The first lecture outline

Historical Introduction

Purves et al., Chapter 1 and figures from Chapters 6 & 26 and Appendix B
(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.

A note on figure references in this outline
Fig. B17 is the figure in the text, useful for you
(15) is just a note for me to find the power point slide on the CD

Appendix B Fig. B17 (15) (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:

Fig. 1.12A (29) (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

Fig. 1.12C (31) (colored view of exterior 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

Fig. 1.12D (32) (human brain drawing showing coronal sections, to reveal basal ganglia)
Fig. 1.12E&F (33&34) 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 (22) (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 (19) (diagram of knee jerk reflex)
Afferent (toward CNS)- Efferent (away from CNS)

Fig. 1.12B (30)
This shows a mid-sagittal section
Decussation- crossing of fibers
The biggest is the corpus callosum

Fig. 1.11A (26) (brain with directions drawn in)
Rostral (toward the front)- Caudal (toward the back)
Superior (above) Inferior (below)
(not shown) Lateral - Medial

Fig. 1.11B (27) (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

Fig. B2 (3) (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

Fig. 26.1 (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.
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. 26.2 (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

Structure of the Nerve cell

Fig. 1.2F (4) - (Purkinje cell)
1836 Jan Purkinje(Czech) - Purkinje cells in cerebellum - these are highlighted with Golgi (see below) staining

Fig. 1.7 (19) (diagram of knee jerk reflex) [again]
1865 Otto Deiters (Bonn) - motor neuron

Fig. 1.3A (5) (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.

Fig. 6.11 (24) 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 A-D (15) Nissl stain shows cells (like cell layers in cortex
Fig. 1.6 E,F (16) Golgi technique only colors a few cells so they can be viewed in their entirety.
Fig. 1.6 G,H (16) a fluorescent dye can be injected.

Here is a slide I prepared in the 1980s to explain how antibodies could be used in the electron microscope to localize proteins. The protein is an antigen, an antibody, here a monoclonal antibody) binds to it. A secondary antibody with an electron dense attachment (colloidal gold) binds the antibody.

Here is a micrograph where Rh1, the rhodopsin of one type of photoreceptor in the Drosophila compound eye, is labeled with immunogold (Sapp et al, J. Neurocytol. 20, 597-608, 1991)

Here is a laser scanning confocal microscope, a fancy fluorescence microscope.

Here is Rh1 labeled with a fluorescent antibody in the confocal

Fig. 1.4 A (10) Tau (red) (microtubular binding protein in axons) accumulates in Alzheimer's, tubulin (green) in cells

Fig. 1.4 B (10) Developing cell in culture has actin in growing tips.

Review utilizing Sylvius

A CD 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, especially 4, 17
Occipital lobe
Postcentral gyrus
Spinal cord (including cervical and lumbar enlargements of gray matter for fore- and hind-limbs
Striatum
Substantia nigra

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. Churchill in Psychology is also a neuroscientist, and he teaches PSYA471 Lab in Neuroscience. 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

This page was last updated 1/7/05






Neurons and glia

from Purves et al., Chapter 1, Figures from Chapters 3, 6, 15, 21, Appendix B

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 (5)
Typical neuron (Nerve cell) soma, perikaryon
nerve cells have typical organelles, nucleus, rough ER, Golgi apparatus, mitochondria
axon hillock, dendrites

Fig. 1.3C (6)
terminal bouton, synapse
vesicles (small, electron lucent)
post-synaptic density

Fig. 1.4 E (11) Dendrites have protrusions (spines) tubulin is labeled
Fig. 1.4 F (11 still) spines, actin is labeled

TRANSPARENCY shows a freshman biology view of a "typical" neuron like a spinal motor neuron

Fig. 15.4 (6) (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 (13) ABC (11) astrocyte, oligodendrocyte, microglial cell
astrocytes - support, repair, grouping, regulate ions, neurotransmitters
microglia -> macrophages (Virchow noted phagocytosis in pathology)

Fig. B4 (10) Astrocyte end feet involved, along with capillary endothelium, in blood brain barrier
central nervous system is well sequestered from the immune system

Fig. 21.11 ABC (37, 38) 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 (6) (again) myelin
also
Fig. 1.3G (9) node of Ranvier between adjacent patches of myelin
Fig. 1.5 B (13) oligodendrocyte
Fig. 1.5F (14) myelin is red, lots of channels at node of Ranvier green

Fig. 3.13 A,B (22)
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.

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 gron 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


This page was last updated 1/19/05







The bioelectric potentials and ion pumps lecture

Bioelectric potentials, Ion pumps

Purves et al., Chapter 2 , also pp. 69-73, Figures from Chapter 4

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 (4)
Insertion of stimulating and recording microelectrodes

Fig. 2.2 B (5)
Voltage as a function of time ("graph") - resting and action potentials
Depending on direction of stimyulation, passive potentials are depolarizing or hypewrpolarizing
Threshold to trigger action potential is shown
Square wave (stimulus) leads to exponential curve (recording) because of capacitance

Fig 2.1C (3) 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 (6)
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 (12) 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 (11)
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 (1 & 2)
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 (11) 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 (5) 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 (6)
shows elementary properties of pump

Fig. 4.10A (26)
Na+-K+-ATPase
Uses 1/3 (2/3 if high electrical activity) of cell

Fig. 4.11B (29)
"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 (31-32)(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 (28) 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, (18) ion gradients for mammalian neuron:
K+ in 140, K+ out 5
Na+ in 5-15, Na+ out 145

Fig. 2.4 C (8) shows dependence on external K+

Fig. 2.7 AB (13, 14) 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

This page was last updated on January 10, 2005








The action potentials and channels lecture

Action Potentials

Purves et al., Chapters 3 & 4

Summary

Fig. 3.8 (10) 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 (17)
An action potential is non-decremental

Passive spread of potential along axon

Fig. 3.10 (15) 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 (5) (again)
TERMS: threshold, generator potential, all-or-none, refractory, unidirectional
NOTE also the membrane acting as a low pass filter

Fig Box C (18) [first figure] shows exponential decay and space constant (lambda)
Fig Box C (19) [second figure] shows exponential charging of capacitance and time constan (tao)

Cable equation
Here's a pdf of the transparency I'm showing you

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 (20)
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" must have established ion gradients in the first place
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 A (Chapter 3) (1) - 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 (4) voltage clamp data
voltage clamp - change voltage then pump and monitor current needed to keep it there
I - t curves

Fig. 3.3 (5) 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 (6) 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 (7)
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 B (chapter 4) (9 & 10)
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 (14, 15)
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 (19)
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 (20) 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 (17)
Sodium channel, now diverse (human 10 genes)
electric eel Electrophorus electricus 600 V book
Huge - 1820 amino acids - "pseudotetramer"
S4 - gating - positively charged (basic) arginine (R) or lysine (K)

Fig. 4.7 (21) rotation
Pore between 5 & 6 (not hydrophobic)

Fig. 4.1B (3)
low current (1-2 pA, (Fig. 4.1) (5), 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 C (Chapter 4)
Toxins
Tetrodotoxin puffer fish (saxitoxin dinoflagellates) block Na+ channel
scorpions
and many others

Fig. Box D - D (35) (Chapter 4)
genetic diseases of channels
myotonia (stiffness from too much excitation) from Cl- channel defect

Fig. Box D - A (33) (Chapter 4)
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 D - B (34) (Chapter 4)
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 (22) Structural studies on bacterial K+ channel - it takes a lot of protein to do X-ran crystallography

Fig. 4.8(23)
selectivity by pore size
interesting that non-hydrated ion passes.
Hydrated - size is inverse
Li > Na > K > Rb > Cs (lyotropic series)

Fig. 4.6 C (19)
There are a lot of configurations of channels


This page was last updated 1/17/05











The synapses and electrophysiology lecture

Synapses

Purves et al. Chapter 5

Major point

Cell theory (cells being separated) implies that cells must communicate with each other through an extracellular connections and most communication is through chemical messages
- "synapse" - = "clasp"

Fig. 5.1B (1)
Vesicles, spine, receptors (the ionotropic type, i.e. channels) are shown

"Electrical synapses"

Fig 5.1A (1)

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, 1959 work by Furshpan and Potter.
They are also used to connect myocardial cells electrically at intercalated disk.
Conductance is high - 120 pS.
They are not in mammalian brain, hence our concentration on chemical transmission.

Fig 5.2A (2)
Gap junction is patch of hexamers forming big channel in register with adjacent cell.
Proteins, called connexons, are very diverse.
They are often named with a number that represents the molecular weight.
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).

Fig. 5.4 (5,6)
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. 5.20AB (47, 48)
Sir John C. Eccles 1963 Nobel (with Hodgkin & Huxley) EPSP & IPSP
Postsynaptic potentials (Eccles, using spinal motor neurons)
Excitatory and Inhibitory integrate

Fig. 5.19A (45)
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 5.19BC (45, 46)
GABA 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 (14) - 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 which gives 40 mV potential

Fig. 5.8 A (16) 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 (4)
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 5.14C (30) 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)"

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. 5.13 (26) 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 ABC (28-30)
SNAREs and SNAP (docking)
In addition to SNAREs and SNAP, Ca binding synaptotagmin is for fusion

Fig. Box C (32) BoTX and TeTX sites.

This page was last updated 1/25/05














The neurotransmitters and neuromodulators lecture

Neurotransmitters

Purves et al., Chapter 6 and selections from Chapters 5, 17 and 20 (for autonomic nervous system)
Sylvius (there are many places where you might want to look at the structures marked on the sylvius CD)
This outline will focus on transmitters. Although transmitter receptors will be mentioned, they will be covered in more detail on the next outline.

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.

Box A (Chapter 5) (7)
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 (41, 42) (I will show you the figures later)
Fig 6.1 (1-5)
Chemical synaptic transmitter substances:
Monamines (acetylcholine, catecholamines, serotonin, histamine, octopamine)
Amino Acids (GABA [gamma amino butyric acid], glutamate, glycine)

Figure 6.15 (32)
Peptides (many)

General aspects about synthesis

Fig. 5.5A (8)
synthesis for small molecules in terminal
enzymes transported by slow axonal transport

Fig 5.5C (10)
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 (30, 21)
Further processing, especially cleavage (common for many peptide transmitters and hormones)

vesicles

Fig. 5.5 B (9)
40 nm (small) electron lucent vesicles and just a few large dense core

Fig. 5.5 D (11)
somewhat larger dense core are catecholamines or peptides
100 nm diameter granules are secretory
Importantly, transporters concentrate transmitters into vesicles

Gasses

like Nitric Oxide (NO), made by neuronal nitric oxide synthase (nNOS), 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.

General

Fig. 5.1.B (1)
Show a typical Synapse figure again
Receptors in this figure are channels

Fig. 5.22 A (50)
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. 5.22B (51)
There is another kind of receptor, the G-protein-coupled receptor.
For cholinergic transmission, the muscarinic receptor is an example

Monamines

Fig. 5.4 (5,6)
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 (6)- Acetylcholine
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 (23) Catecholamines
Adrenergic
(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 (41)
"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. 20.1 (2)
Parasympathetic, cranio-sacral, ACh (nicotinic and muscarinic), ganglion near target

Part of Fig. 21.1 (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. 20.2 A (3)
arrangement of sympathetic output from lateral horn neuron -> white ramus -> sympathetic ganglion -> gray ramus

Fig. 20.3 B (6)
Simpler for parasympathetic, i.e. from brain stem nucleus...

or ...

Fig. 20.3 C (7)
lateral horn in sacral cord to parasympathetic ganglion

Fig. 20.4 A (9)
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 blocks muscarinic synapses and is in anti-diarrhea medications to slow motility.

Fig. 20.8 (23)
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.

Fig. 20.10 (25) male sexual function as an example. This is the only place where parasympathetic affects arterioles, dilating them in corpus cavernosum for erection. Sympathetic contributes to ejaculation.

Serotonin

Fig. 6.13 B (29)
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.

SSRIs (selective serotonin reuptake inhibitor)
Prozac (fluoxetine)
Paxil (paroxetine)
Zoloft (sertraline)
There is new controversy about whether these increase the incidence of suicide, now thqt they ar3e 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.

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.

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.

Amino acid transmitters

Fig. 6.6 (15)
Glutamate
Central excitatory - like inputs to hippocampus - maybe half of CNS synapses
Synthesis is simple from glutamine (from nearby glia) by glutaminase.
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 6D - too much glutamate causes a cycle of Ca2+ influx.
May be involved in ischemia - induced injury.

Fig. 6.8 A (19)
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 (20)
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 (29)
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 (24, 25) Fig. 6.12 B (28)
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 Raphe
Norepinephrine from locus coeruleus
Serotonin from Raohe

Parkinson's
(mentioned here because of dopamine)

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
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 in Dr. Fisher's lab (Bio, SLU) works 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.
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 - 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

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 (voice at the end of Michael Jackson's "thriller) 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]), 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.
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

Table 6.2 (43)
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 (33-35), Fig. 6.17 (36, 37), Box F (39, 40)
R. A. Nicoll and B. E. Alger, The brain's own marijuana, Scientific American, pp 68-75, Dec 2004.
Cannabis sativa

BoxF (39)
THC used to treat anxiety, pain, nausea, obesity, glaucoma.

BoxF (40)
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.
Presynbaptic CB1 prevents GABA release to block glutamate excitation

Fig 6.16A (33)
Anandamide

Fig. 6.16B
2-arachidonoyl glycerol (2-AG)

Fig. 6.17 AB 36, 37)
2-AG released from postsynaptic cell


ATP and purines

ATP (and AMP and adenosine)
excitatory transmitters


This page was last updated 2/1/05





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 (7, 8)
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.

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 C (Chapter 6) (14)
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 (10, 11)
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 (16) 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 (22)
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)

Fig 6.5 A (12)
7 transmembrane domains called G protein coupled receptors.
By hydrophobicity, they all cross membrane in 7 a-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 (13)
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 (4,5)
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 (6)
G protein so named because it (alpha subunit) binds GTP
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 (7)
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)

For dopamine, a Gi (inhibitory) inhibits the cAMP cascade

The phosphoinositide cascade

Fig. 7.7D (11)
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 (12)
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 (10)
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 (13)
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 (17)
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).


This page was last updated 2/1//05





The neuroanatomy lecture

Neuroanatomy

Purves et al. part of Chapter 1, Appendices, the Sylvius CD

Resources

Here is a site I found on mouse brain anatomy
(unfortunately, some of the links are dead)

I found these pictures of stereotactic apparatus at the Kopf Instrument site.
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.

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.

Background

big area of cerebral cortex (2.2 square meters) from folding into sulci and gyri

Fig. 1.6 AC (15)
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. 1.11AB (26, 27)
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. 1.12A (29)
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. 1.12C (31)
frontal lobe - planning behavior
parietal lobe - attending to stimuli
temporal lobe - recognition
occipital lobe - visual analysis

Fig. 7C Appendix B 17
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 A1 (appendix A) (6-9)
and
Fig. A1 (1) (appendix A)
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. B8 B (19)
neocortex (found only in mammals),
hippocampus (archipallium) (one cell layer) (seahorse shaped)
and olfactory cortex

Fig. 1.12B (30)
human midsagittal
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 28)

Fig. A2 (2) (Appendix A)
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. 1.12 E (33)
coronal section
this view is especially good for the basal ganglia and internal capsule
striatum = caudate + putamen

Fig. 1.11C (28)
spinal cord - cervical thoracic lumbar and sacral nerves
Cauda equina branches out toward bottom

Fig. B5 (12) (appendix B)
meninges (as in meningitis)
(1) dura (2) arachnoid (3) pia
subarachnoid space has cerebrospinal fluid (CSF)
So do ventricals.

Fig. B7 (15) (appendix B)
ventricles
the CSF is "isolated" by the blood-brain-barrier (BBB)
and is secreted by the choroid plexus


This page was last updated 2/1/05





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
The directions that follow can be applied to any of the larger mammalian brains (dog, cat, sheep, man). Sheep brains in Carosafe®, a formalin analog, will be supplied to you for the following dissection exercises.

Where some of the dissections of the sheep brain are to be made on the right side of the brain and some on the left, 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 textbooks and atlases particularly for a comparison with the human nervous system. A laboratory notebook in which you record your observations and drawings is very valuable.

 

I. Brain Membranes and Blood Vessels

If your specimen has the brain membranes (meninges) intact, study their structures. Identify the dura mater and the pia mater. The arachnoid, lying between these two membranes, is difficult to see. Note the blood supply, especially the circle of Willis and the other vessels on the ventral surface. The hypophsis (pituitary) can be removed to permit better observation of the circle of Willis. Cut through the infundibulum (the pituitary stalk), which can be seen emerging from the hypothalamus between the optic chiasm and the mammillary bodies. 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

Locate the roots of the twelve pairs of cranial nerves. Each is listed below and its function identified. III. Surface Anatomy of the Brain

Examine carefully the external form of the sheep brain. By referring to the photographs of the dorsal, lateral, and ventral aspects of the brain surface, that will be provided, locate and learn the names of the structures identified in these photographs (omitting only the minor subdivisions off the cerebellum, and the minor sulci and gyri of the cerebral cortex). It will be necessary to remove portions of the brain membranes, especially around the medulla, to view some of the structures. Extreme care must be exercised in this procedure to avoid damaging the surface of the brain. However it is not possible to preserve the cranial nerves entering the medulla since the membranes in this region are very thick and strong. On the cerebellum identify the vermis, hemispheres, and flocculus. On the cerebral hemispheres identify the longitudinal fissure, the lateral fissure, the rhinal fissure and the suprasylvian fissure as well as the following structures identified from the ventral aspects:
  1. Olive
  2. Pons
  3. Cerebral peduncles
  4. Interpeduncular nucleus
  5. Mammillary bodies
  6. Diagonal band
  7. Amygdaloid nucleus
  8. Pyriform area
  9. Hippocampal gyrus
  10. Lateral and medial olfactory gyri and stria
  11. Trapezoid body
  12. 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. 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 pf 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 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. Anteriorly, a thin sheet of tissues called the anterior medullary vellum forms the roof. Behind, the roof is formed by a thin non-nervous membrane (tegmen) part of which is highly vascular and much folded. This is the choroids 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. This plexus is attached to the wall of the medulla at either side of the taenia of the IVth ventricle which forms a distinct line of attachment. The taenia turns abruptly to the lateral margin of the medulla to form the lower boundary of a wide expansion of the IVth ventricle, the lateral recess. This extends dorsally over the cochlear nucleus.

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 the photographs of the median surface provided to you and locate the following structures on your sheep brain:

   

VI. 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.

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.

VII. Dissection of the Tracts VIII. 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 diencephalons and the telencephalon. The thalamus and hypothalamus (including the mammillary bodies) are the major parts of the diencephalons, and the cerebral cortex, corpus striatum (internal capsule, caudate nucleus, putamen and globus pallidus) and rhinencephalon form the telencephalon. IX. 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.

X. 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. Observe the relations of the choroid plexus of the lateral ventricle, the hippocampus, the fimbria, the body of the fornix, the head of the caudate nucleus and the septum pellucidum to one another and the lateral ventricle.

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. Note the reflections of the internal capsule toe the adjacent structures. The corpus striatum is made up of the lentiform nucleus lying far laterally, the caudate nucleus lying medially which projects into the lateral ventricle and the internal capsule, appearing as a band of white fibers between these two nuclei of the basal ganglia, as well as between the lentiform nucleus and the thalamus.

Transverse sections can then be made at several locations to expose the sub-cortical structures already studied. No more than two such cuts should be made in any one brain to avoid losing continuity. Look particularly for the continuation of the cerebral peduncle into the internal capsule. Identify the chief nuclei of the thalamus, reviewing the relations of the various lemniscus systems to them. The medial and anterior nuclei of the thalamus are clearly separated from the lateral group of nuclei, including the lateral and ventral nuclei, the pulvinar and the lateral and medial geniculate bodies. The lateral group of nuclei constitute the "neo-thalamus" which give rise to the thalamo-cortical radiations (sensory projection systems). The medial and anterior nuclei belong to the old thalamus and are connected chiefly with intrinsic thalamic reflexes and connections with allo and frontal cortex. Compare the structures seen in the transverse and other sections with the tract and other dissections you have carried out. Try to visualize a three-dimensional view of the fiber tracts of the brain.


This page was last updated 11/31//05






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. 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. Cuneus. Latin. cuneus = a wedge. 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. 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. Falx. Latin. falx = a sickle.

The flax of the brain is crescent-shaped.

Fasciculu. Latin. diminutive of fascis = bundle or packet. Funiculus. Latin diminutive of funsis = a cord. Ganglion. Greek. ganglion = a swelling. Geniculate. Latin. geniculare = to bend the knee; from geniculum, diminutive of genu.

Glia. Greek. glia = glue. Gyrus. Greek. gyros = a circle. Hippocampus. Greek. hippos = horse, and kampos= sea monster. Hypophysis. Greek. hypo = under and physis =growth. Lemniscus. Greek. lemniskos = a band of fillet.

Lobulus. Latin. diminutive of lobus = lobes.

Medulla. Latin. medulla = marrow. Meninges. Greek. menix = membrane; plural, meninges. 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. 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. Oblongata. Latin. oblongus = rather long or oblong.

Oligodendroglial. Greek. oligos = scanty, dendron = tree and glia =glue. 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. Pineal. Latin. pinea = a pine cone.

Presumably named for the shape of this body.

Pituitary. Lain. pituita = mucous secretion. 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. Sella turcica. Latin. sella = saddle and turcica = Turkish. 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. 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. 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. 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. Tectospinal. Latin. tetcum = roof, and spina = a thorn or spine. Tectum. Latin. tectum = roof. Tegmentum. Latin. tegmentum = a cover. Telencephalon. Greek. telos= end, and encephalon (see above).

Tentorium. Latin. tentorium = a tent. Thalamencephalon. Greek. thalamos = an inner chamber, and encephalon.

Thalamus. Greek. thalamus = aninner chamber. Torcular. Latin, torcular = a wine press or storage vat; from torquere = to twist. Tuber. Latin. tuber = knot or swelling. Uncinate. Latin. uncinatus = hook-shaped.

Uncus. Latin. uncus = a hook. 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 8 (the somatic sensory system) and Chapter 9 (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

Table 8.1 (19 and 20)
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. 8.3 (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

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. 8.5 (10) 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")

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 9 Box A (4) hot related to capsaicin

Fig Chapter 9 Box A (5)
Both involve 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. 9.2 (2)
Pain is faster in A delta fibers than in C fibers
Nociceptors
A delta mechano and mechano-thermal, and C fiber polymodal
Some mediators of pain are in bee and wasp sting venoms (serotonin, histamine, acetylcholine).
Also tissue damage substances (Table 9.1): , serotonin (platelets), prostaglandins, leucotrienes,
Histamine from mast cells, substance P
Bradykinin from blood borne precursor - enzyme from injury

Fig. 9.6 (14)
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. 8.6A (11)
input into spinal cord

Fig. BoxC (13)
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. 8.6B (12)
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. 9.3A (6)
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. 9.4 (10)
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 9 (8, 9)
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 9 (12)
Interestingly, visceral pain goes in dorsal columns.
Very useful since midline myelotomy for palliative treatment in terminal and painful cancer.

Fig. 8.6B (12)
sensation from face - trigeminal
Cell is in trigeminal ganglion and first synapse is in a nucleus at the mid-pons level.

Fig. 9.3B (7)
pain from face - trigeminal

Thalamus and cortex

Fig. 8.7 (14)
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 D Chapter 8 (18)
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. 8.4 (6)
two point threshold
2 mm fingertips, 30 arm, 70 back
this relates to the cortical projection (next:)

Fig. 9.8 (15, 16)
sensory magnifications
Penfield - homunculus

Box D, Chapter 9 (15)
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 9.7 A (16)
Pain modulation includes an efferent system
periaqueductal grey (PAG) enkephalin

Fig 9.7 B (17)
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 (18)
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


This page was last updated 2/21/05








The eye and vision lecture

Eye and Vision

Purves et al Chapter 10 covers optics, the eye and the retina, also some pictures from chapter 11
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. 10.7 (11)
Rhodopsin is the visual pigment
Protein plus chromophore (11-cis retinal) makes visual pigment
George Wald 1967 Nobel Prize

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 10.12 (18)
"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. 10.1 (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 (3)
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)

Fig. 10.2 (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.

Fig. 11.1
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 A (Chapter 11) (5)
demonstrates the blind spot

Fig Box B Chapter 10 (13)
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
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. 10.8 (14)
Photoreceptors- 125 million receptors 20/1 rods to cones
(converge on 1 million ganglion cells)

Fig. 10.10 (16)
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
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
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. 10.11 (17)
fovea is pit without rods and with cells and blood vessels out of the way

Color vision

Fig. 10.12 (18)
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. 10.13 (20)
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)

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 10.5 (8)
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. 10.7 (11, 12)
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. 10.5 (8)
...cell hyperpolarizes...

Fig. 10.6 (9, 10)
...since sodium channel closes.

Retinal processing

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"). Reference: 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.

Fig. 10.15A (25)
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. 10.14 (21)
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.









The brain and vision lecture

Brain and Vision

Purves et al., Chapter 11 (and bits of Chapters 10 and 23)
Note that the Washington University Medical School's Neuroscience Tutorial has good coverage on this topic:
Central Visual Pathway

Retinal circuitry

Retinal processing

Fig. 10.19 (31)
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 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 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.

Blobs in Hermann grid (follow leads - fun things - Hermann) 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.

I already said this:
In frogs, retina does a much greater fraction of the overall processing (since they have no cerebral cortex to do the job), and in some classic work, e.g. Lettvin et al., "What the frog's eye tells the frog's brain," 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

Primate ganglion cells -
Magnocellular (large) 10% - movement
Parvocellular (small) 90% - form and detail
cat ganglion cells -
morphology and function WXY
color opponent cells

Projection to Brain

Fig. 11.2 (2)
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. 11.3 (3)
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. 11.10A (14)
Thalamus
Cells have center - surround receptive fields like ganglion cells
1, 4, 6 contralateral -- thus 2, 3, 5 ipsilateral

Fig. 11.14A (23)
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

Fig. 11.9 (13)
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. 11.12 (19)
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. 11.13 (20)
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. 11.11 (16)
Apparently, cells can preferentially respond to disparity from fixation

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. 11.15A (25)
V4 - color but not movement
MT (middle temporal) - direction of movement but not color

Fig. 11.17 (28)
parietal stream - spatial vision
temporal stream - object recognition

Development of visual connections

Fig. 23.3 (6)
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. 23.4 (9)
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. 23.3 (7), and B after monocular deprivation from 2 weeks to 18 months in monkey Purves et al., Fig. 23.6 (12).


This page was last updated 2/28/05








The Audition and Vestibular sense lecture

Audition and vestibular system

Purves et al., Chapters 12 and 13 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. 12.1 (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. 12.3 (4,5)
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. 12.4 (9,10)
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.

Notice the oscillator is HP, a company that still does well. Also that it is from 1964. Another physics discard I rescued from the dumpster.

For both sets of instructions, set the amplitude to a comfortable level

(1) Set the oscillator at about 1000 (10 x 100)
(2) Hit the 1024 tuning fork and put it between your ear and the speaker
(3) Listen for beats, physical interference in sound waves
(4) Alternate the fork and the speaker to one ear
(5) If there are a lot of beats, the pitch difference should be obvious
(6) By adjusting the knob, you should be able to get the beats down to a few per second
(7) Notice that you can still tell the difference down to a few Hz at 1000 Hz
(8) Hold the speaker to one ear and the fork to the other
(9) Notice there are no beats

(1) Set it to >130 (>13 x 10)
(2) With the 128 fork, between speaker and ear, set the dial it so there are beats
(3) Notice beats
(4) With the speaker close to one ear, press that ear closed to prove you cannot hear with the other
(5) Hold the speaker to one ear and the tuning fork to the other and hear binaural beats
(6) Alternate the fork and the speaker to one ear
(7) If there are a lot of beats, the pitch difference should be obvious
(8) By adjusting the knob, you should be able to get the beats down to a few per second
(9) Notice that you can still tell the difference down to a few Hz at 1000 Hz

Reference.

G. Oster , Auditory Beats in the Brain, Scientific American, Vol 229, October 1973, pp. 94-102

Back to Lecture.

Fig. 12.5 (11, 12)
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. 12.11 (23)
"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. 12.11 (24)
Frequency discrimination at low frequencies
there was another theory, Rutherford's "telephone" theory
phase-locking gives volley principle up to 4 kHz

Fig. 12.15 (28)
map of cortex tonotopy

Auditory transduction

Fig. 12.4 (10)
Fig. 12.6 (13, 14, 15)
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

Fig. 12.7 (16)
EM. Note kinocilium vs stereocilia (B) and tip links ((D)

Fig. 12.8 (17)
and
Fig. 12.9 (18)
kinocilium (real cilium, missing in post-natal human hair cells)
plus about 30 stereoocilia
mechanoreception assisted by tip links - depolarization if move toware kinocilium
hyperpolarize if in opposite direction
Threshold displacement is about 0.3 nm, electric potential in 10 micro seconds

Fig. 12.10 (21)
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. 12.12 (25)
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. 12.15 (29)
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. 12.13 (26)
medial superior olivary nucleus important for coincidence detection of time of arrival
phase locking important in input - barn owls good at this

Fig. 12.14 (27)
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. 13.1 (1)
utricle and sacculus linear motions
3 semicircular canals - rotations

Fig. 13.3 (5)
stones

Fig. 13.4 (6,7)
stones (otoconia) provide mass for bending in utricle and sacculus
striola divides hair cells with differing polarities

Fig. 13.7 (14)
Fig. 13.7 (15)
Ampulla and cupula displaced as semicircular canal fluid is displaced

Fig. 13.10 (23)
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. 13.11 (24)
vestibulo spinal control from vestibular nucleus (integrates with cerebellar input) to lateral vestibulospinal tract and medial longitudinal fasciculus

Fig. 13.12 (28)
also projection to integrate with somatosensory and muscle spindle senses


This page was last updated 3/15/05





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 14 (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. 14.14 (29)
Tongue
Hanig (1901) - preferential localization:
sweet - tip of tongue
salt - front sides of tongue
sour - back sides of tongue
bitter - back middle of tongue
This, and the correlation with specific papillae is not really true.

Papillae: Circumvallate (preference for quinine), foliate, fungiform (preference for sucrose)
also receptors in epiglottis

Fig 14.14 (30)
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

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)

Fig. 14.15 (32)
generally, channel or G-protein linked receptor ultimately increasing calcium somehow for synapse
note receptor does not have axon

Fig. 14.16 (33)
salt - amiloride blocked Na+ channel opens (depolarization)

sour - pH sensitive K+ channel closes (depolarization)
also amiloride blocked Na+ channel

Fig. 14.16 (34)
sweet - G-protein linked cAMP close K+ channel - depolarize

umami (glutamate) - and amino acids, channels as well as G-protein cascade
Note, here is the TRP (transient receptor potential) channel again

Fig. 14.16 (35)
bitter -G-protein cascade involving PLC or quinine sensitive K+ channel
"gusducin" (like "transducin" for vision) is term for heterotrimeric G protein

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. 14.13 (26, 27, 28)
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. 14. 18 (39)
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)

Box A pheromones in moths. 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. 14.2 (6)
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. 14.6A (10)
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. 14.6 B (11)
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. 14.7 A (13)
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. 14.7 B (14)
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.

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 by my alumni magazind 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.

Fig 14.8 (15)
number and organizations of genes and proteins in C. elegans, Drosophila, mouse, human
Note, no introns in mammals

Fig. 14.8 (16)
distribution of genes in human, many on 11

Fig. 14.11(D) (23)
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 (1-4)
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)


This page was last updated on 3/16/05




Spinal motor control lecture

Peripheral motor function

Purves et al., chapter 15, 1, 8
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) (1)
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. 15.5 (8)

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).

(back to Fig. 15.5 (8)

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. 15.4 (6)
Motor units
In 1932, Sir Charles Sherrington won the Nobel Prize. He originated our understanding of the motor unit..
(see also Fig (section opener) (1))
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. 15.2 (4)
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.

Fig. 15.9 B (13)
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 (19, 20)
Fig 8.5 (10)
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. 15.13 (25)
how this integrates in spinal cord
crossed extensor reflex

Fig. 15.11 (18)
Golgi tendon organ

Fig. 15.12 (24)
via Ib (slower than Ia) acts through inhibitory interneuron
to mediate the clasp-knife reflex -give up if stretch is too strong

Fig. 15.3 (5)
"mototopic" organization
axial (proximal) vs distal muscles - medial vs lateral
flexors vs extensors - dorsal vs ventral

ervical vs. lumbar enlargements
- for all the extra motor neurons for the arms vs legs respectively

Amyoropic Lateral Sclerosis (ALS)
Lou Gehrig's disease - he died in 1936 after playing baseball for the New York Yankees 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)

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This page was last updated 3/25/05








Central motor mechanisms lecture

Central Motor Mechanisms

Central Motor Mechanisms

Purves et al., Chapters 16-19, Appendix A
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
Horizontl 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. 16.3 A(4)
Pyramidal system with corticospinal tract

Fig. 16.8 (13)
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. 9.4 (10)
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. 16.8 (13)
Ventral corticospinal tract

Table A1 (6-9)
Corticobulbar
Output for face and upper body via facial nerve (and trigeminal, vagus, accessory, hypoglossal.

Fig. Box B (14)
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. 16.2B (2)
Red nucleus adds control to arm muscles
Rubrospinal tract from red nucleus replaced by corticospinal in evolution

Fig. 16.3 B (5)
corticoreticulospinal tract
Reticular formation controls axial muscles and proximal limbs
pontine reticulospinal- help to maintain posture
medullary reticulospinal - liberates antigravity from reflex

Fig. 16.2 A (2)
Superior colliculus (tectospinal) goes down to control head movements

Fig. 16.2 A (3)
Vestibular control for posture and catching balance

Fig. 16.9 (15, 16)
topographic map of motor cortex- compare with corresponding sensory homumculus
work by neurosurgeon Penfield, note relative "magnifications"
(I think there is a mistake here with genitals (not known for motor dexterity) showing up large, in contrast with most pictures where toes (thought to curl with sexual excitement) in motor cortex across from genital projection in postcentral gyrus.)
Precentral gyrus = Brodmann area 4 = M1

Fig. 16.7 (12)
premotor area (area 6)

Basal ganglia and cerebellum

Fig. 17.1 A (1,2)
summary showing how Basal Ganglia get input from Cerebral Cortex and feed back to Cerebral Cortex

18.7 (12)
summary showing how Cerebellum gets input from Cerebral Cortex and feed back to Cerebral Cortex

In early coverage of functional neuroanatomy, this is where the statement that the thalamus is a motor relay proves true.

Fig. 17.4 (6)
Not just motor cortex, but huge parts of cortex feed to basal ganglia.

Fig. 18.4 (8)
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. 17.2 (3)
inputs to basal ganglia
cortex and substantia nigra and pars compacta

Fig. 17.5 B (8)
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. 17.3 (4,5)
connections are to spiny and aspiny neurons in caudate and putamen

Box B
Parkinson's
(see the neurotransmitter lecture)

Fig. 17.10A (16)
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 A
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. 17.10B (17)
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. 18.3 (6,7)
input to cerebellum
especially from cerebrum, vestibular apparatus and spinal cord

Fig. 18.6 (10,11)
output from cerebellum
via deep cerebellar nucleus via superior cerebellar peduncle to VL complex of thalamus to motor and premotor cortex

Fig. 18.8 (13, 14, 15)
cerebellum is a fairly "simple circuit"

Fig. 18.9 (16)
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 18 B (22, 23, 24)
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 19 A (4,5)
if image is stabilized on the retina the image disappears

Fig. 19.3 (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. 19.7 (10)
horizontal saccades are controlled by paramedian pontine reticular formation PPRF (gaze center)

Fig. 19.9 (15)
Superior colliculus involved (and frontal eye field)

Fig. 19.8 (11, 12)
Stimulate superior colliculus and bring fixation to receptive field of area stimulated

This page was last updated on 3/31/05







Neural development lecture

Development

Purves et al., Chapters 21-22, one figure from Chapter 10

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. 21.3 (12, 13, 14)
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 A
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 23)
Wiring in cerebellum is disrupted in mutants (Chapter 18)

Drosophila Embryology

Drosophila is a model for understanding development, generally
Order of action: maternal genes, zygotic genes, homeotic genes

Fig. 21.6 (22)
a lot has to do with segmentation

Fig. 21.6 (23)
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. 21.6 C (24)
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. 21.10 (36)
(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. 21.3 C (13)
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. 21.1 (2)
Neural plate forms from ectoderm -> neural groove -> neural tube to make CNS

Fig. 21.1C (4)
One area remains outside CNS - neural crest gives rise to PNS structures like sensory ganglia

Fig 21.2 B (7)
Different cells migrate to make (1) sensory ganglia, (2) autonomic ganglia, (3) adrenal, or (4) non-neural tissues like melanocytes

Fig. 21.12 (39)
Factors on how neural crest progenitors turn into specific PNS types
(more on factors later)

Brain subdivisions

Fig. 21.5 (18, 19, 20)
Prosencephalon -> telencephalon and diencephalon
Mesencephalon
Rhombencephalon ->Metencephalon and myelencephalon
Note, "optic vesicle" signifies that retina is outgrowth of CNS

Fig. 10.3 (5, 6)
Induction from optic vesicle makes lens form from ectoderm

Histogenesis

Fig. 21.7 (28, 29)
Cell divisions in monolayer with nuclear migration (mitosis near neural tube lumen (ventricle) and have S-phase near pial surface)

Fig. 21.11 (38)
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. 21.8 (30)
then each layer (e.g. V) migrates past previous (e.g. VI)

Axon pathfinding

Retinotectal projection in frog

Fig. 22.6 (14)
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 (8)
These are drawings from Ramon y Cajal much like Fig.
There are these growth cones (enlargements) at the tip of an extending axon which extend and retract filopodia, feeling their way along.

Fig. 22.1 (1,2)
growth cone, confocal microscopy
SEM growth cone

Fig. 22.4 (11)
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. 22.2 (5)
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 B (20)
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. 22.9 (21, 22)
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. 22.12 (27)
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. 22.15 (33)
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 A, 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.)


This page was last revised 4/5/05














The Memory at the cellular level lecture

"Learning"

Purves et al. Chapter 23 "Modification of brain circuits as a result of experience"
and Chapter 24 "Plasticity of mature synapses and circuits"
also some figures from chapter 22)

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. 22.10 B (23)
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 (first 4 blocks repeated from Vision and the brain lecture)

Hubel & Wiesel share 1981 Nobel for "information processing in the visual sytem"

Fig. 23.3 (6)
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. 23.4 (9)
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. 23.3 (7), and B after monocular deprivation from 2 weeks to 18 months in monkey Purves et al., Fig. 23.6 (12).

Fig. 23.5 B (11)
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. 23.8 (14)
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. 23.9 (15)
In strabismus (lack of fixation), lose binocular cells.

New

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).

references:
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.

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:

Aplysia

Fig. 24.4 (11)
(1) depression of responses during tetany in muscle cell; and
(2) post-tetanic potentiation.

Fig. 24.1 A (1)
Studies of Aplysia (a mollusc) by Kandel (Nobel in 2000)
Aplysia - habituation - nonassociative learning
Personal reflection - I was a 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. 24.1 B (1)
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. 24.1 C (2)
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. 24.1 C (2)
Fig. 24.2 AB (4,5)
There is also sensitization another nonassociative learning

Fig. 24.3 A (7)
short term sensitization
serotonin-induced enhancement of glutamate release
5HT -> cAMP -> PKA -> close K+ channel -> C2+ influx -> transmitter release

Fig. 24.3 B (8)
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, lysoslmes and proteosomes, the latter involving ubiquitin.)

There is also classical conditioning in Aplysia, mechanism not shown.

Drosophila

Fig. Box A (9)
(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

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. 24.5 (12)
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
Preforant pathway (from entorhinal cortex) -> granule cell (mossy fibers) -> CA3 pyramidal cell (Schaffer collaterals) -> CA1 pyramidal cell

Fig. 24.6 (13, 14, 15)
train of stimuli make response to another bigger while in another (control) pathway, the synaptic efficiency is unchanged

Fig. 25.9 (19)
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 D
Epilepsy is a syndrome of sensitized excitation

Cerebellum

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. 25.13 (29, 30, 31)
describes LTD (long term depression)
two synaptic activations must come at about the same time
decrease in effectiveness of glutamate AMPA receptor



This page was last updated 4/7/05




The Language and cognition lecture

Language and Cognition

Purves et al., Chapters 25 & 26

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. 25.1 (2)
Localization of function - note that Chapter 25 refers to "association cortex"
some very interesting case studies of people with specific defects like:

Fig. 25.8 (14)
prosopagnosia (-agnosia - not knowing) - face recognition deficit in right temporal lobe damage in patient L.H.
fMRI activity increase in right temporal lobe

Fig. 25.5A,B (8, 9)
contralateral (hemispatial) neglect syndrome caused by:

Fig. 25.6 A (10)
damage to parietal, temporal and frontal areas.

Fig. 26.2 (2)
Brodmann areas- based on cytoarchitecture

Fig. 25.3 (5)
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 A (6)
fewer layers in "archicortex" (hippocampus)
and
in "paleocortex" (pyriform cortex)
[These were terms used in the sheep brain dissection guide.]

recall the importance of gyrus to gyrus connections (arcuate fibers of the corona radiata, slide from sheep brain dissection: slide 23)

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. 25.11 AB (20, 21)
a face recognition neuron in the temporal lobe which does not respond as well to degraded or wrong images

Fig. 25.13 (25, 26, 27)
a neuron in the frontal cortex which responds specifically in a delayed task (planning)

Language

Fig. 26.2 (2)
Brodmann areas

Fig. 26.1 (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. 26.3 AB (8, 9)
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) a 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 B
argues whether language is actually unique to humans

Border collies (one named Rico) seem able to learn lots of words

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

DPrimack, Language in a chimpanzee, Science 172, 808-822, 1971
success with Sarah to use plastic chips of various shapes

Fig Box B (4)
DRumbaugh and S Savage-Rumbaugh used computer type-writer

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. 26.8 (20)
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).


This page was last updated 4/8/05









The biorhythms lecture

Rhythms

Purves et al. Chapter 27

EEG

Fig. Box C (14, 15, 16)
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).

Fig. 27.6 (12)
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

Fig. 27.6 (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. 27.7 (17, 18)
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 A (4, 5)
Dolphins sleep with one hemisphere at a time.

Why do we sleep (perchance why do we dream)? - lots of half-baked answers and speculations.

Hobson - raphe and locus coeruleus turned off in sleep
Michel Jouvet - The states of sleep Scientific American Feb. 1967 62-72
"" - Biogenic amines and the states of sleep Science 163, 1969, 32-41

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.

Table 27.1 (34)
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. 27.8 (19)
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. 27.4 (8)
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 (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. 27.5 (10)
In higher (bigger headed) animals, the zeitgeber (time giver) is usually a light-dark cycle, most likely with eye as sensory system.
Pigment may be a different opsin (melanopsin [expressed in melanophores]) (and may be in ganglion cells).
[S.Panda et al., Melanopsin is required for non-image-forming photic responses in blind mice, Science 301, 2003, 525-527]

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.

SCN -> -> Superior Cervical ganglion -> Pineal
Pineal's melatonin is a sleep hormone.
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)

Box B (13)
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=aruthmic, 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 B (13)
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.

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 tghe pibment 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.


This page was last updated 4/11/05











The emotion and motivation lecture

Emotion

Purves et al., Chapter 28 (and part of Chapter 20) (and Chap 25 figure)

General
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)

Fig. 28.1 (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 A (in Chapter 20) (14)
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-area based on the defect. Also, LH is where medial forebrain (reward) system goes (dopamine, covered repeatedly already).

Fig Chap 28 Box A (4)
block diagram
Interesting story - voluntary facial paresis inability to volontarily move lower facial muscles on one side due to lesion [pyramidal smile] (see also Box B Chapter 16)

Fig Chap 28 Box A (3)
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 (2)
Duchenne demonstration, electrical stimulation of face ("faradization") mimics emotional expressions.

Brain areas

Limbic system
Started with Broca (1879)- limbic = "border"

Fig. 28.3 (7)
Fig. 28.4 (8,9)
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 B (10)
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.

Fig. Box D (14, 16)
Patient SM has degeneration of amygdala - cannot recognize or draw fear
Urbach-Wiethe disease (autosomal recessive)

Interesting stories:

Fig (opener for Chaps 25-30) Chap 25 (1)
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


This page was last updated 4/13/05











The neuroendocrinology lecture

Sex and Neuroendocrinology

Purves et al., Chapter 29

Hormones

background
"endocrine" - ductless, into blood stream
release - cells with blood vessels

Fig. 29.1 (4)
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 B
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. 29.5 A (12)
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. 29.5 A & B (12, 13)
(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 A - Box C (5)
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 B - Box C (6)
recall that steroids affect transcription

Fig. 29.1 (4) [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 Box A (1, 2, 3)
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. 29.4 (9, 10, 11)
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. 22.9 example of spinal motor neuron count being influenced by limb bud ablation or supranumerary limb buds.)

Fig. 29.7 B (17)
INAH (interstitial nuclei of anterior hypothalamus) can be sexually dimorphic

Fig. 29.8 AB (17, 18)
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. 29.9 (20, 21, 22)
(this could also be in another chapter)
cortical representation and receptive field of female ventrum changes during lactation

This page was last updated 4/18/05





The memory and the brain lecture

Memory

Purves et al., Chapter 30

Chapters23 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 (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 (9)
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).

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
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

spoof:
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.

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

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

Fig. 30.6 (11, 12, 13)
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 (14, 15)
The temporal lobe seems particularly important for establishment, but not storage.
Penfield - electrical stimulations

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.

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.


This page was last updated 4/18/05






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 disease.
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?



This page was last updated 4/21/05



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.


This page was last updated 4/21/05

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