that goes from the cerebral peduncles
through the pyramids. What is this tract (not the pons, rather the tract
covered by the pons) used for?
motor output
The most obvious of the "membranes" (meninges) of an "un-peeled"
brain is a very thick and tough one called the (what)?
dura mater
"Bundle," "capsule,""commisure," and "lemniscus"
are all terms referring to what specific type of tissue?
tracts
Toward the bottom of the spinal cord, there are many parallel tracts. What
is this called?
cauda equina
Sometimes caudate plus putamen is called striatum. Why?
looks striated from branches of white matter off the internal capsule
What vascular tissue, seen dark in dissection, secretes cerebrospinal fluid?
choroid plexus
For 1-3, see here
1. In some brains, this was intact, in others, it was damaged, revealing
a fluid-filled compartment. What is it?
olfactory bulb
2. Hardly anybody had this good of a view of this pair of laterally projecting
nerves found near the stump of this obvious rostrally projecting nerve.
Give the name or number of one of them.
Facial (7) or auditory (8)
3. If this tract is followed laterally and superiorally, with the cerebellum
removed, it is part of a huge structure of white matter. What is this white
matter called?
cerebellar peduncle
For 4-8, see here
4. Here is white matter (covered by the pons). What is the function of this
white matter tract?
motor (pyramidal [corticospinal] tract)
5. Between the two lines (and just on the other side of the optic chiasm)
lies what structure, important in motivation?
hypothalamus
6. With the cerebellum removed, what are the midbrain structures seen
superior (and inferior) colliculi,, lamina (corpora) quadrigemina
7. and what would the visual counterpart be called in the frog?
optic tectum
8. What ventricle is this?
4th
For 9-12, see here
9. What motor nucleus is right on the other side of the septum?
caudate
10. What is the name of this huge area of white matter?
internal capsule
11. Covered by the hippocampus, what is the specific function of this part
of the thalamus?
vilson (lateral geniculate nucleus [body])
12. The fimbria fibers that make this structure white are bundled together
in what tract that can be seen in mid-sagittal section?
fornix
What distinguishes a bundle (like the medial forebrain bundle) from a tract?
several unrelated tracts travel together
What are the diencephalic structures that would be seen in the neighborhood
of the third ventricle?
thalamus and hypothalamus
The surface of the hippocampus is white. How, during the dissection, would
you ascertain the direction that these axons go?
stroke with the grain and across the grain with the cuticle stick
Starting at the lumbar area and going through the sacral area, describe
the spinal cord.
cauda equina, a bunch of nerves
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This page was last updated 2/14/08
The sheep brain dissection lecture
The brains arrive crudely prepared as seen in this lateral
view and ventral
view. There is tissue, and meninges. The white film is dura mater.
TheLateral view of the sheep brain showing cerebrum, cerebellum, brainstem.
Rhinal fissure and olfactory bulb are conspicuous. See slide
1
Dorsal view of the sheep brain. Longitudinal fissure separates cerebral
hemispheres. Vermis is between cerebellar hemispheres. See slide
2
Wide angle of the ventral surface of the brain with all the associated structures.
See slide 4
Close-up of ventral brain centered on optic chiasm. This view is good for
circle of Willis fed by the stump of the internal carotid artery visible
to the left. See slide
3
Close-up of anterior portion of ventral surface of the sheep brain. This
view is especially good for the lateral and medial olfactory stria, mammillary
body, oculomotor nerve and cerebral peduncle. See slide
5
With one optic nerve removed, the diagonal band is visible in this close-up
of the ventral part of the sheep brain. This view is also good for the trigeminal
nerve on one side. See slide
6
This closeup of the posterior ventral lateral part of the sheep brain is
good to show the abducens nerve and the choroid plexus. See slide
7
In this close-up of the venttral surface of the sheep brain, glossopharyngeal
and vagus nerve have been teased apart and the (spinal) accessory nerve
is clear. See slide
8
White and gray matter of cerebrum and cerebellum are compared. See slide
22
The removal of gray matter reveals the crown like appearance of arcuate
fibers collectively referred to as the corona radiata. See slide
23
This midsagittal cut reveals all the structures in such a cut. Most of the
septum pellucidum is intact here. See slide
9
This close-up of the midsagittal cut is good to show anterior commissure,
massa intermedia of thalamus, third and fourth ventricles, habenula, and
lamina quadrigemina of the colliculi, in addition to the more famous structures.
See slide
10
This tract dissection of the midsagittal cut reveals the fornix, the mammilo-thalamic
tract and the habenulo-peduncular tract. The head of the caudate is seen
past the septum through the lateral ventricle. See slide
11
Here is one of the 2 cuts you would make to cut out a pie wedge of the cerebral
cortex to reveal the hippocampus. See slide
13
Bent apart, the hippocampus looks white from the surface layer of fimbria
fibers which form the fornix. See slide
14
This peeling apart toward the midsagittal cut more clearly reveals fimbria
forming into fornix. See slide
16
Further pulling tears some fibers of the internal capsule between caudate
and hippocampus. See slide
17
With trimming, caudate and hippocampus are clear. See slide
18
With the hippocampus removed, the optic tract to lateral geniculate
nucleus connection is revealed as well as the superior and inferior colliculi.
See slide
19
With the cerebellum removed, the floor of the fourth ventrical is viewed,
and the cerebellar peduncle is teased into brachium pontis, brachium conjunctivum
and restiform body. This is a good view of superior and inferior colliculi.
See slide
20
With gray matter removed, the lateral aspect of the cerebellar peduncle
is seen. See slide
21
This dorsal horizontal section is good to reveal the caudate. The hippocampus
is nicked. See slide
15
This horizontal section shows how branches of the internal capsule give
the basal ganglia the nick name "striatum." and how the putamen
and globus pallidus pool structurally to make the lens shaped lenticular
nucleus. Lateral geniculate nucleus and hippocampus are sectioned caudally.
See slide
12
This page was last updated 9/17/98
Dissection of the Sheep Brain
Sheep brains in Carosafe®, a formalin analog, will be supplied to
you for the following dissection exercises. The dissection must be carried
out on the side directed in order not to interfere with the later procedures.
Laboratory work should be supplemented by study of textbook, web and Sylvius.
I. Brain Membranes and Blood Vessels
To make the dissection easier, your specimen has had the brain membranes
(meninges) removed already. In this
lateral view and this
ventral view, with meminges intact, the dura mater is obvious. The pia mater
needs to be teased to retract into fissures (sulci), using this
view of the external anatomy of the cerebral cortex as an example. The arachnoid,
lying between these two membranes, is difficult to see.
Note the blood supply, especially the circle of Willis and the other vessels,
seen in this
ventral view. The hypophsis (pituitary) has probably already been removed
in your brain to permit better observation of the circle of Willis, but
it is intact in this
brain. Find the basilar artery; the posterior communicating arteries; the
posterior, middle, and anterior cerebral arteries; the internal carotid
arteries; and the anterior communicating artery.
II. Cranial Nerves
Using ventral views 1,
2, 3,
4, &
5 locate
the roots of the twelve pairs of cranial nerves. Each is listed below and
its function identified. [Note, "motor" (below) includes parasympathetic
output for nerves 3, 7, 9 and 10.]
- The first "nerve" (olfactory bulb) is olfactory in
function. Sensory.
- The optic "nerves" run off from the optic chiasm.
Sensory
- The oculomotor nerves are large and flat, emerging from the
cerebral peduncles, and running forward to supply four of the muscles of
the eyeball. Motor.
- The trochlear nerve emerges from the lateral surface, in the
angle between the occipital lobe of the cerebrum and the hindbrain. Motor-serves
the superior oblique muscle of the eye.
- The trigeminal nerve is behind the trochlear and is very large.
It emerges from the lateral border of pons. Mixed sensory and motor nerve.
It serves muscles of mastication and sensory fibers from the face.
- The abducens is a small flat nerve arising from the trapezoid
body. It is motor, serving the external rectus muscle of the eye.
- The facial nerve is lateral to the abducens and just behind
the trigeminal. It serves the muscles of the face.
- The acoustic nerve is just behind and slightly lateral to the
facial nerve. Sensory.
- The glossopharyngeal and vagus (X) nerves arise together,
behind and slightly ventral to the auditory nerve and separate later. The
glossopharyngeal is sensory and serves the mouth and tongue area.
- The vagus, as mentioned above, is both sensory and motor, serving
the heart, lungs and other internal organs.
- The spinal accessory nerve runs along the lateral surface of
the medulla and spinal cord, receiving fibers along the way. It is motor
in functions, serving the muscles of the neck.
- The hypoglossal nerve arises from the ventral surface of the
medulla, in a pair of more or less distinct roots. It is motor, innervating
the muscles of the tongue.
III. Surface Anatomy of the Brain
Examine carefully the external form of the sheep brain. On the dorsal
view, note the fissures (sulci) and convolutions (gyri); also identify the
cerebellar vermis and hemispheres, the medulla and the longitudinal fissure.
On the cerebral hemispheres
identify the lateral fissure, the rhinal fissure and the suprasylvian fissure.
Using ventral views 1,
2, 3,
4, &
5 identify
the following structures:
- Olive
- Pons
- Cerebral peduncles
- Interpeduncular nucleus
- Mammillary bodies
- Diagonal band
- Amygdaloid nucleus
- Pyriform area
- Hippocampal gyrus
- Lateral and medial olfactory gyri and stria
- Trapezoid body
- Anterior perforated substance
IV. Brain Stem and Cortex
Observe the relations of the cerebral cortex to the cerebellar cortex.
Note especially the difference in the number of convolutions on each structure.
Use a scalpel to cut off a slice about one centimeter thick from the posterior
pole of the left cerebral cortex and a similar slice from the left lateral
border of the cerebellum. They should look like this.
Compare the cut surfaces and observe the relations of the gray matter to
the underlying white matter.
V. Rhombencephalon
The rhombencephalon (or hindbrain) is composed of the metencephalon
(cerebellum and pons) and the myelencephaon (medulla oblongata). Note the
attachment of the cerebellum to the medulla. Cut these attachments (cerebellar
peduncles) on each side with the aid of a scalpel. Remove the cerebellum
and put it aside for future study. These peduncles should be cut as high
as possible, cutting into the substance of the cerebellum if necessary rather
than into the structures of the medulla. Take care not to injure the delicate
membranes beneath the cerebellum and forming the roof of the IVth
ventricle. The view should look like this.
The IVth ventricle is sometimes called the cavity of the rhombencephalon.
The cerebellum forms the roof of the ventricle but only for a short extent
between the cerebellar peduncles. Behind, the roof is formed by a thin non-nervous
membrane (tegmen) part of which is highly vascular and much folded. Note
the choroid plexus of the IVth ventricle, composed capillary
tufts and columnar epithelial tissue. The choroids plexi form a barrier
between the blood and the cerebrospinal fluid, and are thought to be the
source of the cerebrospinal fluid.
VI. Mid-sagittal view
Now cut the entire brain of the sheep into right and left halves. A long,
thin knife or large steel spatula is best suited to this purpose. The incision
should pass through the longitudinal fissure between the cerebral hemispheres
to cut through the corpus callosum in the floor of this fissure, and then
downward through the entire brain stem. Care should be taken to make this
cut smooth and exactly in the median plane. It should be made with a single,
long sweep of the knife. You may wish to locate the commissures as you cut
through them. Examine carefully the cut surfaces of the brain and identify
the structure brought into view. Refer to these photographs (1
and 2)
of the median surface provided to you and locate the following structures
on your sheep brain:
- Medulla
- Fourth ventricle
- Pons
- Mammillary bodies
- Lamina quadrigemina
- Superior colliculus
- Posterior commissure
- Pineal body
- Habenula
- Splenium, genu and body of the corpus callosum
- Massa intermedia of the thalamus
- Stria medullaris
- Body of the fornix
- Anterior commissure
- Septum pellucidum
- Hippocampal commissure
- Diagonal band
- Lamina terminalis
- Habenular commissure
VII. Cerebellum
There are three cerebellar peduncles: brachium conjunctivum, brachium
pontis, and corpus restiforme. Examine their cut surfaces on the dorsal
aspect of the medulla. Separate the fibers of the three peduncles from each
other on the cut surface. Then continue the separation of the conjunctivum
and middle peduncles for approximately one centimeter downward along the
dorso-lateral border of the medulla as they cross the spinal V tract superficially
to continue into the cord as the dorsal spino-cerebellar tract. Dissect
the fibers of the brachium pontis and the brachium conjunctivum. The latter
can be followed to its decussation in the cerebral peduncle beneath the
superior colleculus. Since you removed the cerebellum, you cannot do this
tract dissection: With gray matter removed, the lateral aspect of the cerebellar
peduncle is seen.
Cut the cerebellum into two halves along the medial sagittal plane. The
cerebellar gray and white matter seen in the median section of the vermis
has the appearance of arbor vitae.
VIII. Dissection of the Tracts
Pyramidal tract
The dissection of the cerebrum outlined below is to be carried out on the
right half of the sheep brain. Locate the pyramid on the ventral surface
just caudal to the pons. Strip the pons fibers back from the cut median
surface for a short distance. Teasing them, you can see the direction the
axons go. Expose the longitudinal pyramidal fibers lying just dorsal to
the pontine fibers. Tease them and you see that they go at right angles
to the pons fibers. In the sheep, the pyramidal fibers interdigitate with
fibers of the trapezoid body which thus must be destroyed to expose the
pyramidal tract. By careful teasing, the pyramidal tract can be followed
spinalward only as far as the decussation. The fibers cannot be followed
any further. The pyramidal tract can be dissected cephalad from the pons
through the cerebral peduncle. This dissection should be deferred until
later.
Association tracts
The arrangement of fibers in the subcortical white matter can be examined
by careful teasing. Only some of these fibers are to be studied at this
time. The dissection outlined in this section should not be carried farther
than indicated.
Refer to this
figure. Select a region along the dorsal border of the medial surface of
the hemisphere. Scrape away the gray matter covering two adjacent gyri to
expose the short associational (arcuate) fibers connecting these
gyri. Further teasing can reveal similar fibers lying deep in the white
matter, which connect the more remote gyri. Corona radiata is the name given
to those fibers running between the cortex and the brain stem via the internal
capsule of the corpus striatum. These include the thalamo-cortical sensory
projection fibers, other thalamo-cortical connections and the cortical efferent
tracts (the corticospinal, corticobulbar and corticopontile). These fibers
diverge from the upper border of the internal capsule like the rays of a
crown, hence "corona radiata."
The cingulum is a long associational tract close to the medial cortical
surface of the hemisphere. It runs parallel with the dorsal surface of the
corpus callosum in part of its course, beginning anteriorly in the gyrus
subcallosus beneath the head of the corpus callosum. It arches upward at
the genu of the corpus callosum, passes around the splenium of the callosum
posteriorly and then bends downward, forward and lateral-ward to the region
of the hippocampal gyrus. Begin its dissection at about the middle of the
corpus callosum, following it both anteriorly and posteriorly.
The corpus callosum are fibers that connect the neocortex of one
hemisphere with that of the opposite hemisphere. Tease the callosal fibers
a small distance and note that the texture tells you the direction the axons
go.
IX. Mesencephalon and Prosencephalon
The mesencephalon includes all of the structures of the midbrain, such
as the superior colliculus, inferior colliculus, cerebral peduncles, and
the interpeduncular nucleus. The prosencephalon is divided into the diencephalon
and the telencephalon. The thalamus and hypothalamus (including the mammillary
bodies) are the major parts of the diencephalon, and the cerebral cortex,
corpus striatum (internal capsule, caudate nucleus, putamen and globus pallidus)
and rhinencephalon form the telencephalon.
Rhinencephalon and Limbic System
In older terminologies the rhinencephalon is often referred to as smell
brain. Although the olfactory bulb can be shown to have connections with
rhinencephalon, this is true for only some of its parts. More recently the
rhinencephalon has been divided into three interconnected parts: 1. Primary
olfactory structures directly related to the olfactory bulb. 2. Second system
receiving fibers from the first consisting primarily of septal region and
amygdaloid complex. 3. The third system consists of cingulate and entorhinal
cortex and the hypothalamus. These appear to be remotely, if at all, related
to olfactory afferents. Both the second and third systems send efferents
to the hypothalamus. The limbic system consists of the second and
third systems in addition to two diencephalic structures, the anterior thalamus
and the mammillary bodies. The structures of the rhinencephalon are relatively
more developed in the sheep, so that dissection is easier than in the human
brain. The primary olfactory neurons give rise to fibers that terminate
in the olfactory bulb, the primary olfactory center of the brain. From here
to the neurons of the second order (mitral cells), give rise to axons forming
the olfactory tracts or striae (lateral and medial) terminating in secondary
olfactory centers in the basal parts of the cerebral hemisphere.
Other tracts of the rhinencephalon usually named by hyphenated compound
words of which the second member designates the center into which the tract
discharges. For example (refer to
this figure) [Also note that, if your cut was a bit off of mid-sagittal,
these tracts may already be visible.]:
Mammillo-thalamic tract . This tract runs from the mammillary body
forward and dorsalward to the anterior nucleus of the thalamus. It can be
readily dissected by scrapping off the ependyma of the third ventricle,
beginning in the region of the mammillary body.
Habenulo-pendunclar tract . This tract also can be readily dissected
(although watch out, it is easy to scrape right through it). It runs from
the habenula into the ventral part of the cerebral peduncle immediately
behind the mammillary body.
The fornix can also be followed down toward the mammillary bodies.
The hippocampus and fornix.
The hippocampus (archipallium) is located in the floor of the posterior
horn of the lateral ventricle, together with the fimbria and hippocampal
commissure. Refer to
this figure. Now cut through the splenium of the corpus callosum to
the tip of the hippocampal gyrus. This is one of the 2 cuts you would make
to cut out a pie wedge of the cerebral cortex to reveal the hippocampus.
Peel apart this opening to reveal the hippocampus (refer to this
figure). Note that the hippocampus looks white. This is because it is covered
by the fimbria, fibers that form the fornix. The column of the fornix thus
is the efferent projection tract from the hippocampus to the mammillary
body (and habenula).
Teasing the fibers of the fimbria, you can tell by the texture what direction
they go. Here
is another view of the hippocampus; Note that, in this view, there is a
nick through the fimbria revealing the gray matter of the hippocampus.
Cut through the genu of the corpus callosum forward and downward towards
the olfactory bulb, to open up the anterior horn of the lateral ventricle.
In the sheep, unlike man, this is directly continuous with the ventricle
of the olfactory bulb.
The ventricular wall can be torn away along the border between the head
of the caudate nucleus and the hippocampus by careful pulling. Refer to
this figure.
This reveals the internal capsule fibers passing downward and backward,
lateral to the caudate nucleus. You can tell, by the texture of the tearing,
the direction of the axons.
XI. Optic System
With trimming, caudate and hippocampus are clear in this
figure. Remove the hippocampus and identify lateral and medial geniculate
bodies (refer to this
figure). You can also see the inferior (auditory) and superior (visual)
colliculi on the lateral surface of the thalamus and midbrain. Follow the
optic tract from the chiasm to the lateral geniculate body.
XII. Further Dissection of the Pyramidal Tract
As the last step of the dissection, careful tearing down of the fibers
will permit you to follow out some of the internal capsule fibers into the
regions of the thalamus, midbrain, and medulla oblongata, especially the
cortico-spinal (pyramidal) tract. Although functionally a motor and thus
a descending tract, it can more easily be traced from the medulla upward
to the higher centers. It appears as an eminence (pyramid) on the ventral
surface of the medulla below the pons near the midline. Its fibers interlace
with those of the pons, where the cortico-spinal tract was located earlier.
It can then be followed along the ventral surface of the mesencephalon through
the cerebral peduncle into the internal capsule. The cell bodies for these
fibers lie in the superior frontal gyrus.
XIII. Dissection of the Left Half
The left half of the specimen may be cut into a series of transverse
or longitudinal slices.
A suggested method of making these sections is first to cut a "horizontal"
section through the neocortex, about three millimeters dorsal to the corpus
callosum and in the same plane as this structure. This section will
actually slope ventrally toward the frontal cortex, as does the corpus callosum.
Then cut laterally through both the genu and splenium of the corpus callosum
to the extremes of the anterior and inferior horns of the lateral ventricle,
respectively. After removing the corpus callosum, extend the cuts anteriorly
and posteriorly to expose the head of the caudate nucleus, and the hippocampus.
Refer to this
figure. Observe the relations of the lateral ventricle, the hippocampus,
and the head of the caudate nucleus to one another.
Another section can be made in the same plane, but at a somewhat smaller
angle from the horizontal, immediately superior to the pineal body, through
the hippocampus and the head of the caudate. Be careful to avoid cutting
through the dorsal surface of the thalamus. Refer to this
figure. Note the relation of the internal capsule to the adjacent structures.
The basal ganglia are made up of caudate, putamen and globus pallidus. Caudate
+ putamen = striatum (striated because strands of internal capsule make
it look striated), clearly seen in this section. Putamen + globus pallidus
= lentiform nucleus [lens shaped], clearly seen in this section. This section
is also excellent for seeing the hippocampus overlying the lateral geniculate
of the thalamus.
Glossary of Neuroanatomy Terms
Amygdaloid. Greek. amygdale = almond, and eidos = resemblance.
The name given to the almond-shaped nucleus.
Astrocyte. Greek. aston = star, and kytos = vessel or cell.
These cells are of a shape to suggest stars.
Autonomic. Greek. auto = self, and nomos = laws.
Hence that part of the nervous system which is self controlled or autonomous.
Axon. Greek. axon = axis
Adpoted for the name of the axis cylinder.
Brachia Latin. brachium = an arm or arm-like process; plural brachia.
Brain. Anglo-Saxon. braegen = brain; or perhaps related to the Greek brechmos
= forehead.
Callosum. Latin. callosus = callous.
Applied to the corpus callosum.
Cerebellum. Latin. diminutive of cerebrum = brain.
Cerebrum. Latin. cerebrum = brain
Cinerea. Latin. cinereus = ashy.
Another term for the gray matter of the nervous system.
Cingulum. Latin. cingulum = a girdle.
In addition to its use in the nervous system, this term may
be applied to other girdles of the body such as the shoulder girdle. From
it, by long corruption, comes the word Shingles, which is the lay term for
the creeping eruption, Herpes zoster, which tends to encircle the thorax
like a girdle.
Cisterna. Latin. cisterna = a reservoir or cistern.
Commissure. Latin. commissura; from con/com = together, and mittere = to
put.
Hence a joining or seam.
Convolution. Latin. con/com = together and volvere = to roll.
Cornu. Latin. cornu = a horn.
Applied especially to horn-shaped structures in the central
nervous system; for example the cornu Ammonis or the horn of Ammon, an Egyptian
name for Jupiter. The same root is also used to indicate anything made of
a horny substance, such as the cornea of the eye.
Cuneus. Latin. cuneus = a wedge.
Decussation. Latin. decussare = to intersect; and decussis
= ten; represented by the symbol X, hence any crossing.
Compare the analogous word chiasm, of Greek derivation. Hippocrates wrote,
"if the wound be situated on the left side, convulsions will seize
the right side of the body," but the observation that the nerve paths
cross had to wait until the sixteenth century.
Dendrite. Greek. dendrites = pertaining to a tree; from dendron = tree,
as in rhododendron.
The term dendrite is used of the processes from a nerve cell.
Diencephalon. Greek. dia/di = through, and encephalon.
Hence the between brain.
Diploe. Greek. diplous = double or folded.
Dura. Latin. durus = hard.
Dura is the femine to agree with mater = mother, for the
original term was dura mater, or the strong mother of the brain. This use
of mater in the sense of protector goes back to the Semitic or Arabic fondness
for fanciful metaphors. Dura mater is said to be Stephen of Antioch's translation
of the term employed by Hali Abbas, the Arabian.
Emissary. Latin. emissarium = a drain; from ex/e = from , and mittein =
to send.
Applied as ananatomical term by Santorini in the eighteenth century.
Encephalon. Greek. encephalon = brain; from en = in, and kephale = head.
Ependyma. Greek. epi = upon, and endyma = a garment.
Hence an outer garment, but in anatomy applied to the lining
of the spinal canal or outer covering of the spinal cord.
Falx. Latin. falx = a sickle.
The flax of the brain is crescent-shaped.
Fasciculu. Latin. diminutive of fascis = bundle or packet.
Fillet. Latin. filum = a thread; descending through the French
fil and its diminutive, filet = a fine thread, but in English the word means
a ribbon or band.
Funiculus. Latin diminutive of funsis = a cord.
Used chiefly, but not exclusively in neuroanatomy.
Ganglion. Greek. ganglion = a swelling.
The term originally meant only a subcutaneous swelling, from
which comes our use of the term for cystic swellings on tendons. However,
Galen limited its application to a swelling on a nerve and it is from this
usage that the word ganglion nowadays is most often applied to a group or
knot of nerve cells.
Geniculate. Latin. geniculare = to bend the knee; from geniculum, diminutive
of genu.
Glia. Greek. glia = glue.
A contraction used as a synonym for neuroglia.
Gyrus. Greek. gyros = a circle.
Our modern words gyrate and gyroscope come from this root.
Hippocampus. Greek. hippos = horse, and kampos= sea monster.
The curved gyrus which bears this name is so called because
its shape suggests that of a well-known sea-horse. The gyrus was well described
by Varolius (1543-1575).
Hypophysis. Greek. hypo = under and physis =growth.
Hence growing under the brain. This is another name for the pituitary
gland.
Lemniscus. Greek. lemniskos = a band of fillet.
Lobulus. Latin. diminutive of lobus = lobes.
Medulla. Latin. medulla = marrow.
Used especially of the nervous system, as is also the term
medullated, which indicates that a nerve fiber is sheathed with myelin.
The adjective describing such fibers is medullary. Medulla is also used
of the non-cortical part of some organs, such as the kidney and adrenal.
Meninges. Greek. menix = membrane; plural, meninges.
The term meninges is reserved for the membranes covering
the brain and spinal cord.
Mesencephalon. Greek. meso = middle, and encephalon (see above).
Myelin. Greek. myelos = marrow (compare to medulla, above), and the ending
in.
Neurilemma. Greek. neuron = nerve and lemma = a husk.
In 1838, Schwann discovered this sheath of the axis-cylinder
of nerves, which is sometimes called after him.
Neuroblast. Greek. neuron = nerve and blastos = germ.
Neurodendrite. Greek. neuron = nerve and dendrite (see above).
Neuroglia. Greek. neuron = nerve and glia = glue.
Neuron. Greek. neuron = nerve.
Hippocrates applied the term neuron to tendons, fascial band
andindeed to all whitish structures. Aristotle limited the word to nerves.
It is now in a still more limited sense. Example: aponeuros.
Oblongata. Latin. oblongus = rather long or oblong.
Oligodendroglial. Greek. oligos = scanty, dendron = tree and glia =glue.
This tissue is composed of small round cells with slender,
inconspicuous, branching processes.
Operculum. Latin. operculum = a lid.
A term used in anatomy applied especially to the brain but applicable to
any lid.
Pallidus. Latin. pallidus = pale.
Parasympathetic. Greek. para = beside, and sympathetic (see below).
A term coined as a name for part of the autonomic nervous system.
Paravertebral. Greek. para = beside, and Latin. vertebra = a joint in the
spine; from vertere = to turn.
The paravertebral ganglia lie alongside the spine.
Pellucidum. Latin. per = through, and lucere = to shine.
Used of the septum pellucidum, through which light can shine.
Pia. Latin. pius =kindly or tender.
Pia is the feminine of pius, which is used in this gender
to agree with mater = mother. This term, pia mater, like dura mater, is
a translation of the fanciful metaphorical phrase of Semitic origin. In
the early Arabic texts, such terms as mother and apple were frequent. Here
pia mater means the tender protector of the brain and spinal cord.
Pineal. Latin. pinea = a pine cone.
Presumably named for the shape of this body.
Pituitary. Lain. pituita = mucous secretion.
In the time of Galen, the mucus from the nose and mouth was
thought to come from the brain, hence this structure was so named. It has
been suggested that the word spit comes from the same origin. It was long
time before Schneider (1614-1680) demonstrated that nasal mucus (pituita)
cam from the glands in the nose, and did not filter through the cribiform
plate of the ethmoid from the brain.
Plexus. Latin. plexus = something woven, a braid.
Pons. Latin. pons = a bridge.
The same root is familiar to us in pontoon.
Posterolateral. Adjective from Latin. posterus = behind, and latus = side.
This is but one of a number of terms compounded with postero-meaning behind.
Precentral. Latin. prae/pre = in front of, and centrum = center.
Pulvinar. Latin. pulvinar = a pillow.
Not a very good name for this part of the thalamus.
Putamen. Latin. putamen = shell (covering) or a paring.
Quadrigemina. Latin. quadric = combining form of quattour = four, and geminus
= twin.
In this form quadrigemina is used sometimes of four, sometimes of eight.
Radicle. Latin radicula, diminutive root of radix = root.
Rhombencephalon. Greek. rhombus = a rhomb or lozenge, and encephalon (see
above).
Rubrospinal. Latin. rubber = red, and spina = the spine.
The name given to the tract from the red nucleus down the
cord. Spina originally meant nothing more than a thorn.
Sella turcica. Latin. sella = saddle and turcica = Turkish.
A descriptive name for the saddle-shaped prominence on the
sphenoid bone. The pituitary gland sits in this saddle.
Solar plexus. Latin. sol = sun, and plexus = something woven.
In this instance the nerves are supposed to radiate like the rays of the
sun.
Splenium. Greek. splenion = bandage.
Applied to any structure whose shape suggests a bandage.
Unfortunately, splenion also means fern, and perhaps the resemblance is
to a fern or frond.
Spongioblast. Greek. spongia = sponge, and blastos = germ.
Spongiocyte. Greek. spongia = sponge, and kytos = vessel or cell.
Stellate. Latin. stella = star.
Hence shaped like a star.
Striatum. Latin. striatus = furrowed.
The neuter form, striatum, is applied to the corpus striatum.
The combing form striato- is used in several combinations, for example in
striatospinal.
Subcortical. Latin. sub = under, and cortex = bark or outer covering.
Applied to anything beneath the cortex of the brain.
Substantia. Latin. substantia = material.
Subtemporal. Latin. sub = under, and temporal.
Subtentorial. Latin. sub = under, and tentorium (see below).
Suprasellar. Latin. supra = above, and sella = saddle.
Applied to anything lying immediately above the sella or
the sphenoid bone. See sella turcica.
Sympathetic. Greek. syn = with, and pathos = suffering. The "n"
or syn is changed to "m" before a labial consonant.
Tapetum. Latin. tapetum = tapestry or carpet.
So named from a supposed resemblance.
Tectospinal. Latin. tetcum = roof, and spina = a thorn or spine.
Applied to pathways passing from the tectum to the spinal
cord.
Tectum. Latin. tectum = roof.
Applied to the roof of the midbrain.
Tegmentum. Latin. tegmentum = a cover.
The upper covering of the cerebral peduncle.
Telencephalon. Greek. telos= end, and encephalon (see above).
Tentorium. Latin. tentorium = a tent.
The name of the fold of dura dividing the cerebellum from
the cerebrum.
Thalamencephalon. Greek. thalamos = an inner chamber, and encephalon.
Thalamus. Greek. thalamus = aninner chamber.
Used to denote the anterior portion of the brain stem.
Torcular. Latin, torcular = a wine press or storage vat; from torquere =
to twist.
Our word torque comes from this root. Torcular is often combined
with the name of Herophilus (335-280 BCE), a physician of Alexandra.
Tuber. Latin. tuber = knot or swelling.
As, for example, the tuber cinereum.
Uncinate. Latin. uncinatus = hook-shaped.
Uncus. Latin. uncus = a hook.
Applied to several hook- shaped structures in the brain.
Velum. Latin. velum = veil or covering.
Adapted from: Pepper, O.H.P. Medical Etymology, Philadelphia: W.B. Saunders
Co., 1949, pp. 45-49.
This page was last updated 1/31/05
The somatic sensory system and pain lecture
Touch (somesthesis)
Purves et al., Chapter 9 (the somatic sensory system) and Chapter10 (pain)
Washington University Medical School's Neuroscience Tutorial has good coverage
on this topic:
Basic Somatosensory
Pathway
Somatosensation from
the Body
Somatosensation from
the Face
General and historical
A very compelling sense, from the pain of a tooth ache to the ecstasy of
an orgasm
considered in domain of "Physiology"
(vision and audition are more in the realm of psychology)
There has been an emphasis on submodalities (qualities such as pain vs.
hot), where modalities refers to different senses like vision and audition
von Frey (turn of the century) - punctate sensitivity - touch forearm with
pencil, sometimes feels cold, sometimes feel pressure.
This approach overemphasized correlation of histoloogical receptor type
with sensory experience.
It fit in well with Muller's (mid-1800's) "doctrine of specific nerve
energies" - in which, if the ears were made to feed in through the
optic nerve, sounds would be experienced as visual sensations because the
quality comes from the nervous system not the physics of the stimulus.
The present view of receptors and axons depends more on nerve type and adaptation,
and the central projection (axon type [A myelinated, C unmyelinated] pathway
[dorsal columns = lemniscal vs anterolateral = spinothalamic]) is critical.
Receptors and axons
Tables 9.1 & 9.2
Much information here (did they forget to fill in conduction velocities?)
- I will emphasize different sizes of myelinated (A) axons, alpha biggest
and delta is smallest, and unmyelinated (C) axons.
Fig. 9.5
Skin (glabrous, there is also hairy)
The different types of receptors (in general, free nerve endings and encapsulated):
Free nerve endings
for pain, temperature and crude touch
the axons are C fibers (unmyelinated) and A delta, also slow
Landmark paper: MMendelson & WR Loewenstein, Mechanisms of receptor
adaptation, Science 144, 554, 1964 (see also J NIH Res., vol 8, 41-45, 1996.
Here is the work attributed mostly to Loewenstein in which he shows that
the Pacinian corpuscle is rapidly adapting because of the layers surrounding
the nerve ending (by dissecting off these layers).
Also, there is an electrical adaptation preventing continued spikes after
stimulus onset.
Pacinian corpuscle - rapid adaptation
A beta axons
Lowenstein - peel to show layers make rapid adaptation
very sensitive, very large receptive field (area which, if stimulated, will
affect the receptor [or higher order sensory nerve])
vibration - 250 - 300 Hz
here is a Pacinian
corpuscle from our histology course
Meisner's corpuscles are fast but not as fast as Pacinian
encapsulation is with Schwann cell layers
most common receptors of fingers, palms and soles
A beta axons
smaller receptive field
"feeling" - active touch - would use fast as finger moves across
textured surface
Merkel's disks are slow and have a small receptive field and are for light
touch
finger tips, lips and genitals
A beta axons
static discrimination of shape
Ruffini slow - large receptive field -
sensitive to stretching in deep skin, ligaments and tendons
A beta axons
also Krauss in lips and genitals (dry vs mucous skin)
Fig. 9.7A
Proprioceptors -
muscle spindles (nuclear bag fibers)
muscle spindle tension presets readiness for reflex, gamma motor neurons
to intrafusal fibers
Ia sensory axon
also Golgi tendon organs Ib afferents
warm and cold
a person can feel a difference of 0.01oC
relation to body temperature
(cold have additional peak at high temp - paradoxical cold - "pins
and needles")
Personal reflection My interest in Drosophila vision started
with an undergraduate project in 1968. In graduate school, I learned that
several scientists had isolated mutants with abnormal vision. DJCosens and
AManning (Nature 224, 285-287, 1969) published "Abnormal electroretinogram
from a Drosophila mutant." I met Cosens one and only one time
in 1978 and asked him "How did you find that mutant?" He told
me it had abnormal mating. By about that time, Baruch Minke, a leader in
that work who I met in 1974, had named the mutant trp (transient receptor
potential) on the basis of its ERG. It is amazing, with hindsight, what
happens when somebody decides to breed that fly and study its progeny.
Recent progress on determining channel properties
C. Seydel, How neurons know that it's cold outside, Science 295, 1451-1452,
2002.
D.E.Clapham, Hot and cold trp ion channels, Science 295, 2228-2229, 2002
cold related to menthol
Fig Chapter 10 Box A
hot related to capsaicin
Fig Chapter 10 Box A
Both involve VR-1 channel with homology to transient receptor potential
(trp) originally discovered in Drosophila because of difficulty in using
visual cues in mating and found not to have sustained photoreceptor potentials.
Fig. 10.2
Pain is faster in A delta fibers than in C fibers
Nociceptors
A delta mechano and mechano-thermal, and C fiber polymodal
Fig. 10.7
Some mediators of pain are in bee and wasp sting venoms (serotonin, histamine,
acetylcholine).
Also tissue damage substances (Table 9.1): , serotonin (platelets), prostaglandins,
leukotrienes,
Histamine from mast cells, substance P
Bradykinin from blood borne precursor - enzyme from injury
Fig. 10.7
In summary, nociceptor is really a chemoreceptor
Nociceptors are in many places, but not in brain, hence brain surgery under
local anesthesia used in mapping studies in humans by Penfield.
Input
Fig. 9.8A
input into spinal cord
Fig. Box 9A
segmental organization of spinal cord - the dorsal root ganglion where input
is
translates into dermatomes - which place is innervated
herpes zoster "shingles" reactivated virus - localized to one
sensory ganglion
Fig. 9.8B
face & head enter via trigeminal nerve
Lower limbs are handled medially in gracile tract.
Upper limbs are lateral in cuneate tract.
ipsilateral projection
First nucleus is in lower medulla
There is a cross-over, and then the next nucleus is in the thalamus.
This lemnicsal system is evolutionarily "new" (reptiles and above)
and is for localized touch.
In projection to the brain, there is processing - lateral inhibition to
sharpen spatial localization.
(This is the first mention of lateral inhibition, a fundamental mechanism
of sensory processing.)
If you tap your forearm, there are big waves but you feel localized touch.
Fig. 10.6A
spinothalamic with synapse and decussation at entry point.
There are separate tracts in spinal cord.
The lateral portion is for pain and temperature.
The ventral (anterior) part is for gross tactile sense.
Hence the nomenclature "anterolateral."
Sharp pain can inhibit inhibit worse pain (example: a hard touch to a door
knob makes an electric shock less annoying)
Jargon -
"neospinothalamic" (more recently evolved) A-delta
"paleospinothalamic" (more ancient) C fibers
A small injury to the former can lead to intractable pain, so "psychosurgery"
can be helpful.
Dull pain (paleospinothalamic, C fiber) has more diffuse projection (see
below) and thus is less localized.
Fig. 10.4
A half spinal cord injury would cause contralateral loss of spinothalamic
below injury and ipailateral loss of lemniscal.
Brown-Sequard syndrome include motor (ipsilateral impairment)
Fig. Box B, Chap 10
referred pain for viscera is interseting
heart attack in neck and left arm
notably, bladder stretch receptors localize pain to genitals
Fig. Box C Chapter 10
Interestingly, visceral pain goes in dorsal columns.
Very useful since midline myelotomy for palliative treatment in terminal
and painful cancer.
Fig. 9.8B
sensation from face - trigeminal
Cell is in trigeminal ganglion and first synapse is in a nucleus at the
mid-pons level.
The diving reflex,
that we study in undergraduate physiology lab, is mediated by the trigeminal
sensory input. There are 3
branches that can be individually manipulated.
Fig. 10.6B
pain from face - trigeminal
Thalamus and cortex
Fig. 9.10
VPL of thalamus to Postcentral gyrus- S1 = areas 1, 2, 3a & 3b
arranged in columns - a vertical electrode penetration same submodality
each S1 nerve responds to only one receptor type
Fig Box B Chapter 9
In sensory map of cortex, all cells as electrode penetrates vertically are
from one area (Mountcastle)
(a) Ocular dominance coumns for vision (Hubel and Wiesel) Nobel
1981
(d) Woolsey - (box) "barrels" from vibrissae (whiskers)
Fig. 9.8
two point threshold
2 mm fingertips, 30 arm, 70 back
this relates to the cortical projection (next:)
Fig. 9.11
sensory magnifications
Penfield - homunculus
Box D, Chapter 10
Phantom limbs and phantom pain
hand maps on face - => plasticity, in that there is a rearrangement in
postcentral gyrus and hand is near face
Higher areas
now thought to be multiple maps not just association area
=> parallel rather than serial processing
Fig 10.8 A
Pain modulation includes an efferent system
periaqueductal grey (PAG) enkephalin
Fig 10.8 B
There are "microcircuits" in the dorsal (posterior) horn of spinal
cord
all sensory input uses glutamate
pain also uses substance P
capsaicin causes release of substance P
Fig 9.7 C
enkephalin from Substantia Gelatinosa interneuron - presynaptic
(of course, opiates are narcotic analgesics)
stimulate - cause analgesia
connect to Raphe
itch - only skin and mucous - opiates not suppress
Exam questions from 2005 - 2007 relating to this outline
What does "trp" stand for when applied to channels?
transient receptor potential
A C (nociceptive) fiber synapses in the dorsal horn, and the post-synaptic
cell ascends in what part of the spinal cord?
antero-lateral system
In the Brown-Sequard syndrome, where is there reduced sensation of two-point
discrimination after a hemisection of the spinal cord?
ipsilateral below lesion
Narcotic analgesics would affect interneurons using what peptide in the
substantia gelatinosa of the spinal cord?
endorphin
In contrast to the anterolateral system for somatic pain, where does visceral
pain ascend?
in center of dorsal column
What aspect of neural organization explains why the irritation of shingles
(Herpes zoster) might be restricted to a small area in the body?
dermatomes
What is the function of bradykinin in sensory reception?
mediator of pain at receptor
A pathway from amygdala and hypothalamus through periaqueductal gray to
dorsal horn modulates what sensation?
pain
Discriminative touch for the face comes into the brain by what nerve?
trigeminal (V)
What aspect of Pacinian corpuscle function did Lowenstein demonstrate by
peeling off layers of the encapsulation?
it is phasic, i.e. responds transiently
Where does a sensory receptor for discriminative touch make its first synapse?
gracile or cuneate nucleus in lower medulla
Tell me a part of the body where the two point discrimination threshold,
measured in mm, is very low. (Pay close attention that "low" refers
to mm.)
finger tips
What is it called when you feel a heart attack in your arm?
referred pain
What sensory receptor has inputs via Group I and II afferent axons?
muscle stretch receptor
What is the difference in information carried in gracile vs cuneate tracts
in the dorsal columns?
lower vs upper parts of body
Why are the hands and face grossly enlarged in the sensory homunculus?
because of increased somatosensory "magnification" (low two point
threshold)
Translate "midline myelotomy is a paliative neurosurgical intervention
for cancer patients whose pain is otherwise unmanageable."
for visceral pain, tract is in dorsal columns, and cutting myelinated fibers
will decrease suffering in terminal patients
A C nociceptive fiber makes its excitatory connection in the dorsal horn
to the cell whose axon is in the contralateral anterolateral system. How
does an enkephalin-containing local neuron mediate descending influence?
the interneuron inhibits via a presynaptic connection to the excitatory
synapse
Why would a Pacinian corpuscle have a larger receptive field than a Merkel's
disk.
being deeper, deformation of a larger skin area would stimulate it
In talking about proprioception, the muscle spindle and the reflex arc,
several different myelinated nerve axons were shown. What are the sensory
axons called?
IA
Capsaicin gates the VR-1 channel that is normally used for what type of
stimulation?
warm
"In summary, the nociceptor is really a chemoreceptor." Name a
chemical.
serotonin, prostaglandins, leukotrienes, histamine, substance P, bradykinin
Where (medial vs lateral) do axons from upper body input travel (relative
to those from lower body) in the dorsal columns?
Lower limbs are handled medially in gracile tract. Upper limbs are lateral
in cuneate tract.
There is somatosensory input from 7 cervical, 12 thoracic, 5 lumbar, and
4 sacral dermatomes. Why doesn't the face input through one of these?
It comes via the trigeminal
"A hemisection of the spinal cord leads to a contralateral loss of
spinothalamic input from below the injury." This is in contrast with
what other loss of what other system?
ipsilateral of lemniscal
About as much of the sensory homunculus is devoted to the lips as to the
legs. Make a statement about two-point discrimination threshold that relates
to this point.
lips, tongue fingers have a 1-2 mm two point threshold, legs and back are
way bigger
In what way is the periaqueductal gray relevant in the somatosensory system?
part of efferent system to modulate afferent input
This page was last updated 3/4/08
The eye and vision lecture
Eye and Vision
"everything there [Emerald City] is of a green color -- just
as everything in this Country of the Gillikins is of a purple color."
"ls everything here purple?" asked Jack.
"Of course it is. Can't you see?" returned the boy.
"I believe I must be color-blind" said the Pumpkinhead, after
staring about him.
--L Frank Baum, The Land of Oz, 1904
Purves et al Chapter 11 covers optics, the eye and the retina, also some
pictures from chapter 12
Note that the Washington University Medical School's Neuroscience Tutorial
has good coverage on this topic:
Eye and Retina
More on color vision and visual transduction can be found in my signalling
course where the text figures refer to Alberts et al., Molecular Biology
of the Cell, 3rd edition, New York, Garland:
Vertebrate Vision
Pep talk
Transduction (how do we get from energy to nerve response?) first and best
understood for light.
Centures old literature on light (e.g. Newton) and color vision
"Medically," vision is very important to the quality of life
"the eye is the window to the brain" -- (NEI phrase) physician
can actually look at CNS.
For instance, increased crainial pressure (like from tumor) shows up as
papilledema
Funding for research and private foundations.
Vision is fundamental to the nature of human experience.
Fig. 11.9A
Rhodopsin is the visual pigment
Protein plus chromophore (11-cis retinal) makes visual pigment
George Wald 1967 Nobel
Prize
Fig. 11.9B
isomerization of retinal
Physics
(A rod can see one quantum, see below)
Energy of one photon = Planck's constant (h) x the frequency (nu)
Frequency = speed (c) / wavelength (lambda)
frequency = for 500 nm (blue-green), 3 x 10 to the 8 m/s divided by 0.5
x 10 to the -6 m = 6 x 10 to the 14 sec to the -1
E = 6 x 10 to the 14 per sec x 6.63 x 10 to the -27 erg-sec = 3.96 x 10
to the -12 erg
Light
Demonstration: A Mercury arc lamp feeds into a monochromator to make monochromatic
lights of the spectrum. In your text, the spectrum is described in Fig.
10-12. We have a monochromator which generates a spectrum using a grating
(the obvious alternative being a prism). On the front of the monochromator
is a slit that picks off a small section of the spectrum. Using another
monochromator, where I could look inside, I obtained this
picture to show how the slit selects a portion of the spectrum. The slit
picks off 6.4 nm/mm, i.e. if it is 1 mm open, it lets through 6.4 nm of
the spectrum. With the slit set at 1 mm, we project the beam onto a screen.
Cranking the monochromator, we go through ROYGBIV (red orange yellow green
blue indigo violet). We note that it is brighter at some wavelengths than
others.I scanned this graph of the spectral output of various light sources
to demonstrate that there are "lines"
in the mercury arc (HBO) spectrum at 580, 550, 438, 405 and 365 nm. At a
setting of about 579 nm, light looks uniquely yellow (Just 5 nm higher looks
orangish, while just 5 nm lower looks greenish). At 365 nm (we need an additional
filter), the screen looks dark but an index card looks blue. That is fluorescence.
A short wavelength excites electron orbitals, then there is some radiationless
deexcitation, so, when the electron falls to its ground state, there is
less energy and a longer wavelength. Neutral density filters are used to
attenuate light. The values are in log to the base 10. A 0.3 log unit filter
would cut the light in half (you do the arithmetic) [it doesn't seem that
much, does it?] and 0.6 would cut it to 1/4. A 0.3 plus a 0.6 is the same
as the 0.9.
Fig 11.14
"Light" is a portion of the electromagnetic spectrum - 400-700
nm
400 is violet, 700 is red
For over a century, it has been known that insects see "near"
ultraviolet (UV) (300-400 nm)
My research contributions in the 1970's concerned UV sensitivity in Drosophila:
site1, site2,
site3
Starting in the early 1980's, researchers showed that various vertebrates,
fish, birds, eventually mice, see UV.
Snakes "see" infrared (IR) (heat of warm blooded prey) with pit
organs - pinhole eye, (reference: RIGamow and JFHarris, The infrared receptors
of snakes, Scientific American, May 1973, 94-100)
Eye dissection
The eye with
orbital fat
The eye with
orbital fat removed clearly showing optic nerve
Here is a sheep
eye showing the exit of the optic nerve
Retina is white
film, black is pigment epithelium
Tapetum gives eye
glow, reflecting light back through retina increases sensitivity for nocturnal
vision
An albino eye
cut around the orbit is better for showing ciliary muscle
Here is the lens
of the eye
Eye structure
Fig. 11.1
the eye picture of an ophthalmologist's office
cornea, iris, pupil, conjunctiva, sclera, extraocular muscles
lens, aqueous, vitreous, retina, fovea, optic n.
there is a blind spot
where the optic nerve exits
Disorders
Fig. Box A
refractive errors
diopters - reciprocal of focal distance in m
cornea is 0.024 m, 42 diopters
Emmetropia-normal,
Hyperopia-far-sighted, need convex lens,
Myopia-near-sighted, need concave lens, involves abnormal elongation of
the eye
visual angle, acuity - Snellen eye chart - 20/20 is seeing letter 5 min
(1/60 degree)
1980's radial keratotomy (RK)
LASIK
Both change shape of cornea
Fig. 11.2
Presbyopia
Accomodation
TRANSPARENCY Fig from another book,
(1) ciliary muscle relaxed, suspensory ligaments taut, lens thin for distance
vision
(2) ciliary muscle contracted, suspensory ligaments relaxed, lens thick
for near vision
loss of accomodation with age explains Presbyopia
Benjamin Franklin developed bifocals
Other disorders:
Glaucoma
pressure is too high because aqueous humor does not drain well, ganglion
cells die, treated with drops or surgery, canal of Schlemm
Floaters
in vitreous especially in people with myopia
Diabetic retinopathy
blood vessels overgrow, leak, blast holes in retina with laser decreases
angiogenesis
Cataract
lens becomes opaque, remove and often replace with intraocular lens, made
of polymethyl methacrylate, known to be tolerated since pieces from airplane
visors would lodge in pilots under fire (and since about 1988, these have
been doped with UV blockers)
Humans see UV, but only if the lens is removed (aphakia), one of my
interests.
Retinopathy of prematurity
High O2 in incubator causes overgrowth of blood vessels
"Little" Stevie Wonder
Fig. 11.3
ophthalmologists view of eye
optic disk = papilla (where optic nerve exits and site of blood supply)
fovea, site of high acuity (cone vision) - point of fixation
Macula lutea pigment
This picture
better shows a yellow pigment that absorbs blue light
Box B (Chapter 11)
demonstrates the blind spot
Fig Box D Chapter 11
Retinitis pigmentosa is tragic, people can see when young, lose rod vision
(tunnel vision [ring scotoma] because rods are in mid-periphery).
Rods go first and eventually cones which is strange if rod molecules are
mutant.
There are autosomal and X-linked types, dominant and recessive.
There are other genetic degenerations and stationary (not progressive) blindnesses
are in molecules of transduction cascade as well as in other rod and cone
molecules.
There is a web site where information relevant to the retina, especially
genetic causes of blindness, accumulates (site)
Box C Chapter 11
Age-related (it used to be called "senile") macular degeneration
(AMD)
People about 80 yrs old lose high acuity vision (cannot read)
"Wet" (10%) is a sudden and treatable (laser surgery) medical
emergency from blood vessel leaking
"Dry" complicated but may have an genetic basis too, worse in
smokers
More on genetic blindnesses can be found in my signalling course:
Retinitis pigmentosa
and age related macular degeneration
Rods and Cones
Fig. 11.5C
Photoreceptors- 125 million receptors 20/1 rods to cones
(converge on 1 million ganglion cells)
Fig. 11.13A
Rod and cone number as a function of visual angle [angle is the way to express
it] (note blind spot)
Rod, peripheral vision, dim black and white, sensitive - "scotopic"
[Explains ring scotoma (loss of vision in mid periphery) in RP]
Very sensitive - 1 photon
Landmark paper
People can see light of 6-14 quanta over a 500 rod area (SHecht, SSchlaer
and MHPirenne, Energy, quanta and vision, J. Gen. Physiol., 25, 819-840,
1942)
Cone, fovea, color, acuity - "photopic"
Shown in rats, rods are supported by retinal
pigment epithelium
Fig. 11.6
disk shedding
RPE: (1) melanin that blocks light reflection
(2) metabolism to provide 11-cis retinal (chromophore ofvisual pigment,
rhodopsin)
(3) phagocytosis and recycling of shed rod tips
Cells are postmitotic and the indigestible residue of the phagolysosomal
system is lipofuscin,
a fluorescent aging pigment, a topic on which I've done research.
Fig. 11.13B
fovea is pit without rods and with cells and blood vessels out of the way
Color vision
PKKaiser The Joy of perception, a web book
Follow leads, table of contents, 3-fun things in vision, afterimages
Fig. 11.14A
spectral sensitivity of rods and 3 cone types
confirms Young -Helmholtz trichromatic theory
3 kinds of cone 420 530 560
3 kinds of cone opsins which are evolutionarily related in humans and OW
monkeys
Fig. 11.16
green and yellow (middle and long wavelength) cone opsins are near each
other on X
(blue cone opsin is on human chromosome 7, rod on chromosome 3)
Fig. 11-14B
technique to see cones
evolution
bottleneck hypothesis color vision re-evolves after nocturnal life (where
adaptive pressure for cone vision is relaxed) early in mammalian evolution
Red or green color blindness - on X, thus preferentially in males.
Blindnesses were thought to be from altered genes, but numbr of copies in
human population is variable, and cross-over accidents can even make chimeric
genes.
Female "carriers" should actually be mosaics of color blind vs
normal retina because of Mary Lyon X-inactivation hypothesis
See recent evolution in superfamily of G-protein-coupled receptors (7 transmembrane
domain receptors)
Phototransduction
I was in graduate school when a seminar speaker (also in a paper) argued
that the separation of disks from the plasmalemma meant that there must
be an intracellular signal that diffuses across the cytoplasm; at that time,
they thought it was Ca2+
Fig 11.7
response is hyperpolarization
response is slow (this is cone, rod is even slower)
"You can walk through the forest with nothing but starlight, but you
cannot run."
Fig. 11.9
details of transduction cascade
Stacks of disks. Lumen is like outside cell
vitamin A is the chromophore
Transducin activates cGMP PDE, less cGMP (ligand) and channel closes so...
Fig. 11.8A
...cell hyperpolarizes...
Fig. 11.8B
...since sodium channel closes.
Retinal processing
Fig. 11.21A
center surround (excitation vs inhibition or vice versa) receptive fields
This kind of processing emphasizes contrast detection.
Feature detection - introduction and summary
Lateral inhibition H. K. Hartline - 1967 - Nobel
"primary physiological and chemical visual processes"
Limulus horseshoe crab
Mach (Ernst) bands - see edges (bright-dark contrast) especially well
TRANSPARENCY
(from Classic paper W.H.Miller, F. Ratliff & HK Hartline, How
cells receive stimuli, Scientific American, September 1961, 222-238)
at a light-dark boundary the response "boundary" from the array
of corresponding nerves is exxagerated
TRANSPARENCY
(from Classic paper F. Ratliff, Contour and contrast, Scientific
American, June 1972, 90-101) The moon seems bright because it is next to
a dark edge, relative to the nearby sky which is next to a shallow gradient
of dark.
Personal reflection. When I applied to graduate school, Rockefeller
invited me down for an all day interview (since I was already in Manhatten
at Columbia College "the gem of the ocean"). Lunch (and a lab
tour) was with Floyd Ratliff. Unfortunately for me (I was rejected by Rockefeller),
I thought he was mispronouncing "stimulus" when he kept saying
"Limulus." I learned about Limulus the very next week in physiological
psychology. (You never know when the knowledge you are armed with will come
in handy.) Oh well. I went to Wisconsin (go Badgers!) and loved it so much
that I gave them my first born.
Purves home page interactive Demos,
find Craik-O'Brien-Cornsweet
Blobs in Hermann grid (Michael Bach, follow leads Optical
illusions and visual phenomena, 6 down 2 over - Hermann grid) explained
by more inhibition at corners
Sensory processing (in lots of sensory systems) uses lateral inhibition
to give feature detection, which for vision is color, contour and contrast
and movement. In other words, the brain does not keep track of a point by
point stimulation of each rod and cone, but rather reduces that information
into evolutionarily (depending on the species) relevant fetures. The retina
does this by lateral connections, and the input to the nervous system, like
at the thalamus and cortex, processes further.
Lower animals, like frogs (with less brain power) have more retinal processing
(since there is less that can be done in the brain). The process of lateral
inhibition gives feature detection, for features such as contrast and movement.
Some ganglion cells in frog retina fire preferentially to small dark spots
moving rapidly through receptive field ("bug detectors"). The
idea is that there are ganglion cells which fire only with quickly moving
small dots, stimuli resembling flies which frogs must detect expeditiously
in order to catch them on their sticky tongues.
Classic Paper J.Y.Lettvin, H.R.Maturana, W.S.McCullock & W.H.Pitts,
What the frog's eye tells the frog's brain, Proceedings of the institute
of radio engineers, 1959, 47, 1940-1951.
Primate ganglion cells -
Magnocellular (large) 10% - movement
Parvocellular (small) 90% - form and detail
cat ganglion cells -
morphology and function WXY
color opponent cells
Fig. 11.18AA
glutamate is "excitatory" transmitter (usually would give an EPSP)
released in dark - but less glutamate in light on
off bipolars respond (depolarize) to increased glutamate (dark) with EPSP
off thus hyperpolarize to light and decrease firing of off ganglion cell
on bipolar hyperpolarize to glutamate (dark) probably through metabotropic
thus on depolarize in light and increase firing of on ganglion cell
Fig. 11.17AB
all this comes in center surround organization mediated by horizontal connections
Color contrast
(not well covered in book)
If red in center of visual field excites ganglion cell filing, then red
in periphery inhibits.
In this same cell, green in periphery excites and green in center inhibits.
Also there are cells that are the opposite.
In the LGN, there are center - surround cells and color processing
End
My interests center around vision, so a visit to the
research interests of my home page will offer various topics about vitamin
A, ultraviolet light, and Drosophila mutants. Dr.
Fliesler in SLU's Ophthalmology Department and Dr.
Ariel in SLU's Anatomy and Neurobiology Department are some of my fellow
wizards in visual science.
Exam questions from 2005 - 2007 relating to this outline
Hartline won a Nobel Prize for showing that lateral inhibition contributes
to detection of what feature in Limulus?
contour and contrast
What is the specific defect in AMD (age-related macular degeneration)?
cone vision in fovea
If stimulation in the center of the receptive field of an on-center ganglion
cell increases firing a lot, how would stimulation of the whole receptive
field with the same intensity affect
firing?
way less
Out of the "corner of your eye," you see a dim star. You do not
see it when you look right at it. Why can you see it when you look away
from it?
rods are more sensitive and they are off fovea
When would you use Planck's constant in calculations concerning sensory
transduction?
to calculate the energy of a photon of light
How does PDE (phosphodiesterase) affect the membrane potential in the rod?
decreases cGMP, channel closes, cell hyperpolarizes
Why is there a "ring scotoma" (dougnnut-shaped blind area) in
people afflicted with retinitis pigmentosa?
rods go first, that is where they are prevalent
"There are bug detectors in the frog retina." State this in a
less casual way.
Movement of a small dark spot in the receptive field preferrentially increases
firing in some ganglion cells.
"Three nuclear layers and two plexiform layers" describe the histology
of what sensory structure?
retina
What is the status of cation channels of rods in the dark?
open
Unless something is wrong with them, the proteins in the cornea and lens
transmit light quite well. How come, by contrast, the G protein-coupled
receptor (rhodopsin) absorbs light?
is has a chromophore, a pigmented portion, 11-cis retinal
Capillaries are in the choroid, a pigmented layer behind the retinal pigment
epithelium. Why is it that an ophthalmologist can see the other blood supply?
those pass on the vitreal side of the retina
Scotopic sensitivity would be highest at about 15o off fovea. Why?
that is where rod concentration is highest
The age pigment, lipofuscin, is the indigestible residue of the phagolysosomal
system. How does this apply to the rods and retinal pigment epithelium?
rods shed their tips and the RPE phagocytoses them
What is the cause of blindness in diabetes, and how does laser photocoagulation
of the retina slow the progression of diabetic retinopathy?
angiogenesis, formation of new blood vessels that leak, burning out part
of retina, though it causes some vision loss, inhibits angiogenesis
How come surgical manipulations of the cornea such as LASIK and RK can be
so effective in correcting myopia?
because the curved cornea-air interface, with its huge difference in index
of refraction, is a powerful lens and these surgeries change the shape of
that lens
What is the name and cause of the disorder that makes people over 40 need
reading glasses or bifocals?
presbyopia is from stiffness of the lens
"You can walk through the forest with nothing but starlight, but you
cannot run." Why not?
phototransduction is slow especially in rods
Pick a person, any person. How many copies of middle- and long-wavelength
(green- and yellow-) coding genes would you find on one X chromosome?
cannot say. could be one, 2 or even more
You are recording intracellularly from a rod. What would happen if the cGMP
decreased?
it would hyperpolarize
What is the term for the enhancement of contour-contrast information in
which the gradient of neural responses across the retina is more exaggerated
than the intensity gradient?
hyperpolarization, feature detection, Mach bands
"Magnocellular" and "parvocellular" are terms applied
to retinal ganglion cells based on size and processing (movement vs contrast
respectively). What is the difference in projection to the brain?
they project to different layers in the LGN. M-> 1 & 2, P -> 3-6
Long before they could record intracellularly from single rods or cones,
they knew that a rod could see a single photon of light. How?
testing whether subjects could see carefully calibrated lights (psychophysics)
Under what circumstances would a person be able to see ultraviolet light?
if the lens is missing
"The blue cone opsin is on human chromosome 7 while rod rhodopsin is
on 3." Where are the genes for yellow- and green-absorbing opsins?
the X
There is a huge amount of phagocytosis that retinal pigment epithelium (RPE)
cells must do. Phagocytosis of what?
the tips of rod outer segments are shed daily
"The blind spot is at about 15o on the nasal retina at the horizontal
plane." Why is there a blind spot?
there can be no receptors where the optic nerve exits
Abnormal elongation of the eyeball is associated with what refractive error?
myopia
Cones would be preferentially damaged in what debilitating disorder affecting
the elderly?
age related macular degeneration (AMD)
A woman has lots of sons, half red-blind (protanopic) and half with normal
color vision. How would her retina be with respect to red color vision?
mosaic
Specifically, what gates the channels in the rod plasmalemma?
cGMP
Hartline found that there is increased firing from brightly lit facets (of
a crab's eye) near a dark area than a brightly lit area near only brightly
lit areas. Why?
less inhibition
Rhodopsins (such as the 4 of rods and cones) are sometimes called visual
pigments, yet proteins usually do not absorb visible wavelengths of light.
What makes rhodopsin a pigment?
11-cis retinal
This page was last updated 3/6/08
The brain and vision lecture
Brain and Vision
Purves et al., Chapter 12 (and bits of Chapters 11 and 24)
Note that the Washington University Medical School's Neuroscience Tutorial
has good coverage on this topic:
Central Visual Pathway
Projection to Brain
Fig. 12.1
Overall Visual Projection
Eye -> LGN (Lateral geniculate nucleus, genu= knee, part of thalamus)
-> striate cortex
Temporal retinal field = nasal visual field stays ipsilateral at chiasm
Nasal retinal field = temporal visual field crosses to contralateral side
at chiasm
From LGN to striate cortex = area 17 = V1
Retinotopy (like somatotopic organization) is preserved
*Eye -> pretectum - pupil size (iris) and control of lens (accomodation)
Eye -> superior colliculus - eye and head movements (Chap. 19)
Eye -> hypothalamus - to regulate circadian rhythms (see, in chapter
27)
*Fig. 12.2
pupillary reflex
Pretectum -> Edinger-Westphal nucleus -> cranial nerve III->ciliary
ganglion ->parasympathetic fiber.
Note connection to both ipsilateral and contralateral sides after pretectum,
so pupillary reflex should be bilateral.
Kids, go ahead and try this.
Important test in neurology.
Fig. 12.13 A & B
Thalamus
Cells have center - surround receptive fields like ganglion cells
1, 4, 6 contralateral -- thus 2, 3, 5 ipsilateral
Fig. 12.15A
large and small retinal ganglion cells
Magnocellular - large receptive fields for processing movement - connect
to LGN 1 & 2
Parvocellular cells connect to layers 3, 4, 5, & 6 and process color,
also for acuity
Cortical processing
Landmark papers
DHHubel & TNWiesel, Receptive fields, binocular interaction and functional
architecture in the cat's visual cortex, JPhysio, 160, 106-154, 1962
TNWiesel, DHHubel & DMKLam, Autoradiographic demonstration of ocular
dominance columns in the monkey striate cortex by means of transneuronal
transport, Brain Res 79, 273-279, 1974 (see also J NIH Res, 5, 61-67, 1993)
DHHubel & TNWiesel, Brain mechanisms of vision, Scientific American
September 1979 (vol 241, #3), pp 150-162.
Tom Yin's home page, follow
links, Simple cell is a good video to show how work was done
Fig. 12.8 A & B
cat (monkey) looks at screen, cell responds best to line at angle
Striate cortex - physiology and anatomy
Hubel & Wiesel share 1981 Nobel
for "information processing in the visual sytem"
Fig. 12.11
there are vertical columns of preferred angle (just like in somatosensory
system)
presumably, to prefer line at angle, cell receives inputs from from alligned
center surround cells
these are called simple cells
complex cell - line at algle moving in direction
hypercomplex cells - line has end - corner
vertical electrode penetration gives cells with all the same preferred angle
an oblique penetration tracks different angles
Note that there are 6 layers of cells, IV has inputs from LGN
"Philosophical question" -- does processing get to more and more
levels of complexity until you find "grandmother cells" which
recognize, specifically, your grandmother's face?
Fig. (like 12.13 B & C)
experiment to determine ocular dominance columns (0.5 mm wide)
There are cortical cells with input from one eye, from the other eye, and,
in between, from both eyes.
Binocularly driven cells should be necessary for stereopsis, the kind of
depth perception which relies on the focussing of both eyes.
Fig. 12.14
Apparently, cells can preferentially respond to disparity from fixation
depth-perception
stereopsis
Even higher order visual processing
With all that color processing in the LGN, it seemed odd how far the work
on the cortex got without any mention of color
Fig. 12.16A
V4 - color but not movement
MT (middle temporal) - direction of movement but not color
Fig. 12.18
parietal stream - spatial vision
temporal stream - object recognition
Development of visual connections
Fig. 24.3
If a radioactive amino acid is injected into one eye, labeled proteins cross
synapses at LGN and mark ocular dominance columns in cortex; this is detected
by microscopic autoradiography.
Binocular cells connect up correctly at first
Fig. 24.4
Then there is a sensitive (critical) period in the first few months of life
during which patterned visual input from both eyes is necessary to maintain
binocular input to cortical cells.
Thus early visual defects like cataract or strabismus (cross-eyes or lazy
eye) need to be corrected right away.
Here are autoradiographs.
A of normal visual cortex, nd B after monocular deprivation from 2 weeks
to 18 months in monkey
Exam questions from 2005 - 2007 relating to this outline
How would you test whether a patient's contralateral connection from the
pretectum to the Edinger-Westphal nucleus were disrupted?
light to one eye would not consstrict the contralateral pupil
Specifically, what crossed the LGN (lateral geniculate nucleus) synaptic
cleft to allow Hubel to see the ocular dominance columns using autoradiography?
3H labeled protein
Where do the axons of the the temporal retina (nasal visual field) go at
the chiasm?
to ipsilateral LGN
What is the word for the special type of "depth perception" mediated
by the parallax from focussing both eyes (and neural interactions of binocular
cells)?
stereopsis
If a child were born with a congenital cataract in one eye, why should this
deserve immediate attention?
brain connections from that eye would vanish without patterened vision
Light stimulation to one eye activates that eye's optic nerve. By what mechanism
would there be efferent output to the iris from both occulomotor nerves?
connection to one pretuctum goes bilaterally to Edinger-Westphal nuclei
The inputs from the two eyes to the lateral geniculate nucleus do not mix.
In what manner are they kept separate?
they go to different layers, contralateral to 1, 4, & 6, ipsilateral
to 2, 3, & 5
A thin bar of light made the simple cell fire quickly. Why did a wider bar
not do likewise?
Because the wider bar also hit the inhibitory areas in the receptive field
of that cell
What technique did Hubel and Wiesel use to get that picture of the visual
cortex with stripes?
Autoradiography, or, inject radioactive amino acid into one eye and observe
the protein transported transynaptically from ganglion cell across LGN to
cortex
As an electrode is advanced obliquely across columns in the visual cortex,
what changes?
One could say preferred eye of input or one could say preferred angle of
line
Why did Hubel and Wiesel feed their microelectrode amplifier into a loud
speaker?
easy to judge firing rate by the sound
Why did a wide line centered on the simple cell's receptive field elicit
less of a response than a narrow line?
even though it stimulates the excitatory receptive field, it also stimulates
the surrounding inhibitory ones
While an electrode is advanced obliquely through the cat's visual cortex,
first the left eye predominates, then the right eye. What else has been
changing during that advancement?
preferred angle
When is the critical (sensitive) period for development of binocular connections
in the cat visual cortex?
birth to 2 & 1/2 mo
When autoradiography was used to demonstrate ocular dominance columns, how
did the film (photographic emulsion) get exposed?
radioactivity (in cortex protein) exposed film in the dark
This page was last updated 3/18/08
The Audition and Vestibular sense lecture
Audition and vestibular system
Purves et al., Chapters 13 and 14 respetively
Note that the Washington University Medical School's Neuroscience Tutorial
has good coverage on this topic:
Auditory and Vestibular
sense
Sound
(not all of this is in the book)
Intensity dB = 20 log (pressure 1/pressure2)
standard is 0.0002 dynes/cm2
Threshold amplitude of vibration is 10-11 m (10 pm)
Fig. 13.1
waves of compressions and rarefactions of air (must have medium) described
by sine wave
Frequency Hz cycles per sec
vibration - 20 - 20,000 Hz, above which is ultrasound .
Audibility curve - Intensity [dB] vs log (freq) [Hz] very sensitive
Ear
Fig. 13.3
Ear structure
pinna, eardrum=tympanic membrane, ossicles, cochlea, part of nerve VIII
= cochlear nerve
hammer, anvil, stirrup=malleus, incus, stapes - to match impedance of air
-> fluid
Eustachian tube
oval window is "inner ear drum"
20:1 "amplification" tympanic to oval
cochlea near vestibular apparatus
Fig. 13.4
higher magnification, most importantly basilar and tectorial membrane
also inner hair cells (with afferent neurons) and outer hair cells with
efferent axons
possibly outer hair cells do some motor thing to sharpen frequency discrimination
Frequency discrimination
Background.
At about 1000 Hz, you can tell the difference of a few Hz. This is explained
by Helmholtz's place theory as modified by lateral inhibition as described
in Bekesy's (1961) Nobel
Prize winning work. You can get the audio oscillator calibrated to be slightly
different from a tuning fork by listening for beats. At low frequencies,
frequency discrimination is better explained by Rutherford's telephone theory.
Here, frequencies to both ears can cause neural impulses that stay true
to the frequency so that beats can be from neural comparison from the two
ears.
Demonstration.
Two tuning forks that are near but not identical give beats if you listen
to them simultaneously. Beats arise from the constructive and destructive
interference of sound waves at the physical level. There would be one beat
per second if the two tuning forks differed by 1 Hz. Then, if the tuning
forks differ by a few Hz, you can hear the difference in pitch if you listen
to one then another.
For low frequencies:
Landmark paper
G. Oster , Auditory Beats in the Brain, Scientific American, Vol 229, October
1973, pp. 94-102
Back to Lecture.
Fig. 13.5
Vibration of basilar membrane is mapped by tonotopy
fluid vibration at oval window through helicotrema
released at round window
Frequency discrimination is mapped at high frequencies this way
Frequency discrimination very good - 2 Hz at 1000 Hz
Georg von Bekesy's data pertaining to Helmholtz's place (resonance) theory
1961 Nobel "physical mechanism of stimulation within the coclea"
Fig. 13.11
"tuning curves" at different frequencies
for receptor is broad, while for higher order nerves, it is sharp
Lateral inhibition in ascending path sharpens tuning curve
Basilar membrane - high vs low maps to "place" in cochlear nerve
- there is a frequency mapping on the cortex
tonotopy - in A1 = Brodman # 41
Fig. 13.11
Frequency discrimination at low frequencies
there was another theory, Rutherford's "telephone" theory
phase-locking gives volley principle up to 4 kHz
Fig. 13.15
map of cortex tonotopy
Auditory transduction
Fig. 13.4
Fig. 13.6
hair cells on basilar and tectorial membranes
3,500 inner hair cells
many more outer hair cells
Bend as basilar membrane vibrates relative to tectorial membrane
Recent paper
IABelyantseva et al., Myosin-XVa is required for tip localization of whirlin
and differential elongation of hair-cell stereocilia, Nature Cell Biol,
7, 148-156, 2005
Myosin-XVa is product of shaker2 gene
whirlin is product of whirler gene
mutants cause deafness and improper detection of head movement.
Stereocilia need to be different lengths, shaped like a staircase, deficient
in mutant
Myosin transports whirlin to tips
Fig. 13.7
EM. Note kinocilium vs stereocilia (B) and tip links (D)
Fig. 13.8
and
Fig. 13.9
kinocilium (real cilium, missing in post-natal human hair cells)
plus about 30 stereoocilia
mechanoreception assisted by tip links - depolarization if move toward kinocilium
hyperpolarize if in opposite direction
Threshold displacement is about 0.3 nm, electric potential in 10 micro seconds
Recent paper
SSidi et al., NompC TRP channel required for vertebrate sensory hair cell
mechanotransduction, Science 301, 96-99, 2003.
TRP discussed n somatosensation.
and smell and taste.
NompC=no mechanoreceptor potential (in Drosophila bristles) also
in C. elegans.
In this paper, it is shown that this is a hair cell channel in zebrafish
Danio rerio.
Fig. 13.10
perilymph is fluid of scala vestibuli and scala tympani is like CSF - bathes
baso-lateral hair cell
High K+ in endolymph of scala media (bathing hairs)
stria vascularis (endothelium lining scala media) pumps ions to produce
this unusual extracellular fluid
thus when channels open, K+ comes into cell
endocochlear potential endolymph 80 mV more + than perilymph
Projection
Fig. 13.12
Very complex- but eye does have synapses in eye (retina), while ear does
not
Auditory nerve to dorsal and ventral cochlear nucleus - no crossing
Then connect in superior olivary nucleus ipsi- & contra- lateral
whose postsynaptic cells, in turn, go to inf. colliculus
Postsynaptics of inferior colliculus go to Medial Geniculate Body
Medial Geniculate to ipsilateral auditory cortex
Fig. 13.15
various parts of auditory cortex
Auditory localization
difference in time of arrival and intensity (in big headed animals) [human
700 micro sceond difference]
(speed of sound 1087 ft (331 m) / s in air)
Localization up and down does not rely on 2 ears, may relate to pinna
small-headed animals are extraordinary
Fig. 13.13
medial superior olivary nucleus important for coincidence detection of time
of arrival
phase locking important in input - barn owls good at this
Fig. 13.14
lateral superior olive (and median nucleus of the trapezoid body) calculates
on the basis of intensity difference
Ultrasound
bat echolocation biosonar
bat nocturnal, predator, insect "flickers"
moths avoid bats
medial geniculate important
Disorders
Box A hearing loss
conduction deafness, nerve deafness
also tinnitus - ringing in the ears
Vestibular sense
lecture is not as detailed as text.
Fig. 14.1
utricle and sacculus linear motions
3 semicircular canals - rotations
Fig. 14.3
stones
Fig. 14.4
stones (otoconia) provide mass for bending in utricle and sacculus
striola divides hair cells with differing polarities
Fig. 14.7
Ampulla and cupula displaced as semicircular canal fluid is displaced
Fig. 14.10
circuit for eye movements
involving Scarpa's ganglion, vestibular nucleus, abducens (VI) nucleus and
oculomotor (III) nucleus
Box C - neurology done by irrigating one ear with cold water
Fig. 14.11
vestibulo spinal control from vestibular nucleus (integrates with cerebellar
input) to lateral vestibulospinal tract and medial longitudinal fasciculus
Fig. 14.12
also projection to integrate with somatosensory and muscle spindle senses
Exam questions from 2005 - 2007 relating to this outline
What does the striola divide?
two sides of utricle or saccule with mirror imazge hair cells
A tip link helps in the opening of a channel to what ion?
K+
Bekesy won a Nobel Prize for showing that Helmholtz's place theory was fundamentally
correct but that the localization was much more crude than Helmholtz envisioned.
How did
he rationalize this discrepency to account for very narrow tuning curves
and high resolution localization higher up?
lateral inhibition
What is unusual about the axons connected to the outer hair cells (in contrast
with those for the inner hair cells)?
they are efferent
The medial lemniscus is part of what system?
auditory
What kind of stimulus do bats use to find moths at night?
ultrasound
The cupula and the ampulla are part of what system?
vestibular (semicircular canals)
How do stereocilia differ from the kinocilium structurally?
they lack 9+2 microtubules
For what aspect of hearing is the speed of sound relevant?
auditory localization
A pathway from vestibular nuclei through nuclei for cranial nerves III and
VI is important for what behavior?
eye movement, vestibular ocular reflex
When the audio oscillator and tuning fork are a few Hz apart at about 1000
Hz, what explains beats that you hear with one ear?
constructive and destructive interference of sound waves
Endolymph and perilymph are both extracellular fluid compartments. Why is
there an 80 mV potential where the endolymph is more positive than the perilymph?
because of the high potassium ion concentration in the endolymph
Depolarization of the inner hair cell causes entry of calcium ions. What
effect do these calcium ions have?
release of synaptic transmitter vesicles
What is the difference in localization of vibrations for low vs high frequencies
in the basilar membrane?
low toward helicotrema, higher toward stapes
Neurons of the olive were diagrammed in your book involved in sound localization.
Why are there no such neurons in the spiral ganglion or in the cochlear
nuclei?
they do not have inputs from both ears
Between the inferior colliculus and the auditory cortex is a synapse in
what specific relay station?
medial geniculate of thalamus
Hair cells are located only in a bulge, not throughout the semicircular
canal. What is this bulge called?
ampulla where cupula resides
Name one of the two compartments connected by the helicotrema.
scala vestibuli and scala tympani
Describe the results leading to the conclusion that there is tonotopic organization
of the primary auditory cortex.
rostral part responds to low freq & caudal to high
Mutants of the whirler gene cause improper detection of head orientation.
Why is it no surprise that the animals are also deaf?
affects stereocilia, and hair cells are used in hearing and balance
There is an 80 mV endocochlear potential between the endolymph and the perilymph.
Why?
endolymph has high K+, perilymph low
In terms of ions or potential, what causes release of transmitter vesicles
in auditory receptor cells?
influx of K+ causes depolarization causes transmitter release
What is missing in the following list of sites for auditory synapses: (Cochlear
nuclei, nucleus of lateral lemniscus, inferior colliculus, medial geniculate
of the thalamus, and primary auditory cortex)?
superior olive
What notable control does the vestibular apparatus exert in addition to
descending influences to the ventral horn of the spinal cord and input to
the sensory cortex?
eye movements
This page was last updated 3/18/08
The olfaction and gustation lecture
The Chemical Senses
...taste, being the lowest or least intellectual of our five senses,
is incapable of registering impressions on the mind;consequently, we cannot
recall or recover vanished flavours as we can recover, and mentally see
and hear, long-past sights and sounds. Smells, too, when we cease smelling,
vanish and return not...
W. H. Hudson, Far Away and Long Ago, 1918
Purves et al., Chapter 15 (organization somewhat odd, outline does not
follow chapter).
This chapter has been wonderfully updated!
There is a slightly more advanced lecture on this topic, based on papers
rather than text, for my 2002 signal transduction course: Chemical
senses. The text figures referred to in that outline are to Alberts
et al. Molecular Biology of the Cell (3rd edition) Garland.
Taste (Gustation)
VGDethier, To know a fly, San Francisco, Holden-Day, 1962. Flies taste through
hairs on legs and are attracted to sugar accordingly.
Taste is a term applied to chemicals dissolved in water.
Many "flavors" are smell
Receptors
Fig. 15.16
Tongue
Hanig (1901) - preferential localization:
sweet - tip of tongue
salt - front sides of tongue
sour - back sides of tongue
bitter - back middle of tongue
The correlation is not exclusive is not really true.
Papillae:
Circumvallate back of tongue
foliate sides of tongue
fungiform front of tongue
also receptors in epiglottis
Fig 15.16 & 15.17
Several types of papilla including the circumvallate papillae on the back
of the tongue, shown in this picture
from our histology
course
Within each papilla are numerous clusters of cells called taste
buds shown in this histology picture. support cells, sensory cells,
and basal cells
As with olfaction, a unique feature is the turnover of receptor cells
Recent paper Note that there are genetic taste "blindnesses"
Ptc = phenylthiocarbamide, taster is dominant.
Use taste vs. non-taste to screen for G-protein coupled receptors (M. Barinaga,
Family of bitter taste receptors found, Science 287, 2133-2135, 2000)
Demonstration PTC taste test strips
Recent paper. Denis Drayna, Founder mutations. Scientific American
Oct 2005, 78-85. (There are also several letters to the editor and reply
Feb 2006, 12-14)
"...seven different forms of the PTC gene exist in sub-Saharan Africa.
But only the major taster and nontaster forms have been found...outside
of African populations."
taster detects chemicals with C=N-S
They suggest
(1) taster and nontaster are ancient
(2) tasters and nontasters populated the world as in the "Out of Africa"
hypothesis
(3) these people did not interbreed with others (like Neanderthals).
only taster in all other primates
Recent paper U-K Kim et al....D. Drayna, Positional cloning of the
human quantitative trait locus underlying taste sensitivity to Phenylthiocarbamide,
Science 299, 1221-1225, 2003
In small area of human chromosome 7q, there are nine TRA2R (bitter taste
genes) and 7 olfactory receptor genes in this area.
PTC is 1002 bp and 1 exon
3 single nucleotide polymorphisms (SNPs) explain PTC taste insensitivity,
A49P, V262A, I296V
A colleague and friend of mine, Charles
Zuker, made important recent contributions isolation of taste receptors
T1R1, T1R2, T1R3, T2R, also the involvement of the TRP channel. Earlier,
he made tremendous contributions in Drosophila phototransduction. HHMI =
Howard Hughes Medical Institute which has helped to fund innovative and
productive scientists like Charles. There are easy to read HHMI press releases
here.
Fig. 1517
generally, channel or G-protein linked receptor ultimately increasing calcium
somehow for synapse
note receptor does not have axon
Fig. 15.18AB
salt - amiloride blocked Na+ channel opens (depolarization)
sour - pH sensitive K+ channel closes (depolarization)
also amiloride blocked Na+ channel
Fig. 15.18CD
sweet - G-protein linked cAMP close K+ channel - depolarize
receptor is T1R2-T1R3
umami (glutamate) - and amino acids, channels as well as G-protein cascade
receptor is T1R1-T1R3
This is very unusual! (G protein linked receptors in dimer)
Note, here is the TRP (transient receptor potential) channel again
Fig. 15.18E
bitter -G-protein cascade involving PLC or quinine sensitive K+ channel
"gusducin" (like "transducin" for vision) is term for
heterotrimeric G protein
receptor is T2R
Tuning
(how selective is receptor?)
work by Carl Pfaffman, 1941, & since - receptors are not all that specific
Contradicted by very modern data supporting "labeled line hypothesis"
(well covered in book).
This applies to G protein coupled receptors, T2R1 plus T1R3 for sweet, T1R1
plus T1R3 for umami, and T2R for bitter,
Projection
Fig. 15.15
Taste Projection (much simpler than for olfaction)
epiglottis via nerve X (vagus), circumvallate (9 of them) via IX (glossopharyngial),
others via VII (facial)
Gustatory (solitary) nucleus in medulla,
there to thalamus and then to sensory cortex
(note overlap to touch area - postcentral gyrus)
also from solitary to hypothalamus
Trigeminal chemoreception
Capsaicin (covered in the chapter on pain, Chapter 9)
for polymodal nociceptive fibers
Fig. (not in 4th edition)
Trigeminal (5) mediates irritants
I corresponded with Dr.
Lindemann who has an interesting site about taste.
Smell- Olfaction
chemicals (air, but definition hard for aquatic animals)
Landmark paper:
PKarlson & MLuscher, 'Pheromones': A new term for a class of biologically
active substances, Nature 183, 55, 1959 (see also J NIH Res 6, 63-66).
It is hard to imagine that something as fundamental as pheromones was not
even a word before 1959
Box A pheromones - vomeronasal organ. For insects, there are many variations,
but the most famous are sex attractants from female moths detected by feathery
antennae on male moth. (Here,
from my butterfly collecting days, is a male luna moth.) Usually it is a
simple molecule like a 10 carbon acetate. It can attract male from a few
miles who flies upwind at first. Pheromones have been used to trap pests.
Fig. 15.2C
There are unusual primaries like aromatic and putrid , there may be many
primaries, although mixtures give a single perception confounding the ability
to define primaries
Relative to other senss, receptors difficult to stimulate
Perhaps more than with the sense of touch, olfaction is related to motivational
"affect"
The sense of smell is especially important in other animals (dogs)
Fig. 15.6A
Anatomy of olfactory epithelium.
Note: the receptors are neurons
Receptors turn over (this is unusual), as noted by dividing stem cell and
developing (immature) receptor, since cells are very exposed (to dry air,
pathogens, etc.). New cells must establish connections.
There are also sustaining cells
Fig. 15.6 BC
Receptors are ciliary with "9 + 2" arrangement of microtubules
as seen structurally.
Cilia are in mucus
slowly adapting (receptors) even though it seems otherwise (processing)
Fig. 15.9A
Transduction - G protein coupled receptor via adenylate cyclase
There is a specialized olfactory alpha subunit of the G protein (Golf)
Na+ - Ca2+ channel is like that of photoreceptor in that cAMP acts as a
ligand to open the channel from inside the cell
Ca2+ opens Cl- channel
there is also a pathway involving PLC and IP3, but which is otherwise similar
in the background, there is a Na+/Ca++ exchanger
Fig. 15.7 B
G-protein coupled receptor is very variable (there may be thousands, meaning
that olfactory receptors contribute predominantly to diversity of G-protein-coupled
receptors) and has specific variable regions.
Reflection In the early 1990's, olfactory receptors were found to
be G protein coupled receptors, and there are lots of olfactory receptors;
Richard Axel and Linda B. Buch won the 2004 Nobel
prize for this work. I see from my alumni magazine that Axel was class of
67 at my college (Columbia College) while I was class of 69. He kept working
there (at the med school) and joins 70 from Columbia to get the Nobel Prize,
19 in Physiology and Medicine. I followed the link suggested by my alumni
magazine and found this.
Recent work
G. Barnes, S. O'Donnell, F. Mancia, X Sun, A. Nemes, M. Mendelsohn, and
R. Axel, Odorant Receptors on axon termini in the brain, Science, 304, 1468,
2004
Each cell expresses only one type of receptor.
Seemingly randomly arranged on olfactory epithelium.
Axons of axons with same receptors converge at glomeruli.
The same receptors are used in axon guidance.
Recent work
D-J Zou et al., Postnatal refinement of peripheral olfactory projections,
Science 304 1976-1979, 2004.
"A hallmark of mature glomeruli is that they are innervated exclusively
by axons from olfactory sensory neurons expressing the same olfactory receptor."
(summary of above)
Here they show:
(1) Glomeruli start our heterogenious and the frequency of heterogenious
glomeruli decreases with development.
(2) Sensory stimulation contributes to the final unique mapping.
Fig 15.7B
number and organizations of genes and proteins in C. elegans, Drosophila,
mouse, human
Note, no introns in mammals
Fig. (not in 4th edition)
distribution of genes in human, many on 11
Fig. 15.13D
Projection
Glomeruli - > Mitral cells -> lateral olfactory tract (stria)
Also Periglomerular cells and Granule cells for processing
There is specificity of projection (space) of specific odorants to olfactory
bulb favoring labeled line scheme of processing
Fig. 14.1 A - D
Olfaction is a complex sensory system in part because of the CNS projection
to amygdala, and, via pyriform cortex, to thalamus, hypothalamus, amygdala
and entorhinal cortex (and even to higher areas, hippocampus, orbitofrontal
cortex) , areas involved in "emotion" (Chapter 29)
Test questions from 2005 - 2007 relating to this outline
What does "trp" stand for when applied to channels?
transient receptor potential
What type of molecules are the two components of the dimer (T1R1 + T1R3)
used for umami?
G protein coupled receptor
What type of molecule is gusducin and what cell is it in?
G-protein of taste cell
Why is it important for all the types of taste cell transduction mechanisms
to ultimately increase intracellular Ca2+ concentration?
must release transmitter vesicles
Linda B. Buch and Richard Axel won the 2004 Nobel Prize for discovering
the nature of the olfactory receptor. What type of molecule is it?
G rotein coupled receptor
Why do male moths have more elaborate antennae than females?
to detect sex attractant pheromones from female
What is the organelle responsible for chemoreception in an olfactory receptor
cell?
cilia
What are the 9 big papillae at the back of the tongue called?
circumvallate
In what way are the G protein coupled receptors unusual for sweet and umami
tastes?
this is the only time they have been mentioned as being dimers
Bigger than a taste bud, what is the term for the bump that is visible on
the surface of the tongue?
papilla
Histology of the olfactory epithelium shows mitoses and developing cells
(as well as mture receptor cells). What does this mean, regarding receptor
maintenance, also true for taste but different for vision and audition?
cells turn over, old ones die, new ones replace them
In olfactory transduction, cAMP is made by adenylate cyclase. What does
this cAMP do?
gate channels
In contrast with somatosensation, vision and audition, with respective primary
cortical projections, what is the situation for higher projection in olfaction?
to limbic system
All the olfactory receptor cells that synapse into one glomerulus have something
in common. What?
use same G protein coupled receptor
What is the significance of the solitary nucleus in the medulla?
synapses for taste
Bitter stimulation, or stimulation with amino acids, activates PLC (phospholipase
C) to create IP3. In this example, the IP3 activates a different Ca2+ channel
than the IP3 receptor of the endoplasmic reticulum. Give the name or location
of this channel.
TRPM5 in plasmalemma
The facial (7), glossopharyngeal (9) and vagus (10) nerves carry standard
taste information. What additional nerve carries information from polymodal
nociceptive receptors responsive to capsaicin?
trigeminal
Relative to gustation (taste) how many primaries (different receptor types)
are there for olfaction (smell)?
many more (500-1000)
There's a Na+/Ca2+ channel in olfactory receptors like the one in rod cells
(that one gated by cGMP). What gates the olfactory receptor channel?
cAMP
"A hallmark of mature glomeruli is that they are innervated exclusively
by axons from olfactory neurons expressing the same olfactory receptor."
What kind of molecule is this receptor?
G protein coupled receptor
Many genes for olfactory receptor molecules are found in clusters on the
human chromosomes. How did they come to be near each other?
a gene gets duplicated and its neighboring twin can evolve to take on new
function
"The olfactory projection is more complicated than those of other senses."
Name one of the many targets beyond the olfactory bulb.
pyriform cortex, olfactory tubercle, amygdala, entorhinal cortex, orbitofrontal
cortex, thalamus, hypothalamus, hippocampal formation
This page was last updated on 3/19/08
Spinal motor control lecture
Peripheral motor function
Purves et al., chapter 16, 1, 9
The Biology Department at SLU has a faculty member, Dr.
Fisher, who does research on muscle
Note that the Washington University Medical School's Neuroscience Tutorial
has good coverage on this topic:
Spinal motor structures
Review of some muscle physiology mostly not in book
Sliding filament - well covered in Bio 106 & cell - only reviewed here
Ca2+ binding to troponin gets tropomyosin off actin sites
myosin can bind actin, ATP unbinds - explaining rigor mortis in ATP depletion
Duchenne (and Becker) muscular dystrophy X linked
additional protein - dystrophin - also in brain axon terminals
Excitation - contraction coupling
Fig (section opener)
Axon and collaterals go to the huge NMJs of one motor unit
Here is a picture
from our histology
course of the neuromuscular junction.
Here is a transmission electron micrograph of a portion of a neuromuscular
junction. Note the folds, increasing the area on the muscle cell. Note
the space with electron density in the cleft. Note the numerous vesicles.
t-tubules get excitation to near sarcoplasmic reticulum
dyhydropyridine (blocking drug) receptor in t-tubule
homology to sodium channel - voltage sensitive
ryanodine receptor in sarcoplasmic reticulum same family as IP3 receptor
coupled with t-tubule
Nervous control of muscle
Fig. 16.6
In BL A347 (General Physiology Lab)
one lab goup stimulated the forearm of subject Joel with increasing frequency
and obtained this
record of finger twitches using a sensitive force transducer; this was our
non-invasive equivalent of a tetanus experiment.
Recall that "tetanus" was the term for the disorder caused by
the clostridial toxin that cleaved synaptobrevin (vSNARE).
twitches summate (to tetanus)
Types of muscle (review) - best seen in turkey
slow, actually tonic, oxidative (and hence dark meat because of hemoglobin,
myoglobin and cytochrome)
fast fatigable, phasic, glycolytic
and intermediate
It is possible to stain, in this case for ATPase, to show mixed
muscle cells in a muscle (dark is slow, aerobic).
autonomic nervous system (controls smooth muscle and influences cardiac
muscle)
Fig. 16.5
Motor units
In 1932, Sir Charles Sherrington won the Nobel
Prize. He originated our understanding of the motor unit..
(see also Fig (section opener))
One spinal motor neuron connects to several muscle cells scattered through
muscle
How many cells innervated depends on how fine vs gross the muscle's control:
13 muscle cells per nerve in extraocular muscle
1730 in calf
Fig. 16.2BC
Motor unit pool - motor units to one muscle.
Spinal motor neuron cell bodies are labeled by injection of marker into
the muscle (soleus vs gastrocnemius)
Also (this is a different point) each motor neuron innervates only one type
(white meat, dark meat) of muscle.
Reflex
Fig. 16.10 B
Stretch reflex - simplest behavior
Ia sensory -> alpha motor neuron -> muscle
alpha motor neuron to striated muscle
gamma motor neuron to intrafusal muscle (fusimotor system) to preset stretch
on stretch receptor
Fig. 1.7 A,B
Fig 9.7A
This pathway was also described for proprioception and in introduction
With inhibitory interneuron, there is an inhibition of the antagonistic
muscle
Complex behaviors
Up to and beyond fixed action pattersn (FAPs)
built up from complex of reflexes - with many other influences
Sir Charles Sherrington Integrative action of the nervous system (1906)
1932 Nobel
Prize (with Adrian) "discoveries regarding the function of neurons"
Fig. 16.14
how this integrates in spinal cord
crossed extensor reflex
Fig. 16.12
Golgi tendon organ
Fig. 16.13
via Ib (slower than Ia) acts through inhibitory interneuron
to mediate the clasp-knife reflex -give up if stretch is too strong
More on the anatomy of the spinal cord
Fig. 16.3
"mototopic" organization
axial (proximal) vs distal muscles - medial vs lateral
flexors vs extensors - dorsal vs ventral
Fig3. A2 & A5A (appendix)
cervical vs. lumbar enlargements
- for all the extra motor neurons for the arms vs legs respectively
ALS
Amyoropic Lateral Sclerosis (ALS) Box 16.D
Lou Gehrig's disease
- he died in 1941 after playing baseball for the New York Yankees (retired
in 1939) and (until recently) holding the record for consecutive games played
a familial variety is on chromosome 21 and codes for copper/zinc superoxide
dismutase (SOD)
Recent paper
P. Aebischer & A.C. Kato, Playing defense against Lou Gehrig's Disease,
Scientific American, November 2007, pp. 86-93
Cells die from cell terminal back in to cell body
Interesting that bladder and eye movement spared
Most die in a few years, Physicist Stephen Hawkins lived 4 decades
Exam questions from 2005 - 2007 relating to this outline
What cells degenerate in ALS (amyotrophic lateral sclerosis, Lou Gehrig's
disease)?
spinal motor neurons
Relative to adjacent areas, what would be more plentiful in the cervical
enlargement?
spinal motor neurons
In the ventral horn of the spinal cord, where are motor neurons controlling
the hand relative to those controlling the shoulders?
lateral
Where is the cell body for the stretch receptor involved in the monosynaptic
reflex?
dorsal root ganglion
What are gamma motor neurons used for?
to preset stretch in intrafusal muscle fibers
The sensitivity for the reflex can be preset by the fusimotor system. What
type of nerve and what type of muscle are used in this efferent system?
gamma motor neuron to intrafusal system
What muscles are excited and inhibited in the crossed-extensor reflex?
ipsi + flexor to withdraw, - extensor, contra + extensor to support and
- flexor
Consecutive muscle twitches that come close enough together in time fuse
to a steady and stronger contraction. What is this called?
tetanus
One motor neuron connects to quite a few muscle cells. What is this called?
motor unit
There's a muscle protein called "dystrophin." Why did they give
it that name?
it is the product of a gene that, if mutant, leads to Duchenne (or Becker)
muscular dystrophy
Name a Ca2+ channel relevant to excitation-contraction coupling.
dihydropyridine receptor and ryanodine receptor (also synaptic calcium channel)
I compared 13 for extraocular muscle and 1730 for gastrocnemius. 13 and
1730 what?
muscle cells per neuron in a motor unit
In the knee-jerk reflex, the flexor is inhibited. How?
there is an inhibitory interneuron
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This page was last updated 3/20/08
Central motor mechanisms lecture
Central Motor Mechanisms
Purves et al., Chapters 17-20, Chap 10, Appendix
Sylvius is also very useful here.
Note that the Washington University Medical School's Neuroscience Tutorial
has good coverage on these topics:
Basic Motor Pathway
Basal Ganglia and
Cerebellum
Pep-talk:
There are many deficits in motor function and coordination. After you have
learned how much of the brain is dedicated to motor function and coordination,
you will appreciate what a gift it is not to be spastic.
Spinal tracts have names like cortico-spinal tract (from -> to).
Above and beyond spinal reflexes, these tracts mediate descending influences
on spinal motor neurons.
Anatomical review:
Ventral
view of sheep brain shows cerebral peduncle and pyramids
Horizontal
section of sheep brain shows caudate and lentiform n. (putamen and globus
pallidus), as well as internal capsule (and cerebellum)
Even before considering basal ganglia and cerebellum, paths are complicated
and numerous
Fig. 17.9
Pyramidal system with corticospinal tract
Corticospinal tract Pyramidal motor system (75-90% crosses) 10 to the 6th
axons
Named because it goes through pyramids on ventral medulla
(though it might have been named from pyramidal shaped neurons in layer
V incl. Betz cells)
Lateral and ventromedial pathways
Summary of corticospinal:
precentral gyrus -> internal capsule -> cerebral peduncles -> pyramids
->
decussate in brain stem -> lateral cortical spinal tract (see below)
(uncrossed in medial cortical spinal tract) (see below)
(only primates among mammals have monosynaptic pathway to motor neurons)
Initiation of voluntary motor movements
Refer back to the lecture on the somatosensory system:
Fig. 10.4
A half spinal cord injury would cause contralateral loss of spinothalamic
below injury and ipailateral loss of lemniscal.
Brown-Sequard syndrome include motor (ipsilateral impairment)
The pathway is neatly organized topographically at the levels of internal
capsule, Cerebral peduncle in midbrain, Pyramid in medulla
Fig. 17.9
Ventral corticospinal tract
Table A2 (Appendix)
Corticobulbar
Output for face and upper body via facial nerve (and trigeminal, vagus,
accessory, hypoglossal).
Fig. Box 17B
Interesting in that upper face has bilateral innervation, lower face is
only contralateral in its control
The famous Sunday night TV anchorman Ed Sullivan ("We have a really
big shew for you tonight") had the lopsided mouth described in Box
B for unilateral damage (or stroke).
Fig. not in 4th edition
Red nucleus adds control to arm muscles
Rubrospinal tract from red nucleus replaced by corticospinal in evolution
Fig. 17.2B
corticoreticulospinal tract
Reticular formation controls axial muscles and proximal limbs
pontine reticulospinal- help to maintain posture
medullary reticulospinal - liberates antigravity from reflex
Fig. 17.6
Fig. 17.2C
Superior colliculus (tectospinal) goes down to control head movements
Fig. 17.2A
Vestibular control for posture and catching balance
Fig. 17.10
topographic map of motor cortex- compare with corresponding sensory homumculus
work by neurosurgeon Penfield, note relative "magnifications"
Precentral gyrus = Brodmann area 4 = M1
Fig. 17.7
premotor area (area 6)
Basal ganglia and cerebellum
Basal Ganglia get input from Cerebral Cortex and feed back to motor Cortex
Cerebellum gets input from Cerebral Cortex and feed back to motor Cortex
In early coverage of functional neuroanatomy, this is where the statement
that the thalamus is a motor relay proves true.
Fig. 18.4
Not just motor cortex, but huge parts of cortex feed to basal ganglia.
Fig. 19.4
Not just motor cortex, but huge parts of cortex feed to cerebellum.
Basal ganglia and cerebellum take a lot into account to integrate motor
control.
Basal ganglia
Extrapyramidal (because it lies outside the pyramids)
caudate + putamen = striatum (striated because strands of internal capsule
make it look striated)
putamen + globus pallidus = lentiform nucleus [lens shaped] (see
sheep brain horizontal section)
Fig. 18.2
inputs to basal ganglia
cortex and substantia nigra and pars compacta
Fig. 18.5 A
outputs from basal ganglia
The globus pallidus is a relay nucleus for the caudate and putamen and so
is the subthalamus.
To VA/VL complex of thalamus to motor cortex
also to substantia nigra pars reticulata to superior colliculus
Fig. 18.3
connections are to spiny and aspiny neurons in caudate and putamen
Box 18A
Parkinson's
(see the neurotransmitter
lecture)
Fig. 18.11A
Lowered excitatory input from substantia nigra via D1 dopamine receptors
leads (through globus pallidus and thalamus) to decreased excitation at
motor cortex, explaining the hypokinesia of motor cortex.
Also there is another interaction via D2 receptors to subthalamic nucleus
Box 18B
Huntington's (1872) disease (chorea) choreoathetosis
Dominant late onset - many interesting genetic counseling issues. The Folk
singer Woodie Guthrie died of Huntingtons. There is a big family tree derived
from Venezuela near lake Maracaibo
On post-mortem, degeneration of putamen and caudate is observed.
It is on short arm of chromosome 4
1983 and since: cloning -CAG repeat (polyglutamine repeat), 15-34 (normal)
-> 42-66 (Huntington's)
Other trinucleotide repeat diseases: fragile X syndrome, myotonic dystrophy,
and others
sometimes they get worse from generation to generation (anticipation)
Fig. 18.11B
The diagram is more complicated, but in some ways, Huntingtons is the opposite
of Parkinsons in that circuit has thalamus increasing excitation to cortex.
Cerebellum
Dysmetria (cannot approach target), ataxia, intentional tremor if cerebellar
damage.
Cerebellum highly developed in electric fish.
Cerebellum is involved in rhythmic activity and plasticity.
An additional decussation makes it so that cerebellum controls the ipsilateral
side of the body.
Fig. 19.3
input to cerebellum
especially from cerebrum, vestibular apparatus and spinal cord
Fig. 19.7
output from cerebellum
via deep cerebellar nucleus via superior cerebellar peduncle to VL complex
of thalamus to motor and premotor cortex
Fig. 19.10
cerebellum is a fairly "simple circuit"
Fig. 19.11
excitatory and inhibitory interactions are known
Mossy fibers input to 10-100 billion granule cells to parallel fibers, and
many connect to each spectacular Purkinje cell.
Also inpput from climbing fiber makes more 1:1 connection to Purkinje fiber.
Also local circuits from basket cells, Golgi cells, and stellate cells
Fig Box 19 B
There are very interesting mouse mutants, reeler, weaver, leaner, lurcher,
nervous, Purkinje cell degeneration (those last two interestingly cause
blindness too) and staggerer.
reeler is cloned, had a defect in protein like extracellular matrix proteins
and has defect in migration of cells during development.
weaver is a K+ channel.
Eye movements make an interesting example
Fig. Box 20 A
if image is stabilized on the retina the image disappears
Fig. 20.3
a reminder of muscles and wiring
Abducens (VI) to lateral rectus
Trochlear (IV) to (contralateral) superior oblique
Occulomotor (III) to the rest (and eyelid control and the pupil)
Types of eye movements: saccades (also in REM sleep), smooth pursuit, vergence,
drift, and vestibular control
Fig. 20.8
horizontal saccades are controlled by paramedian pontine reticular formation
PPRF (gaze center)
Fig. 20.11
Superior colliculus involved (and frontal eye field)
Fig. 20.0
Stimulate superior colliculus and bring fixation to receptive field of area
stimulated
Exam questions from 2005 - 2007 related to this outline
What is the main motor nerve to control facial expression?
facial (7)
What portion of the cerebral cortex projects to the basal ganglia?
most
Why is Huntington's referred to as a "triplet repeat disease?"
CAG nucleotide triplet increases coding for polyglutamine
Why would paralysis be a more likely consequence of stroke in the lower
portion of the face than in the upper portion?
upper is bilaterally innervated, lower is not
Which nerve innervates more than one extraocular muscle?
occulomotor (III)
Increased motor excitation from thalamus to motor cortex is the hallmark
of what genetic disease?
Huntington's
"The left side of the brain is for the right side of the body"
is the conventional wisdom that most people learn early in their science
education. Where is the cross-over for the direct
output from the primary motor cortex to the spinal motor neurons?
caudal medulla
Here is a partial list of descending motor tracts to spinal cord: colliculospinal,
rubrospinal, reticulospinal and vestibulospinal. What major descending tract
is missing from that list?
corticospinal
What is the extrapyramidal system?
motor system outside pyramids involving basal ganglia
What part of the brain is especially altered in the ataxic weaver mouse
mutant ?
cerebellum
When specialized optics are used to stabilize the image on the retina despite
eye movements, what does the subject perceive?
everything disappears
What conspicuous midbrain structure is missing from the following list of
areas involved in eye movement: PPRF (gaze center), vestibular system, abducens,
trochlear, occulomotor?
superior colliculus
What cell, a well-known cell type, is the output to the deep cerebellar
nuclei?
Purkinje
"The thalamus is a major motor relay station." Justify this statement
when the pyramidal motor system does not synapse in the thalamus.
extrapyramidal system feeds back to cortex via thalamus
The rectus muscles move the eyes up and down and side to side. What are
the muscles that rotate the eyes?
oblique
"Diminished excitation and increased inhibition to the globus pallidus
inner segment contribute to chorea in Huntington's disease." Name one
of the brain areas that input to the globus pallidus.
caudate, putamen
What cranial nerve is missing from the following list for motor output to
the face: trigeminal, vagus, accessory, hypoglossal.
facial
A unilateral lesion in the cranial nerve would cause unilateral weakness
in the top and bottom of the face. Why might only the lower part of the
face be afflicted if the lesion were in the brain?
because there is ipsilateral and contralateral control
Where is the first synapse of a cell of the precentral gyrus whose axon
is in the pyramidal motor system?
on the spinal motor neuron
Where would there be a motor defect below a hemisection of the spinal cord?
ipsilateral to the lesion
In somatotopic organization, there is a homunculus of the body, with face
and hands over-represented, on the postcentral gyrus. Where is the corresponding
motor map, also with exaggerated face and hands, located?
precentral gyrus
Basal ganglia feed via the globus pallidus to the cerebral cortex. What
relay area is between the two?
thalamus
While discussing extrapyramidal control of motor movements, there was a
figure showing the entire cerebral cortex shaded (except primary auditory
and visual cortex areas). What does this shaded area represent?
the part of the cerebral cortex with input to the basal ganglia
"Polyglutamine repeat." Translate.
glutamine is an amino acid. polyglutamine repeat is a string of them, with
a low number in normals and a high number in Huntington's
Granule cells and climbing fibers both connect to Purkinje cells, but in
different numbers. Specify.
1:1::CF:PC, many:1::GC:PC
In the diagrams, middle and inferior cerebellar peduncles are inputs to
the cerebellar cortex. The superior cerebellar peduncle is output from deep
cerebellar nuclei to (where)?
thalamus
The trochlear is the contralateral output. Which two nerves, subserving
the same overall function, have ipsilateral output?
occulomotor and abducens
This page was last updated on 3/20/08
Neural development lecture
Development
Purves et al., Chapters 22-23, one figure from Chapter 11
Pep talk
The overall theme relates to "plasticity." In that regard, learning
and memory are considered to be continuations of development, so the boundary
line between development and memory is not clear.
Dogma is that invertebrate nervous systems are hard-wired with little plasticity
or learning (though there are lots of exceptions) and that vertebrate adaptability
relies on rewiring, alterations, and learning.
Prof Schreiweis teaches
a course in embryology (BL A344, Fall, 5 credits, lecture plus lab). Traditionally,
embryology, specifically comparative embryology, has been fundamental in
organizing life in biology.
Developmental biology is a very different field, and workers in developmental
biology, Lewis, Weichaus, and Nusslein-Volhard -won the1995 Nobel
Prize.
Prof Ogilvie teaches developmental
biology (BL A460, Spring, 3 credits, lecture; BL A493-36, lab)
Fig. 22.3 B-E
Signal transduction, refer back to Chapter 7
Here are several of the ligand-receptor pairs covered in this figure:
wnt-frizzled
shh-patched
fgf-rtk
The entire cascades for these pathways (and others) are really fundamental
in modern biology. To a limited extent, find coverage in my signal
transduction course outline.
Box 22A
Stem cells (instead of presenting what is in the box, I will talk about
my work)
Because cells lose their pluripotency, researchers have focussed on their
discovery that embryonic stem cells are better at differentiating into cells
that can repair cell damaged areas such as in the case of spinal cord injury;
the issue is very controversial because it may encourage practitioners to
create and destroy human embryos for no other purpose than to harvest stem
cells. Of note, there may be "left-overs" (it is hard to find
a diplomatic euphemism) from in vitro fertilization after a couple has had
all the children they want (that might go to "waste"). For this
reason, for humans, only the use of some 60 cell lines that are already
in culture was dictated in the US by President Bush.
Several colleagues and I are collaborating
to cure blindness in a mouse mutant with cells that started as embryonic
and were induced to become precursors of nerve cells; identified by green
fluorescent protein, here
is a cell that has been put into the retina and is beginning to show a neuron-like
phenotype.
Review
Know from earlier this semester:
No regeneration of neurons in the (mammalian) CNS. Interesting regeneration
in olfactory and taste receptors.
Hubel and Wiesel (1981 Nobel)
(and others since) - need for patterned vision during critical period to
maintain visual cortical binocularity and feature (contrast) detectors (this
will come up in chapter 24)
Wiring in cerebellum is disrupted in mutants (Chapter 19)
Drosophila Embryology
Drosophila is a model for understanding development, generally
Order of action: maternal genes, zygotic genes, homeotic genes
Fig. 21.6A
a lot has to do with segmentation
Fig. 21.6B
Maternal means that the gene was transcribed in the mother; that is how
bcd (bicoid) was deployed
zygotic genes have the order of action as shown in Fig.
gap such as kr (kruppel), pair-rule such as h (hairy), and segment polarity
such as wg (wingless)
TRANSPARENCY
Imaginal discs are structures in larvae destined to become structures in
the adult (entomologists call the adult the "imago")
Fig. 22.6 C
Homeotic mutants - with names like "antennapedia" - (with leg
where antenna should be)
(i.e. often transplanting something which should be in one segment to another)
Homeotic gene has homeobox (["box" is in DNA] 183 bp of DNA) which
codes for DNA binding protein with 61 amino acid homeodomain (["domain"
is in protein] helix turn helix)
The sevenless signalling pathway
Fig. 22.10
(I put more information below than is in the book)
How do > 750 ommatidia with some 19 cells develop?
(receptors (R1-6, R7 & R8, cone cells, bristles, pigment cells)
Development in the eye imaginal disk.
In sev (sevenless) mutants, the R7 precursor becomes cone cell.
(I wrote the paper that introduced sevenless, see here)
Sevenless is a receptor tyrosine kinase, and signalling involves ras = small
G protein.
Sequential addition of receptor cells in Drosophila eye: R8, R2 & R5,
R3 & R4, R1& R8, R7
Boss = bride of sevenless is 7 transmembrane domain ligand
Fig. 22.3 C
sevenless is receptor tyrosine kinsae -
2 transmembrane subunits, 2 extracellular subunits
expressed everywhere except R2 R5 and R8
It is a topic of intense present interest how this signals across membrane
Drk = downstream of receptor tyrosine kinase
which is a small SH adaptor protein, SH = src homology
src = oncogene of Roux sarcoma virus
Sos = son of sevenless, a GNRP (guanine nucleotide releasing protein) to
exchange GTP for GDP on ras
ras = rat sarcoma [viral ras oncogene of normal protooncogene]
other steps -> signalling to nucleus
MAPK = mitogen activated protein kinase
alias ERK = extracellular signal regulated kinase
Embryology
Fig. 22.1AB
Neural plate forms from ectoderm -> neural groove -> neural tube to
make CNS
Fig. 22.1D
One area remains outside CNS - neural crest gives rise to PNS structures
like sensory ganglia
Fig 22.2 B
Different cells migrate to make (1) sensory ganglia, (2) autonomic ganglia,
(3) adrenal, or (4) non-neural tissues like melanocytes
Fig. 22.11C
Factors on how neural crest progenitors turn into specific PNS types
(more on factors later)
Brain subdivisions
Fig. 22.5AB
Prosencephalon -> telencephalon and diencephalon
Mesencephalon
Rhombencephalon ->Metencephalon and myelencephalon
Note, "optic vesicle" signifies that retina is outgrowth of CNS
Fig. 11.4
Induction from optic vesicle makes lens form from ectoderm
Histogenesis
Fig. 22.7
Cell divisions in monolayer with nuclear migration (mitosis near neural
tube lumen (ventricle) and have S-phase near pial surface)
Fig. 22.12
Then cell migrates out along tracks made by radial glia
Recall Weaver mutant mouse in which cerebellar granule cells are missing:
Bergman glia screwed up - granule cells not migrate, die
Fig. 22.8
then each layer (e.g. V) migrates past previous (e.g. VI)
Axon pathfinding
Retinotectal projection in frog
Fig. 23.6B
Background was that Weiss had proposed the resonnance principle which goes
something like this -- that growing and connecting axon induces the cell
type in the postsynaptic cell.
Then Roger Sperry did an important experiment (1981 Nobel
prize, though not for this)
turn frog eye upside - down and projection reverses
(would jump in the wrong direction)
note - advantage of amphibian system - regeneration of optic nerve in adult
this work being in the adult
Sperry proposed "neurobiotaxis" gradients
- recently shown retinoic acid gradient in zebrafish
Jacobson and Hunt - specified after stage 28, first AP laid down, then DV,
implying that something about position of eye in head picks up information
specifying DV, AP
First neuroblasts which develop undistinguished neurites
Pathfinding complex - growth cones
growth cones secrete protease, express growth associated protein GAP43
feel way with filopodia
Work since then
Fig. 22.3
These are drawings
from Ramon y Cajal
There are these growth cones (enlargements) at the tip of an extending axon
which extend and retract filopodia, feeling their way along.
Fig. 23.1BC
Fig. 23.2
growth cone, confocal microscopy
SEM growth cone
netrin elicits axon
growth from explant from spinal cord
Although, netrins (Sanscrit "to guide") serve as chemoattractants,
Sperry's neurobiotaxis idea was overly simplistic:
Fig. 23.3
Growth cone with integrin follows laminin and stops when laminin runs out
Axons stick to eachother and to growth cones with cadherins and CAM's (cell
adhesion molecules) like Ng-CAM (neuro-glial) and N-CAM (neuronal)
Synaptogenesis
Fig. Box 23B
Synaptogenesis at neuromuscular junction
agrin & its geceptor cause aggregation of AChR
Trophic factors
Inductive interaction is important - like trophic effect of nerve on muscle
(in polio, nerve disease leads to wasting away of muscle)
Fig. 23.9
This would also work in reverse, those nerves deprived of muscle vanish,
or if extra limb, there are more spinal motor neurons.
Thus, there are too many nerves at first, then those which do not connect
degenerate.
This would rely on programmed cell death (apoptosis), not really emphasized
in chapter.
Rita Levi-Montalchini 1986 Nobel
Prize "discoveries of growth factors"
NGF (nerve growth factor) is from targets like glands.
Fig. 23.12
Here is a dorsal root
ganglion (somatosensory ganglion) without (A) and with (B) NGF making it
obvious, from the neurite outgrowth in B, why it is named NGF (work of Rita
Levi-Montalchini)
Take-up makes sympathetic (and other nerve cells, like certain sensory nerves)
survive.
Antibody to NGF kills sympathetic nervous system.
Oddly, one good source of NGF is male salivary gland.
Cytokines include:
Neurotrophins like NGF, BDNF (brain derived), NT-3, NT-4/5
Hematopoietic factors (like interleukins)
Growth factors like EGF, FGF, TGF, IGF
Fig. 23.15
Trk ("track") receptors (with tyrosine kinase activity)
TrkA for NGF, TrkB for BNDF, TrkC for NT-3
There is a box on retinoic acid (Box B, Chapter 22). I am and have been
very interested in retinoic acid and have written a lecture on retinoic
acid and its relation to steroid and other hormone signalling for my
last semester's signal transduction course, but will not talk about it much
here. (The figure referenced from Alberts et al. is from Molecular Biology
of the Cell Third Edition.)
Exam questions from 2005 & 2006 related to this outline
The patched receptor acts in concert with the smoothened protein to mediate
the response to what famous developmental ligand?
shh
Larvae of holometabolous insects have tissues determined to become adult
structures. What are these called?
imaginal disks
Name something that neural crest gives rise to.
sensory ganglia, autonomic ganglia, adrenal, melanocytes
What process is agrin involved in in muscle cell development?
aggregation of ACh receptors
In the sevenless signal transduction cascade, what is the name of the small
GTP binding protein?
ras
Contradicting Weiss's resonance principle, how did Sperry explain proper
connection of ganglion cells to tectum?
neurobiotaxis directs axon tips to correct places in tectum
Why is bicoid referred to as a maternal gene?
the mRNA is transcribed in mother
What is the output neuron of the cerebellar cortex?
Purkinje
On what kind of a molecule would you find a domain such as a homeodomain?
protein
An antibody to nerve growth factor (NGF) causes what part of the nervous
system to be lost?
sympathetic n.s.
In axon path-finding, what is the bulbous knob with extensions at the tip?
growth cone
Name a neurotrophin that uses the Trk ("track") receptor.
NGF (and others)
Shh and Wnt are two important secreted ligands used in developmental signalling.
Tell me the receptor (for one of them).
patched frizzled
The word "pluripotent" is used in reference to what type of cell?
embryonic stem cells, neural precursors
How does Sperry's notion of "neurobiotaxis" explain the poor visual
performance of a frog whose eye has been inverted?
upside down eyes axons grew to addresses in tectum as if the eye did not
know it was upside down
The optic vesicle is an outpocket from the diencephalon. What does the optic
vesicle induce in the overlying ectoderm?
lens
The structure that will eventually fold in to make the neural tube is called
the neural plate. From what major embryonic layer is the neural plate partitioned?
ectoderm
What is it that gives rise to sensory and autonomic ganglia, adrenal neurosecretory
precursors and melanocytes?
neural crest
"Receptor tyrosine kinase." What does that mean? Give an example
in developmental signalling.
it is a membrane receptor protein with enzymatic activity to phosphorylate
itself on tyrosine residues, sevenless
A sympathetic progenitor can either become cholinergic or adrenergic. What
determines which pathway?
NGF vs CNTF
What is the difference in distribution of the nicotinic acetylcholine receptor
in a muscle cell before vs. after a neuromuscular junction is formed?
before distributed, after under junction
What effect does transplantation of a supernumerary limb bud in the chick
embryo have on spinal motor neurons?
extra ones formed
What is the difference in appearance of an explanted dorsal root ganglion
with vs. without NGF in the medium?
with has neurites growing out
Ligands such as shh, RA, FGF, BMP and Wnt eventually control transcrption.
Nane one receptor corresponding to any of these ligands.
patched, retinoic acid binding protein, receptor tyrosine kinase, receptor
serine kinase, frixxled
R8 tells a cell to become R7. Name one famous protein in this cascade.
boss, sev, sos, ras, MAPK, (others)
What is the precursor of sensory ganglia, autonomic ganglia, adrenal medulla
or melanocytes (depending on which factors are acting)?
neural crest
The optic vesicle, an outpocket of the diencephalon, eventually forms the
retina. What do these induce the overlying ectoderm to form?
lens and anterior portion of eye
"The S stage occurs near the pial surface." Translate.
synthesis of DNA in the cell cycle (between mitoses) is when nuclei are
on the outer part of the neural tube
In Weaver mutant mice, granule cells are missing, but it is the fault of
what other cell type?
(Bergman) glia
Rotating the frog eye up-side-down gives opposite results if done in the
adult vs. a few days before Harrison stage 28. What is the behavior in the
adult after early rotation?
animal will flick its tongue (to catch an insect) in the correct direction
Filopodia protrude from what important structural specialization in axon
path finding?
growth cone
What are integrins and cadherins used for in nervous system development?
contact guidance
What was changed in the adult spinal cord if a limb bud had been ablated
earlier?
number of spinal motor neurons for that limb is lower
What is apoptosis and why is it so important in development?
programmed cell death. If too many cells are made, extras must be eliminated.
"Cytokines include trophic factors, hematopoietic factors and growth
factors." In which category is NGF?
Despite ist name (nerve growth factor), it is a trophic factor.
This page was last revised 3/21/08
The Memory at the cellular level lecture
"Learning"
Purves et al. Chapter 24 "Modification of brain circuits as a result
of experience"
and Chapter 8 "Synaptic plasticity"
(Figs from chapter 19 and 23)
Introductory remark
There was a famous textbook in the late 1940's by Donald Hebb which proposed
that there were loops of neurons with excitation, "reverberating circuits,"
and that excitation alters synapses. Imagine looking up a phone number and
repeating it in your mind until you dial the phone, but, if you use it often
enough, you will remember it always (like your friend's number from when
you were a kid).
Fig. 23.10 B
One example involves a story from last chapter on synaptogenesis at neuromuscular
junction.
Overlapping connections of multiple spinal motor neurons onto multiple muscle
cells is sorted out after birth.
Development of visual connections
repeated from Vision
and the brain lecture)
Hubel & Wiesel share 1981 Nobel
for "information processing in the visual sytem"
Fig. 24.3 (not shown again)
If a radioactive amino acid is injected into one eye, labeled proteins cross
synapses at LGN and mark ocular dominance columns in cortex; this is detected
by microscopic autoradiography.
Binocular cells connect up correctly at first
Fig. 24.4 (not shown again)
Then there is a sensitive (critical) period in the first few months of life
during which patterned visual input from both eyes is necessary to maintain
binocular input to cortical cells.
Thus early visual defects like cataract or strabismus (cross-eyes or lazy
eye) need to be corrected right away.
Here are autoradiographs.
A of normal visual cortex, like Purves et al., Fig. 24.3, and B after monocular
deprivation from 2 weeks to 18 months in monkey Purves et al., Fig. 24.6.
not covered before
Fig. 24.5 B
Just 6 days of monocular deprivation right around one month of age has this
effect.
There are columns early which get reinforced during early development.
Fig. 24.8
Ocular dominance shift from deprivation sould be blocked if TTX (tetrodotoxin)
were injected into the eye. In the experiment shown here, replacing activity
in a synchronous way would maintain normal binocularity while asynchrouous
optic nerve stimulations would let binocularity disappear. Thus alterations
are activity dependent.
Fig. 24.9
In strabismus (lack of fixation), lose binocular cells.
Recent literature
TKHensch & MPStryker, Columnar architecture sculpted by GABA circuits
in developing cat visual cortex, Science 303, 1681, 2004
MFagiolini et al., Specific GABA-A circuits for visual cortical plasticity,
Science 303, 1681-1683, 2004.
DFerster, Blocking plasticity in the visual cortex, Science 303, 1619-1621,
2004.
At birth, there is complete overlap, sort out in a few weeks.
Potentiating GABA inhibition with diazepam widens columns.
An agonist DMCMnarrows them.
GABA- A receptors with alpha 1, 2, and 3 subunits specifically (alpha 4
and 6 are insensitive to benzodiazepines and alpha 5 is insensitive to zolpidem,
also used).
On the topic more closely related to what most people think of as learning
American Psychology dominated by Associative Learning - repeated pairings
(1) Classical conditioning
Pavlov - 1904 Nobel
Prize "physiology of digestion"
UCS (e.g. food) -> UCR (salivation)
pair UCS (bell) with CS repeatedly
then CS -> CR (salivation)
(2) Instrumental conditioning from Watson's behaviorism
B. F. Skinner box response (bar press) paired with reinforcement (food,
water)
Early attempts to determine cellular mechanisms of learning in mammals had
problems (see memory
lecture)
For that reason, some simple cellular responsivity changes which could possibly
account for learning were demonstrated like:
Landmark paper
Donald Kennedy, Small systems of nerve cells, Scientific American May 1967.
Work on crayfish is in one of the early papers touting simple cell systems
in invertebrates.
Kennedy has been
presedent of Stanford and is now editor-in-chief of Science, the weekly
journal of the AAAS (American Association for the Advancement of Science)
Aplysia
Landmark papers
ERKandel & LTauc, Heterosynaptic facilitation in neurons of the abdominal
ganglion of Aplysia depilans, J. Physiol, 181, 1-27, 1965, Mechanism of
heterosynaptic facilitation in the giant cell of the abdominal ganglion
of Aplysia depilans. J Physiol 181, 28-47, 1965. (see also J NIH Res 2,
63-72, 1990).
Fig. 8.2
(1) depression of responses during tetany in muscle cell; and
(2) post-tetanic potentiation.
Fig. 8.3 A
Studies of Aplysia (a mollusc) by Kandel (Nobel
in 2000)
Aplysia - habituation - nonassociative learning
Personal reflection - I was an undergrad student at Columbia College
in New York when my physiology professor said "Come on with me, there's
a neat seminar," when Kandel was new at Columbia.
Fig. 8.3 B
The nice thing is that there are big identified cells.
(Recall that invertebrate neurons are on the outside of neuropil [where
synapses are made].)
Fig. 8.3 C
Lots of work in the 1960's to 1970's - habituation of gill withdrawal reflex
Habituation is a diminution in the response after repeated stimulus administrations
which is not attributable to sensory adaptation or muscle fatigue.
It is one (motor neuron L7) synapse.
EPSP gets smaller - modification is at presynaptic level - Ca2+ channels
less effective.
Fig. 8.4 AB
There is also sensitization another nonassociative learning
Fig. 8.5 A
short term sensitization
serotonin-induced enhancement of glutamate release
5HT -> cAMP -> PKA -> close K+ channel -> C2+ influx -> transmitter
release
Fig. 8.5 B
long term sensitization
CREB - cAMP response element binding protein, turn genes on
ubiquitin hydrolase break down PKA regulatory subunit, persistent activation
In Chemistry, Ciechanover, Hershko and Rose won 2004 Nobel
for ubiquitin
(There are 2 main pathways in intracellular degradation, lysosomes and proteosomes,
the latter involving ubiquitin.)
Several of biology"s new faculty are interested in ubiquitinization
(Wang, Downes)
There is also classical conditioning in Aplysia, mechanism not shown.
Drosophila
Fig. Box 8A
(Earlier, there had been some shoddy work on learning, so researchers had
to be more careful with controls [for sensitization], but it became clear
Drosophila could be trained to avoid odors associated with shock.)
mutants Benzer and Quinn work in 1970's all involve cAMP
dunce - phosphodiesterase
rutabaga - adenylyl cyclase
amnesiac - peptide transmitter that stimulates adenylyl cyclase
Summary
Learning and memory are very complex
so simple "learning" and simple preparations predominate
but parts of the brain can be simple, if studied for simple "learning"
Hippocampus
Landmark paper
TVPBliss & TLomo, Long-lasting potentiation of synaptic transmission
in the dentate area of the anesthetized rabbit following stimulation of
the perforant path, J Physiol 232, 331, 1973 (see also J NIH Res 7, 59-67,
1995).
The hippocampus is involved in spatial learning (and lots of other things)
Brain slice technique
Cells can be reached by thin brain slice to keep metabolism (oxygen, nutrients)
while having enough thickness (0.5 mm) to still have wiring
Fig. 8.6
hippocampus is rather a simple neural circuit
Hippocampus anatomy: CA1 CA3 & Dentate gyrus
Long term potentiation is a simple form of learning
Input specific long-term potentiation (LTP) can last weeks
Perforant pathway (from entorhinal cortex) -> granule cell (mossy fibers)
-> CA3 pyramidal cell (Schaffer collaterals) -> CA1 pyramidal cell
Fig. 8.7ABC
train of stimuli make response to another bigger while in another (control)
pathway, the synaptic efficiency is unchanged
Fig. 8.10
NMDA receptor important, rise in Ca2+ is important, the same mechanisms
of Mg2+ expulsion and spiral of ligand, voltage and C2+ activation which
can lead to excitotoxicity is responsible for long lasting excitation
Box 8C
Epilepsy is a syndrome of sensitized excitation
Cerebellum
Fig. 19.10B
recall simple wiring of few cell types in cerebellum from motor lectures
Purkinje cells use GABA for inhibitory output
climbing fiber from inferior olive makes big EPSP in Purkinje cell
yet many parallel fibers contact Purkinje cell each with one contact
Fig. 8.16BCD
describes LTD (long term depression)
two synaptic activations must come at about the same time
decrease in effectiveness of glutamate AMPA receptor
(LTD was first mentioned on the second
messenger system outline)
Exam questions from 2005 - 2007 relating to this outline
Even though it has been over 50 years since his famous textbook, Donald
Hebb is still mentioned frequently in neuroscience. In what context?
reverberating circuits of excitation for short term memory
How does transcription of ubiquitin hydrolase promote long term sensitization?
breaks down regulatory (inhibitory) subunits of PKA
Why has the brain slice technique proved useful in studies of long term
potentiation in the hippocampus?
enough neural circuitry remains, yet neurons can be reached by electrodes
In addition to Na+, what ion is expecially important in the signal transduction
cascade from the NMDA receptor to long term potentiation?
Ca2+
What is the output neuron of the cerebellar cortex?
Purkinje
Habituation of the gill withdrawal reflex was used by the Nobel Prize winner,
Kandel, as a model of learning in what organism?
Aplysia
One question implied that the NMDA receptor is a channel. The AMPA receptor
is invoked in addition to the NMDA receptor in long-term potentiation and
depression.
What kind of a receptor is the AMPA receptor, and to what transmitter does
it respond? (2 points)
channel, glutamate
Drosophila were shocked each time they went toward a particular odor, and
mutants like dunce did poorly. What kind of learning is this?
operant
To what kind of molecule does CREB (cAMP response element binding transcription
factor) bind (other than cAMP, of course)?
DNA
A difference between short- vs. long-term sensitization was the breakdown
of PKA's regulatory subunit. How would this change the duration of the cellular
effects?
regulatory is inhibitory so catalytic stays activated
Suturing a cat's eye closed alters the occular dominance columns. How can
this be when light can still pass through the eyelids?
it deprives of patterned input
Adaptation and fatigue are decreases in responsivity at sensory and muscle
levels. An analogous decrease, mediated at the synaptic level, is considered
a simple type of learning. What is this called?
habituation
"EPSPs are bigger in CA1 pyramidal cells after stimulation to Schaffer
collaterals." What simple type of learning is this, and in what location
in the brain?
LTP long term (lasting) potentiation, hippocamus
"In summary, a cellular explanation of learning involves changes in
synaptic signal transduction." Give an example from Drosophila.
dunce - phosphodiesterase, rutabaga - adenylyl cyclase, amnesiac - peptide
transmitter that stimulates adenylyl cyclase
Internalization of AMPA receptors weakens the Purkinje cell's response at
the parallel fiber synapse. What simple type of learning is this, and in
what location in the brain?
LTD long term depression, cerebellum
What happens between birth and maturity that makes the wiring of motor neurons
to striated muscle cells a model of plasticity?
muscle end plate may have more than one motor neruon connected at first,
only one later
What model of learning is "a diminution in the response after repeated
stimulus administrations not attributable to sensory adaptation or motor
fatigue?"
habituation
By what molecular mechanism would breaking down a PKA regulatory subunit
cause long term sensitization?
the catalytic subunits would be activated long term
Drosophila are shocked repeatedly in the presence of a particular
odor, then they avoid that odor. What kind of learning is that?
beyond habituation and sensitization, this is associative learning (operant
(instrumental) conditioning)
This page was last updated 3/24/08
The Language and cognition lecture
Language and Cognition
Language and Cognition
Purves et al., Chapters 26 & 27
General
Consider how much communication enhances the human experience.
Also think about how your thought patterns are guided (perhaps constrained)
by language.
aphasia is loss of language ability
studies of brain damage (stroke) but some attempts to get at live brain
function with imaging techniques
Fig. 26.1
Localization of function - note that Chapter 26 refers to "association
cortex"
some very interesting case studies of people with specific defects like:
Fig. 26.8
prosopagnosia (-agnosia - not knowing) - face recognition deficit in right
temporal lobe damage in patient L.H.
fMRI activity increase in right temporal lobe
Fig. 26.5A,B,C
contralateral (hemispatial) neglect syndrome caused by:
Fig. 26.6 A
damage to parietal, temporal and frontal areas.
recall the importance of gyrus to gyrus connections (arcuate fibers of the
corona radiata, slide from sheep brain dissection: slide
23)
Recent paper. MT de Schotten et al, Direct evidence for a parietal-frontal
pathway subserving spatial awareness in humans, Science 309, 2226-2228,
2005 (see also DGaffan, Widespread cortical networks underlie memory and
attention, perspectives, Science 309, 2172-2173).
In the old days, stroke victims were studied on autopsy.
Neurosurgeons (removing cancer for instance) still test awake subject.
Electrical stimulation will temporarily inactivate small areas.
(If there is a loss of function, that area will be spared.)
Here, tumors were in parietal area.
So do line bisection task.
Although gray matter had been implicated, superior occipitofrontal fasciculus
(white matter) was found to be most important.
DGraffan (perspectives) argues for a relationship with memory in work on
monkeys.
Fig. 26.2
Brodmann areas- based on cytoarchitecture
Fig. 26.3
6 layers in human neocortex, I-not really cells,
II & III - pyramidal cells send and receive input from other areas of
cortex
IV - stellate cells receive input
V & VI - Pyrimidal output from cortex
Fig. Box 26A
fewer layers in "archicortex" (hippocampus)
and
in "paleocortex" (pyriform cortex)
[These were terms used in the sheep brain dissection guide.]
There is a lot of emphasis on neural correlates (a nerve in such-and-such
are of the brain that does so-and-so) like:
Fig. 26.12 B
a face recognition neuron in the temporal lobe which does not respond as
well to degraded or wrong images
Fig. 26.14ABC
a neuron in the frontal cortex which responds specifically in a delayed
task (planning)
Language
Recent literature
FOXP2 transcription factor defect leads to dyspraxia (cannot learn speech)
Use RNAi to show defect in zebra finch in area X of brain
("editors' choice," Science 318, 1835-7, 2007, summarizes work
published PLoS Biol 5 e321, 2007)
FOXP2 knockout homozygous infants do not make ultrasonic cries when separated
from their mothers
(in "Random Samples," CHolden, Science 309, 47, 2005, Gene knockout
leaves mice squeakless)
Fig. 26.2
Brodmann areas
Fig. 27.2
Fig. 27.1
Broca - language on left side of brain
Language is one of the most interesting examples of localization of function.
Broca's area and Wernicke's area
Lesions in Broca's area-difficulty speaking but understand (motor aphasia)
Lesions in Wernicke's area - fluent but senseless speech
Some recovery of function => other areas can take over
Wada procedure: inject sodium amytal to one carotid-
show that speech is on left even in most left handed people.
Fig. 27.3 AB
Surgery to cut corpus callosum (to prevent the spread of epilepsy)
Here is the midsaggital close-up from the sheep brain dissection which view
is predominated by a collosal body, the corpus callosum slide
10
There are 2 consciousnesses and the two sides of the brain have different
capabilities
This work won Roger Sperry (who also did the eye to tectum regeneration
in the frog and inferred neurobiotaxis) the 1981 Nobel
Prize. Then the work was taken up by Gazzaniga.
Because of the orderly visual projections to the brain, it is possible to
present visual stimuli to 1/2 of brain, and, if presented to the left half
of the brain. the person can say what it is, but if presented to the right
half of the brain, (s)he cannot say what it is but can pick it out (multiple
choice) by touch.
Thus experiments distinguish comprehension vs. speech.
Box 27B
argues whether language is actually unique to humans
Border
collies (one named Rico) seem able to learn lots of words
Landmark paper RAGardner and BTGardner, Teaching sign language to
a chimpanzee, Science 165, 664-672, 1969
American Sign Language (ASL) [used by deaf in North America]
22 months of training in a young female
paper lists 30 signs Washoe could use
Landmark paper DPrimack, Language in a chimpanzee, Science 172, 808-822,
1971
success with Sarah to use plastic chips of various shapes
Fig Box 27B
DRumbaugh and S Savage-Rumbaugh used computer type-writer
Landmark paper HSTerrace et al. Can an ape create a sentence?, Science
206, 891-902, 1979
Nim Chimsky (Noam Chomsky, famous MIT linguist who thought language is unique
to humans)
criticized above approaches and created a controversy.
Fig. 27.8
Signers are also impaired by brain damage to language areas
Native English speakers' vs. Non-native speakers' scores on tests as a function
of age suggests that there is a critical period for learning language broadly
centered early in life (which, of course, everybody knew already in terms
of how easy it is relatively for young people to learn a foreign language).
Exam questions from 2005 - 2007 relating to this outline
In testing a split-brain subject (with a severed corpus callosum), how can
you show a visual stimulus to only one hemisphere?
present to temporal retina that innervates ipsilaterall;y (with eye fixation)
Washoe, Sarah and Nim Chimsky were all used in a study of what capability?
language in chimps
What is the more common name applied to the "archicortex" folded
in between the neocortex and the paleocortex?
hippocampus
Hemispatial (contralateral neglect was found to result in damage to what
brain area (or the white matter under that surface feature)?
parietal lobe
In a subject with a severed corpus callosum, can the right hemisphere "know"
what stimulus was presented to it?
yes but it cannot say
How could administering sodium amytal to the carotid address the question
of the unilateral location of speech?
into one carotid anesthetizes one side of the brain
How is performance on the line bisection task diagnostic of neglect syndrome?
easy to see if patient cannot decide where the middle of a line is, even
during brain surgery
In studies of speech localization to Broca's area, how did Sperry present
a visual stimulus to only the left hemisphere?
Right visual field goes to left temporal retina and right nasal retina (to
left brain)
This page was last updated 3/25/08
The biorhythms lecture
Rhythms
Purves et al. Chapter 28
EEG
Fig. Box 28C
EEG (electroencephalogram) set of pooled potential waves recorded from head.
This is as opposed to the "evoked potential," evoked by some stimulus.
To get regular waves, there must be some synchrony in neuron firing.
Thalamus to cortex loop may contribute.
Reticular formation involved in arousal (reticular activating system) (RAS)
may also contribute.
Fig. 28.6
The relaxed EEG with eyes closed is 8-13 cycles per second (Hz), called
alpha (not shown).
During arousal there is alpha-blocking, and with eyes open, 14-60 Hz (beta)
makes it almost as if there were no rhythm.
Sleep
Landmark paper
EAserinsky & NKleitman, Regularly occurring periods of eye motility,
and concomitant phenomena, during sleep, Science 118, 273-274, 1953 (see
also J NIH Res, 4, 63-66, 1992).
Fig. 28.6 (continued)
There are various stages of non REM (rapid eye movement) sleep, as defined
by the EEG.
Deep sleep - slow wave sleep- delta (and theta) rhythm-stage 3, 2 Hz - stage
4 (slow wave sleep).
REM is associated with dreaming.
There is an atonia (lack of muscle control) during REM sleep.
PGO spikes at onset of REM (pontine reticular formation -> geniculate
-> occipital cortex).
Birds do not have REM sleep but most mammals do.
Fig. 28.7
During a night of sleep, go back and forth
REM - heart rate, respiration, erection all increase.
Called "paradoxical sleep" because it seems like awake state.
Deprivation of paradoxical sleep makes a person or animal irritable.
Because of loss of muscle tone, a cat restrained over a dish of water will
wake up when it goes into REM sleep.
Box 28A
Dolphins sleep with one hemisphere at a time.
Why do we sleep (perchance why do we dream)? - lots of half-baked answers
and speculations.
Landmark papers
Michel Jouvet, The states of sleep, Scientific American, February 1967,
62-72
Michel Jouvet- Biogenic amines and the states of sleep Science 163, 1969,
32-41
Hobson - raphe and locus coeruleus turned off in sleep. Note, the section
which follows could have been placed in any of a number of places throughout
this course, but, because of the involvement of several neurotransmitter
systems in the wake-sleep patterns, it is here. Also, an important period
of of historical excitement in the mid 1960's is underplayed in which Swedish
workers (Dahlstrom and Fuxe) developed the techinique of histochemical fluorescence
in which 5-HT, NE and DA pathways could be visualized since the products
of transmitter reacted with paraformaldehyde vapor can be seen.
Transmitters in sleep
Table 28.1
Ascending reticular activating system:
(1) Raphe (which means ridge or seam) nuclei uses 5-HT (serotonin)
The caudal part innervates downward, while the rostral part innervates upward.
Since it fires during wakefulness, it must be involved in sleep.
The hallucinogenic drug LSD (lysergic acid diethylamide) is an agonist of
presynaptic raphe 5-HT receptors inhibits firing (like in sleep), working
like peyote (cactus) Aztec and psilocybin (mushroom) Maya.
(2) The locus coeruleus (blue spot), bilateral in the pons, spreads NE around
brain.
12,000 neurons (each) with lots (e.g. 250,000) of synapses.
Like sympathetic ganglion in brain- activated by sensory stimulation
(3)The pontomesocephalotegmental complex regulates thalamic sensory relays
using acetylcholine.
Note that there are other systems which distribute acetylcholine in the
brain:
septal area (->hippocampus)
basal nucleus of Meynert (->neocortex) [these cells die early in Alzheimer's
disease]
Note that dopamine is also distributed via the nigrostriatal pathway, disrupted
in Parkinson's and involved in the mesocorticolimbic (reward) system and
from the tegmentum to the forebrain and limbic system.
Cocaine blocks DA reuptake, amphetamine blocks NE & DA reuptake, potentiating
reward
Depletion by alpha-methyl-para-tyrosine blocks stimulant action.
Fig. 28.8
Circuits
5HT & NE -> -> Glycine to spinal motor neuron to inhibit motor
movement.
GABA to dorsal column nuclei to inhibit sensation.
Biological clocks
There are many rhythms in nature and man, for instance the 3/min Parkinson
tremors, the 21 day cycle in manic-depression, the 28 day human menstrual
cycle, circannual (about a year), ultradian (fast, less than a day).
Fig. 28.4
photophase, scotophase, free-run, endogenous
Entrainment, zeitgeber (time giver)
biological rhythms, periodicity, biological clocks
circadian (about a day)
Note human volunteer goes to >24 hr.
Ashoff - light on - nocturnal increase period - like waiting for night
light off - diurnal increase period - like waiting for day
What is the photoreceptor (it can be extraretinal in sparrows and fruitflies)?
Where is the clock? (These are different questions.)
The pineal is important in small-headed animals like lizards.
Light may even hit the pineal in birds, and old experiments with enucleated
sparrows used India ink under skin in head to decrease light and feather
plucking to increase light
Landmark paper
M.Menaker, Nonvisual light reception, Scientific American, March, 1972,
22-29.
In seasonally reproductive birds, testes size in affected by more light
in reproductive season. The pineal has photoreceptors, rhodopsin and molecules
of the phototransduction cascade.
Fig. 28.5B
In higher (bigger headed) animals, the zeitgeber (time giver) is usually
a light-dark cycle, most likely with eye as sensory system.
Recent Paper S.Panda et al., Melanopsin is required for non-image-forming
photic responses in blind mice, Science 301, 2003, 525-527
Pigment may be a different opsin (melanopsin [expressed in melanophores])
(and may be in ganglion cells).
The suprachiasmatic nucleus is important - lesions in SCN disrupt rhythm.
There is a mutant (named "tau") in the hamster affecting the SCN
with altered rhythm.
(The melatonin story was here but is now consolidated in the transmitter
lecture)
Drosophila
Box 28B
Drosophila have locomotory rhythm and rhythm of pupal emergence.
Some classic work
Action spectrum for entrainment drops off dramatically above 500 nm.
Deprivation of carotenoids does not decrease sensitivity for entrainment.
Suggests thqat the photoreceptive pigment is not rhodopsin.
Seymour Benzer at Caltech used Drosophila in "genetic dissection"
of various systems, and, with Ron Konopka, found "period" gene.
Mutants: per=period, l=long, s=short, 0=arythmic, perl 29 hr, pers 19 hr,
per0 - arythmic or fast rhythm.
Clock or photoreceptor were localized to brain.
There is also a rhythm in courtship song, an ultradian rhythm, and it is
affected by per.
Fig. Box 28B
The early excitment, imagining a clock in the head coded by a gene, was
too simple.
PER is a nuclear protein whose mRNA and protein cycle.
Recent paper
A Busza et al., Roles of two Drosophila CRYPTOCHROME Structural domains
in circadian photoreception, Science 304, 1503-1506, 2004.
Cryptochrome is blue sensitive protein (relates to points above about the
pigment not using carotenoids and being short wavelength sensitive).
PERIOD and TIMELESS dimerize and act as negative transctiption factor.
Interfere with action of CLOCK and CYCLE.
CRY binds to TIM, and they are degraded by proteasome.
Exam questions from 2005 - 2007 relating to this outline
During paradoxical sleep, what inhibitory transmitter goes down to spinal
motor neurons?
glycine
Relate the conventional wisdom that most people would like to stay up later
and stay asleep when the alarm goes off to the expression "circadian
rhythm."
about a day is a little longer than 24 hrs for most people
In which cells does melanopsin reside to mediate photic entrainment in mammals?
ganglion cells
EEG spikes from pontine reticular formation to geniculate to occipital cortex
(PGO spikes) are associated with the onset of what?
REM sleep
What is cryptochrome used for?
blue light receptor interacts with other proteins for circadian rhythm
What part of the brain spreads norepinephrine to a wide brain distribution?
locus coeruleus
When are there slow (delta) waves in the EEG?
deep (non REM)
What happens with the levels of the protein product of the period gene in
Drosophila?
it cycles
In an experimental animal, what does the researcher change to go from entrainment
to free-run?
the lighting cycle (to constant light or dark)
Why is REM (rapid eye movement) sleep called "paradoxical" sleep?
EEG as if awake (and respiration and circulation higher)
"A person's endogenous circadian rhythm has a period of >24 hours."
What would you do to demonstrate that?
after entraining on a 24 hr photoperiod, go to constant lighting (free run)
and watch it go to over 24 hr
Very recent literature demonstrated that mice lacking rod and cone photoreceptors
are blind but they still could be entrained to a photoperiod. What is the
photoreceptor (pigment and cell type)?
melanopsin ganglion cells
Sleep disorders and their treatments were put into the context of excitatory
vs inhibitory transmitters. Serotonin was depicted as excitatory. What transmitter,
derived from serotonin, was in the inhibitory category?
melatonin
"PGO spikes are seen at the onset of REM." Translate.
PGO (pontine reticular formation-geniculate-cortex) spikes are seen in the
EEG at the beginning of rapid eye movement sleep
What is the transmitter of the locus coeruleus?
NE
Why do they call them "circadian" rhythms?
about (not exactly) a day for endogenous biological rhythms
In lizards, light stimulates the pineal. In humans, light affects the pineal.
How?
from eye to hypothalamus by circuitous route to pineal
Cryptochrome is one interesting pigment and circadian receptor. Name another
(other than rod and cone rhodopsins).
melanopsin
"PER is a nuclear protein whose mRNA and protein cycle." Translate.
the way circadian genes work in circadian timing is that the protein feeds
back to regulate its mRNA (which of course makes the protein) hence levels
go up and down
This page was last updated 3/28/08
The emotion and motivation lecture
Emotion
Purves et al., Chapter 29 (and part of Chapter 21) (and Chap 25 figure,
Chap 17 figure)
General - historical
Darwin - Expression of emotion in man and animals - 1872
James-Lange theory: physiological changes -> emotional experience "we
are afraid because we tremble" counterintuitive
Cannon-Bard theory: emotional experience is primary (Cannon coined "fight
or flight") (and, of course, it is the sympathetic nervous system that
prepares the body for both)
Hypothalamus
Fig. 29.1
Bard did experiment implying that cortex inhibits hypothalamic (sham - directed
at everything) rage unless the caudal hypothalamus is also disrupted.
Hypothalamus -> reticular formation for rage
Walter Hess (1949 Nobel
prize) - rage or fear if hypothalamus stimulated.
(shared with Moniz who developed frontal lobotomy)
not in book: Electrical self-stimulation (Olds and Milner) - of hypothalamus
is positive reinforcement in operant conditioning paradigm in a Skinner
box
Fig Box 21A
hypothalamus
surprisingly not in book: Lesions to ventromedial nucleus makes a fat rat,
so older literature called this a satiety center, lesions to lateral hypothalamus
makes a thin rat, so LH was once called a hunger center. There are problems
with calling a small lesioned area a such-and-such-center based on the defect.
Also, LH is where medial forebrain (reward) system goes (dopamine, covered
repeatedly already).
Facial expression of emotion
Fig Chap 29 Box A
block diagram
Interesting story - voluntary facial paresis inability to volontarily move
lower facial muscles on one side due to lesion [pyramidal smile]
Fig. Box B Chapter 17
Fig Chap 29 Box A
Photos to demonstrate above
Duchenne (1862) cannot will certain spontaneous smiles
Inability is over-riden (symmetrical) in involuntary movement ["Duchenne
smile"] as hypothalamus and amygdala feed to reticular formation and
hence to motor neurons.
Fig Chap 28 Box A
Duchenne demonstration, electrical stimulation of face ("faradization")
mimics emotional expressions.
Brain areas
Limbic system
Started with Broca (1879)- limbic = "border"
Fig. 29.3
Fig. 29.4
Limbic system
Papez (1937) circuit
Note that in sheep brain tract dissection, the fornix and mammillo-thalamic
tract were shown in slide
11
rabies affects hippocampus - exxagerated fear etc.
tumors in cingulate cortex - fear & other emotions
Figs A & B, etc., Box 29B
Amygdala
Amygdala connects to hypothalamus so it is related to the Papez (limbic)
circuit.
lesions - fearlessness, difficulty recognizing emotions
stimulation - fear and violence
Box C (no figure)
Kluver-Bucy syndrome with amygdala lesion.
A terribly hostile monkey becomes docile with temporal lobe lesion (loss
of fear) - hypersexuality, mouthing objects, etc.
Box D
Patient SM has degeneration of amygdala - cannot recognize or draw fear
Urbach-Wiethe disease (autosomal recessive)
Interesting stories:
Fig (not in 4th edition)
Lesions can be big- Phineas Gage - spike through brain then acted oddly
(is it any wonder?)
Aprosody - inability to express emotion (like with monotone) with suprasylvian
parietal cortex (on right side)
Box E - Affective disorders
Lincoln "I am now the most miserable man living...I must die or be
better, it appears to me,"
Depression (counting several categories) will affect 10 % of people.
Relieved by lots of drugs, fluoxetine (brand name Prozac) [serotonin uptake
inhibitor] widely prescribed likened to "soma" in Aldous Huxley's
"Brave New World" Late 1980's, now one of the most prescribed
drugs. Also sertraline (Zoloft) and paroxetine (Paxil)
Depression more common in females
Other coverage of depression in transmitters
outline
and in "alumnus e-interview."
Exam questions from 2005 - 2007 relating to this outline
What is the main motor nerve to control facial expression?
facial (7)
Why would paralysis be a more likely consequence of stroke in the lower
portion of the face than in the upper portion?
upper is bilaterally innervated, lower is not
Lesions to the lateral hypothalamus resulted in a thin rat, and so the lateral
hypothalamus was referred to as a hunger center. An alternative interpretion
involved the disruption of
what system involved in affect and motivation?
interrupt dopaminergic motivational tract
What part of the cerebral cortex is in the limbic system?
cingulate
Dopamine comes to the caudate from what brain structure?
substantia nigra
With brain cuts in and around the hypothalamus and with stimulations of
the hypothalamus, Bard and (the Nobel prize-winning) Hess (respectively)
studied what process?
rage (emotion)
Under what circumstances would a rat give itself electrical stimulation
of the brain?
electrode in hypothalamus, stimulation is reinforcement (reward), will press
bar in Skinner box
In voluntary facial paresis, a person with unilateral damage to fibers from
the motor cortes, the smile will be crooked. Under what circumstances will
the same person give a symmetrical smile?
a spontaneous smile resulting from humor
What happens to a monkey with a lesion in the amygdala?
get less aggressive, hypersexual
Why is it an oversimplification to call the lateral hypothalamus a hunger
center on the basis of lesion experiments?
there are logical problems, also the medial forebrain bundle traverses the
LH, and it has many controls on motivation
In the many functions attributed to the limbic system, what function did
Kluver & Bucy attribute to the amygdala?
mood on a scale from cuddly to ferocious
This page was last updated 3/28/08
The neuroendocrinology lecture
Sex and Neuroendocrinology
Purves et al., Chapter 30, Figure from Chapter 21
Hormones
background
"endocrine" - ductless, into blood stream
release - cells with blood vessels
Fig. 30.3A
steroids from cholesterol.
They can have permanent perinatal organizing effects
(e.g. neonatal testosterone will make heavier adult female [males eat more])
in addition to sustained or adult effects
Box 30B
John -> Joan -> John (medical pseudonyms), actually Bruce -> Brenda
-> David
Electrocautery mishap during circumcision of twin.
Sex change operation.
John Money (Hopkins) - theory that upbringing is as important as chromosomal
make-up in gender identity.
Poorly adjusted, demanded to know truth at age 14.
Change back to guy eventually
Money's research seemed interesting at first but was infamous with hindsight
Fig. Box A Chapter 21
Hypothalamus (peptides)
(1) Posterior pituitary (peptides
magnocellular neurosecretory cells
oxytocin (milk, delivery)
synthetic to induce labor
vasopressin (ADH), H2O and blood pressure
ADH action on kidney
alcohol, caffein inhibit anti [diuresis] hormone
also low blood pressure -> renin (kidney) ->
angiotensinogen (from liver) - renin -> angiotensin I ->II
affects kidney, blood vessels,
subfornical organ to lateral hypothalamus (for thirst)
Fig. Box A Chapter 21 (again)
(2) Anterior pituitary Master gland
portal system etc.
Hypothalamus parvocellular neurosecretory cells to anterior pituitary
releasing factors
inhibiting factors
Example: CRF-> ACTH->cortisol feeds back to body, hypothalamus, brain
Adrenal cortex - Glucocorticoids, metabolism, inflamation
negative feedback in stress response
Fig. 30.4B
Thus (obviously) hormones (estradiol shown here) must bind to brain, and
this has been known for a long time (note the reference to McEwen and Pfaff,
famous names in this work from the 1970's
Fig. 30.4A
recall that steroids affect transcription
Fig. 30.3A [again]
Hormone synthesis
note testosterone can have its affects as 17-beta-estradiol
androgen receptor mutation (androgen insensitivity syndrome [AIS]) ->
testicular feminization, children think they are females until there is
no menstruation
There are androgens from adrenal, so with Congenital adrenal hyperplasia,
CAH, clitoris is large and behavior is "tomboy"
lack of 5-alpha-reductase
-> "testes-at-twelve" (at puberty, testes descend, clitoris
becomes penis etc when there is enough testosterone to overcome deficit)
There is a pedigree in the Dominican Republic.
When I typed "five alpha reductase" or the like into my search
engine, I got hits on hair loss, concerning male pattern hair loss (androgenetic
alopecia) accelerated by DHT and alleviated by a drug, Propecia
Steroids are involved in photomorphogenesis in plants, and there is a mutant
(in Arabidopsis) of a gene with homology to 5-alpha reductase.
Sexual dimorphism
Fig 30.2
sex organ development
Sry gene on Y codes for TDF (testicular determining factor)
In female, Wolffian ducts degenerate and Mullerian ducts develop into oviducts,
uterus, and cervix (default pathway).
In male, testes make testosterone and MIH (Mullerian inhibiting factor),
Mullerian ducts degenerate, Wolffian ducts become epididymus, vas deferens
and seminal vesicles (active, not default)
urogenital groove becomes external genitals
A lot of the chapter concerns neural dimorphism, surprisingly not mentioning
(much) the original famous example of the part of the bird brain controling
song which is male-specific
Fig. 30.5
motor neuron count in spinal cord of Onuf's nucleus controling perineal
muscles which function differently in male and female rats
(This is in many ways parallel to the Fig. 23.9 example of spinal motor
neuron count being influenced by limb bud ablation or supranumerary limb
buds.)
Fig. 30.6A
INAH (interstitial nuclei of anterior hypothalamus) can be sexually dimorphic
Fig. not in 4th edition
in work by LeVay, the suggestion is made that homosexuals and heterosexual
males differ and that homosexual males resemble more females in hypothalamic
area
The book also covers some specific details in differences in cognitive function
(a fairly controversial topic and one where it is sometimes difficult to
get robust, unconfounded data)
Fig. 30.8
(this could also be in another chapter)
cortical representation and receptive field of female ventrum changes during
lactation
Exam questions from 2005 - 2007 related to this outline
What changes, and in whom, in congenital adrenal hyperplasia?
females may be masculinized (anatomically and behaviorally)
Simon LeVay presented evidence that waht sexually dimorphic area of the
brain was altered in homosexual males?
part of hypothalamus
Why would there be a different number of motor neurons in males vs. females
in Onuf's nucleus of the spinal cord controlling the perineal muscles?
to mediate male specific behavior
Adult male rats are heavier than females. What is the schedule of testosterone
administration to effect a change toward male weight in the female?
one neonatal application
Money's attempt to demonstrate that upbringing predominated over chromosomal
makeup in gender identity backfired. How?
boy surgically changed to girl was never adjusted
A figure was shown demonstrating estradiol binding in many parts of the
brain, especially the hypothalamus. Where, in the affected brain neurons,
would you expect most of this binding to occur?
bound to intracellular receptor protein to control gene trancription
How does the somatosensory projection change during lactation?
larger area and smaller receptive fields for ventrum of dam
This page was last updated 4/1/08
The memory and the brain lecture
Memory
Purves et al., Chapter 30
Chapters 23 and 24 dealt with "learning" at the cellular level,
sort of an extension of development.
General considerations:
Consider how important memory is in defining the human experience.
In many ways, memory seems to be like an input to the CNS, as significant
as the only real input, namely sensory input.
Probably most believers' concept of an after-life relies on memories being
intact.
In many ways memory formation is a continuation of development.
Forgetting (?) - intuition indicates how widespread forgetting is, but,
when operant conditioning dominated American psychology, forgetting was
denied - only extinction (sort of an "unlearning") existed.
Dementia - Alzheimer's syndrome is a reminder as to how fundamental memory
is to the quality of human life.
The entire literature empahsizes short- and long-term memory.
Amnesia is informative: "retrograde" for period long ago (rare)
vs. anteriograde, cannot learn new.
Recent memory loss, a patient might know how to play cards but not know
how (s)he came to be playing that particular game.
Fig. 30.1
Chapter emphasizes declarative memory (for facts, possibly involving language)
and procedural (skill, practiced skills) memory.
Interesting stories:
Extraordinary memory of Luria's subject Sherashevsky.
Fig. Box C
Famous patient HM studied by Brenda Milner - lesion temporal lobe + hippocampus
and amygdala at age 27 for epilepsy [grand mal seizures]- has anteriograde
amnesia -after 50 yrs of study Milner still has to introduce herself - but
HM can learn mirror drawing task (procedural memory).
Landmark Paper: WBScoville & B Milner, Loss of recent memory
after bilateral hippocampus lesions, J Neurol Neurosurg Psychiat 20, 11,
1957, see also J NIH Res 8, 42-51, 1996
Another subject - NA, lesion [accidentally stabbed by roomate playing with
fencing] of dorsomedial thalamus, mammillary bodies, right medial temporal
lobe - amnesia like HM.
Another, RB, had ischemia with only loss of hippocampus, verified after
his death.
Short-term memory-
presumably something electrical like Hebb circuits - easily disrupted,
say, by electroconvulsive shock (used to treat depression).
Then there must be a consolidation for the sake of long-term memory which
must involve permanent changes like changes in synapses. mRNA and protein
MUST mediate change.
Retrieval is an important consideration.
Long term memory-
Biochemistry of memory got off to a terrible start
RNA
Classic (bad) papers
R. Thompson and J.V.McConnell (1955) Classical conditioning in planarian,
Dugesia dorotocephala, J. Comp. Physiol. Psych. 48, 65-68.
Poor controls, not replicated
J.V.McConnell, (1962) Memory transfer through cannabalism in planarium,
J. Neuropsychiat. 3 suppl 1 542-548 (eat RNA of worm that has learned, then
worm knows it already)
very silly
Classic (spoof) paper
J. G. Nicholls, D. A. Baylor et al.. (i.e. the whole physiology department
at Yale), Persistence transfer, Science 158, 1967:
...demonstrate the transfer of certain innate characteristics from one oscilloscope
to another. Accordingly, a Tektronix Storage oscilloscope (RM 564)...was
pounded with a Sears ball peen hammer (Cat. No. 28B4652) on a Fischer Lab
bench (Cat. No. B158)...until all electronic components and the tube were
reduced to sufficiently small pieces to pass through a filter made of 007-mesh
nylon stocking (seamless). The storage oscilloscope fragments (SOF)...sprinkled
over the chasis of a Tektronix 502 oscilloscope. The persistence of the
afterglow was used as an index... In 18 of 33 experiments, there was an
increase which was highly significant (,.001, t-test). While the average
increase in persistence was not large - 3.2 msec - it nevertheless suggested
that some change had been wrought in the recipient oscilloscope by the SOF.
etc.
Hollywood
A book,
(also a 1970 movie) Hauser's
memory, describes events after a dead spy's RNA is transferred to gain his
information.
Personal reflection.
One of the professors whose work I had to learn (to pass my Ph.D. exam)
worked in this area. His graduate student was in my peer group. His research
involved quickly dissecting the brain after teaching a rat in a T-maze and
showing that RNA in the hippocampus changed. Before he was finished, his
work was on control experiments showing that these changes might not be
attributed to the maze learning experience.
In summary, RNA experiments were naively done with great optimism &
poor controls
Protein
Landmark papers
B. W. Agranoff Memory and protein synthesis, June 1967 Scientific American,
115-122
long term memory must involve something like protein synthesis L. B. Flexner
et al. Memory in mice analysed with antibiotics, Science, 155, 1967, 1377-1383
antibiotics like puromycin block protein synthesis
but return of memory with saline washout suggests interference with retrieval
How is memory stored in the brain?
Fig. 30.6
How and where are memories stored?
Lashley - search for engram - found "equipotentiality" [in cortex]
(vs. localization of function)
Pribram - it is like
a hologram - everything is stored a little bit everywhere (lasers and holograms
were popular science in the 1960s; half a hologram has all the information
of the whole hologram, but degraded -- you have to "look around the
corner" to see everything.).
Fig. 30.7
The temporal lobe seems particularly important for establishment, but not
storage.
Penfield - electrical stimulations
Working memory for spatial location
Animal model of "working memory" - radial 8 arm maze put a
food pellet on the end of each arm and rat uickly learns to visit each arm
one time before any repeats - David Olton - rat has amazing spatial memory
and hippocampal lesion disrupts that.
Personal reflection - he was an associate professor where I was an
assistant professor; this demonstration, that became standard in many learning
labs across the country, was the undergraduate project of Robert Samuelson,
an undergraduate student, and was made by 2x4's thrown together in the wood
shop. Although Scientific American was known to publish mostly articles
invited from famous people, Dave broke the mold by submitting the paper
(Spatial memory, June 1977, 82-98) that made their work known even in undergraduate
courses across the country.
Alzheimer's disease
Box D - Alzheimer's disease - neurofibrillary tangles (tau) in cells and
amyloid plaques (BA) outside cells -
5% are familial early onset -
beta amyloid precursor protein mutations on chromosome 21 (695-770 aa long.
beta and gamma secretase cut to 42 aa fragment - bad-
presenillin 1 on chromosome 14
presenillin 2 on chromosome 1
also apolipoprotein E (E4 allele) varient (on chromosome 19) predisposes
for this.
tau on chromosome 17
There is lots more information and it pours in fast these days.
Recent paper G Miller Computer game sharpens minds, Science 310,
1261, 2005
Can mental exercise help?
Garden view care center activity based dementia care
Exam questions from 2005 & 2006 relating to this outline
Without answers
Even though it has been over 50 years since his famous textbook, Donald
Hebb is still mentioned frequently in neuroscience. In what context?
Why did researchers put puromycin, an antibiotic, into the brain?
What is the precursor for the material that makes extracellular plaques
in Alzheimer's disease?
What was the mental defect in Brenda Milner's famous patient HM, with lesions
of the hippocampus?
Name the intracellular accumulation product in Alzheimer's disease.
Although "memory transfer through cannabalism" [of RNA] was debunked
in planaria, mRNA must be involved in long-term memory. By what mechanism?
What does Lashley's "search for the 'engram'" have to do with
memory and localization of functions
Brenda Milner's famous subject, HM (who had hippocampal lesions) ,could
not remember what had just happened but could learn to draw in a mirror.
What famous distinction between types of memory is addressed?
By what mechanism would Alzheimer's disease interfere with axon transport?
Mutations in Presenilin 1, Presenilin 2, and the E4 allele Apolipoprotein
are genetic risk factors. Mutations in what other protein is missing from
the above list of risk factors for the accumulation of beta-amyloid plaques.
"Presenilins are key mediators of Notch signalling." How does
that relate to Alzheimer's disease?
In what nervous system compartment are neurofibrillary tangles?
With answers
Even though it has been over 50 years since his famous textbook, Donald
Hebb is still mentioned frequently in neuroscience. In what context?
reverberating circuits of excitation for short term memory
Why did researchers put puromycin, an antibiotic, into the brain?
blocks protein synthesis
What is the precursor for the material that makes extracellular plaques
in Alzheimer's disease?
amyloid precursor protein
What was the mental defect in Brenda Milner's famous patient HM, with lesions
of the hippocampus?
anterograde amnesia
Name the intracellular accumulation product in Alzheimer's disease.
neurofibrillary tangles of tau
Although "memory transfer through cannabalism" [of RNA] was debunked
in planaria, mRNA must be involved in long-term memory. By what mechanism?
in mediating any long term changes in synaptic function by protein synthesis
What does Lashley's "search for the 'engram'" have to do with
memory and localization of function?
memory is stored everywhere with equipotentiality
Brenda Milner's famous subject, HM (who had hippocampal lesions) ,could
not remember what had just happened but could learn to draw in a mirror.
What famous distinction between types of memory is addressed?
declarative vs procedural
By what mechanism would Alzheimer's disease interfere with axon transport?
the hyperphosphorylated protein, tau, regulates microtubules
Mutations in Presenilin 1, Presenilin 2, and the E4 allele Apolipoprotein
are genetic risk factors. Mutations in what other protein is missing from
the above list of risk factors for the accumulation of beta-amyloid plaques.
amyloid precursor protein
"Presenilins are key mediators of Notch signalling." How does
that relate to Alzheimer's disease?
enzymatic cleavage of membrane proteins is not just a pathological mechanism,
it causes release of intracellular domains of important signalling proteins
In what nervous system compartment are neurofibrillary tangles?
inside neuron (axon)
This page was last updated 4/26/07
The Synthesis lecture
But when for the fourth time they had come around to the well springs
then the Father balanced his golden scales, and in them
he set two fateful portions of death, which lays men prostrate,
one for Achilleus, and one for Hector, breaker of horses,
and balanced it by the middle; and Hector's death-day was heavier
and dragged downward toward death, and Phoibos Apollo forsook him.
Homer
The mind - brain (fate - free will) problem
George W. Gray "The Great Ravelled Knot" Scientific American October
1948
(optimism to the study of the brain)
But consider how a "belief" in natural laws (e.g. conservation
of momentum) can justify a "cosmic" determinism, and thus the
mind-brain problem becomes a problem of fate vs. free will.
Me: "if you put the momentum of every particle in the universe into
a big computer, you should be albe to predict all events"
But you cannot know all of that - Heisenberg uncertainty principle
(1932 Nobel
Prize in Physics "creation of quantum mechanics, the application of
which has, inter alia, led to the discovery of the allotropic forms of hydrogen")
Personal reflection. I know his son, Martin, who studies Drosophila, and
I stayed at his castle in 1978 when I visited his lab. (see also Memoirs
on this page)
Schrodinger "quantum physics has nothing to do with the free will problem"
(1933 Nobel
Prize in Physics "new productive forms of atomic theory")
Sherrington "energy scheme brings us to the threshold of the act of
perceiving and there bids us goodbye"
(1932 Nobel
Prize "functions of neurons")
Lloyd Morgan's
"cannon" was very influential and is often summarized as not
to attribute anything to consciousness if a mechanistic explanation can
be used instead (but some passages read differently).
Walter R. Hess, Causality, Consciousness, and Cerebral Organization, Science,
158, 1967, 1279-1283
(1949 Nobel
Prize "functional organization of the interbrain as a coordinator of
the activities of the internal organs")
"physiology must give up in the attempt to submit a comprehensive explanation"
"where do the activating forces come from?"
"display of behavior presupposes the action of forces...voluntary acts
are no exception"
"possibility as yet undiscovered forces may be active which belong
to none of the known categories, forces inherent in the living neuronal
system of man and other higher animals"
Eccles - a "one quantum below threshold" theory
(1963 Nobel
Prize "ionic mechanisms involved in excitation and inhibition in the
peripheral and central portions of the nerve cell membrane")
"critically poised neurons" "fields of influence" "a
shifting harmony of subpatterns"
which seems to indicate that a little variability in the EEG gives room
for some input (from consciousness) to feed in and change things
Sperry, R.W.
(1981 Nobel
Prize "functional specialization of the cerebral hemispheres")
Emergent properties
Mind-brain interaction: mentalism, yes; dualism, no Neuroscience 5, 195-206,
1980
Changing concepts of consciousness and free will Perspectives in Biology
and
Medicine 20, 1976, 9-19
Changing priorities Ann Rev. Neurosci, 4, 1-15, 1981
quotes:
A fundamental premise of materialistic science holds that a complete explanation
of brain function is possible in purely objective physiological and biophysical
terms.
In other words, in the world view of materialist science, real mental freedom
to act and choose is only an illusion, and the whole value-rich world of
inner subjective experience gets set aside as some kind of passive, impotent
by-product, an epiphenomenal correlate, or just an interior aspect of the
one prime material brain process.
The resultant view of human nature and the kinds of values that emerge are
hardly uplifting.
All of us would prefer to think that we are more than mere puppets of environmental
reinforcement and our brain's physiology and that the inner experience we
live with most of our waking life is something real and of some material
consequence.
At stake are central key concepts that directly involve fundamental convictions
regarding the nature of man's inner being, physical reality, the meaning
of existence, and related matters of ultimate concern.
...recall that a molecule in many respects is the master of its inner atoms
and electrons. The latter are hauled and forced about in chemical interactions
by the overall configurational properties of the whole molecule. At the
same time, if our given molecule is itself part of a single-celled organism
such as paramecium, it in turn is obliged, with all its parts and partners,
to follow along a trail of events in time and space determined largely by
the extrinsic overall dynamics of Paramecium caudatum. When it comes to
brains, remember that the simpler electric, atomic, molecular, and cellular
forces and laws, though still present and operating, have been superceded
by the configurational forces of higher-level mechanisms. At the top, in
the human brain, these include the powers of perception, cognition, reason,
judgment, and the like, the operational, causal effects and forces of which
are equally or more potentent in brain dynamics than are the outclassed
inner chemical forces.
Evolution keeps complicating the universe by adding new phenomena that have
new properties and new forces that are regulated by new scientific principles
and new scientific laws--all for future scientists in their respective disciplines
to discover and formulate. Note also that the old simple laws and primeval
forces of the hydrogen age never get lost or cancelled in the process of
compounding the compounds. They do, however, get superceded, overwhelmed,
and outclassed by the higher-level forces as these successively appear at
the atomic, the molecular and the cellular and higher levels.
Exam questions from 2005 & 2006 relating to this outline
Without answers
"Lloyd Morgan's canon" is a fundamental statement in comparative
psychology applied to what aspect of animal behavior?
According to Sperry, "the simpler ... molecular ... forces ... have
been superceded." How then does he rationalize free will even though
"materialistic science" would explain brain function in "biophysical
terms."
With answers
"Lloyd Morgan's canon" is a fundamental statement in comparative
psychology applied to what aspect of animal behavior?
whether consciousness is needed to explain behavior
According to Sperry, "the simpler ... molecular ... forces ... have
been superceded." How then does he rationalize free will even though
"materialistic science" would explain brain function in "biophysical
terms."
because there are emergent properties of higher level configurations
This page was last updated 3/22/07
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