***Historical Introduction
The first lecture outline

Historical Introduction


Purves et al., Chapter 1 and figures from Chapters 6 & 27 and Appendix
(there will also be a review that introduces you to the Sylvius CD)

(some of this is a review of "Bio 1" and "Cell biology")

Brain - ancient history

Hippocrates (460-379 BC), of "hippocratic oath" fame, understood the influence of the brain in determining normal and abnormal functions, emotions, learning, insanity.

Appendix Fig. A23A, p. 743

(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]) secreted by choroid plexus, and this fit in with belief in vital "humors."

Neuroanatomy terms:

Appendix Fig. A10A p. 728
(view of exterior of human brain)
sulcus (plural=sulci) = fissure
For instance, central sulcus is major landmark
gyrus (plural=gyri) = convolution -> lobes (a larger area)
For instance, precentral gyrus is motor cortex
And postcentral gyrus is somatosensory (touch) cortex

Appendix Fig. A3 p. 720
(colored view of exterior and mid-sagittal section of human brain)
Emphasis is on "localization of function" in different lobes
For instance, occipital lobe is where vision projects
And Temporal lobe is where audition projects

TRANSPARENCY shows the version of this picture the Biology Department teaches to freshmenjust to put into perspective the degree to which much of this information is background,

CNS = central nervous system (brain and spinal cord)
PNS = peripheral nervous system

Appendix Fig. A14 p. 734
(human brain drawing showing coronal sections, to reveal basal ganglia)
shows the coronal sections indicated
white matter, bundles of myelinated axons (Tracts in CNS, Nerve in PNS)
[misnomer - optic "nerve," second cranial nerve, is actually a tract since retina and optic nerve are considered part of the CNS on embryological grounds]
and
gray matter (Nuclei in CNS, Ganglia in PNS)
[misnomers - basal ganglia are nuclei and ganglion cells in retina]

Fig 1.9 p. 13
(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 p, 12
(diagram of knee jerk reflex)
Afferent (toward CNS)- Efferent (away from CNS)

Appendix Fig. A12A p. 730
This shows a mid-sagittal section
Decussation- crossing of fibers
The biggest is the corpus callosum

Appendix Fig. A1A p. 718
(brain with directions drawn in)
Rostral (toward the front)- Caudal (toward the back)
Superior (above) Inferior (below)
(not shown) Lateral - Medial

Appendix Fig. A1B p. 718
(brain with sections drawn in)
Coronal (would be cross section if human brain were anterior)
Horizontal vs Sagittal - (would be like longitudinal sections)

Some more recent historical figures and issues

Appendix Fig. A17A p. 738
(blood supply of brain)
Thomas Willis (1621-1675) (English) circle of Willis
fed by both internal carotids, a block would not deprive half of brain of blood supply

Here is the equivalent picture from our sheep brain dissection

Fig. 27.1 p. 610
Pierre-Paul Broca (1824-1880) (France) brain surgery
patient with damage in left hemisphere shows speech loss => lateral localization
vs. Lashley (cortical lesions in learning experiments) mass action and equipotentiality

In the old days, stroke (defects while living and damage in post-mortem) was the way to make conclusions in humans; now there are imaging techniques.
In animal models, stereotactic lesions can be made.
Electrical stimulation can also be applied, and, in general, it has the opposite effect of lesioning.

Fig. 27.2 p. 611
(Brodmann areas drawn onto human brain)
Korbinian Brodmann (early 20th century) has lots of brain areas with numbers
famous ones: 17-vision, 4-motor, based on cellular cytoarchitecture

Stroke

Current affairs
Jan 5, 2006, Israel's premier Ariel Sharon has a stroke complicated by being on blood thinners.
Box B, Appendix p. 735
Brain's need of oxygen makes interruption in blood flow dangerous
3rd leading cause of death in US
(1) thrombus (local occlusion) 50%
(2) embolus (object in blood stream) 30%
(such interruption in blood supply is called "ischemia")
(3) hemorrhage (e.g. from aneurism) 20 %
Tissue plasminogen activator (TPA) to dissolve clot
Recent reading: CM DeLude "Widening the window" (news scan, medicine) pp 21-22 Scientific American August 2005
Few get TPA because they come in too late for it to be effective (<3 hr)
If neurons are not dead, TPA may still work; newer CT and MRI scans can now show this.
Giving oxygen also buys time.
New drug: Desmoteplase (from vampire saliva) like TPA (breaks fibrin) but more potent and selective.

Structure of the Nerve cell

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

Fig. 1.7 p. 12
(diagram of knee jerk reflex) [again]
1865 Otto Deiters (Bonn) - motor neuron

Fig. 1.3A p. 6
(cells and connections in brain)
axis cylinder -> axon, dendrites (branches)
reticular theory (connected like blood stream) vs. cell theory (cells are separate)
1885 Camillo Golgi (Italy) - potassium dichromate fix silver impregnation, still believed reticular theory
1888-> Santiago Ramon y Cajal - real thorough descriptions of many systems, believed in cell theory
1906 Nobel Prize in Physiology and Medicine for "the structure of the nervous system"

Advancements in cell anatomy methodology

Figs 1.3, 1.4, 1.5 & 1.6 are amazing preview of many semester topics

Beyond the level discussed above, tracts could be found by dissection. Looking ahead to the sheep brain dissection, this tract dissection of the midsagittal cut reveals the fornix, the mammilo-thalamic tract and the habenulo-peduncular tract. See slide 11

Fluorescence. Excitation with short wavelength. While electron is in excited state, there is some radionless de-excitation. When electron comes to ground state, it has less energy, so photon emitted has less energy (longer wavelength).

Here is a fluorescence microscope.
Short wavelength comes (through color filters) from above, hence "epi-illumination" or "incident illuminator."
Of course, there is a camera.

Fig. 6.11A p. 127
In the 1960s there was a lot of excitement about how specialized techniques (histochemical fluorescence) allowed researchers to trace the pathways used by a specific neurotransmitter substance. Fig. 6.11 shows dopamine pathways from the substantia nigra to the striatum and the cerebral cortex.

Fig. 1.6 E-H p. 11
Nissl stain shows cells (like cell layers in cortex)

Fig. 1.6 A,B p. 11
Golgi technique only colors a few cells so they can be viewed in their entirety.

Fig. 1.6 C p. 11
a fluorescent dye can be injected.

Here is a figure I prepared to explain how antibodies could be used in the electron microscope to localize proteins. The protein is an antigen. An antibody, binds to an epitope on the protein. A secondary antibody with an electron dense attachment (colloidal gold for electron microscopy or a fluorescent label for fluorescence microscopy) binds the antibody. Here is a figure I found subsequently) in this very useful site.

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

Here is a laser scanning confocal microscope, a fancy fluorescence microscope.
This machine is from a grant obtained by Prof. Spencer (and a few others of us).
For a light source, a laser is used.
Light is measured and fed to a computer for image acquisition.
Low depth of field (only one plane is in focus) provides "optical sectioning"
Images are very clear.

Here is Rh1 labeled with a fluorescent antibody in the confocal

Fig. 1.4 A p. 8
Tau (red) (microtubular binding protein in axons) accumulates in Alzheimer's, tubulin (green) in cells

Fig. 1.4 B p. 8
Developing cell in culture has actin (red) in growing tips.

Confocal

Because of "optical sectioning," (low depth of focus) many planes in a "z-stack" can be put into a Quick-time movie, [and this one shows disorganization of rhabdomeres, indicative of degeneration, where R1-6 rhabdomeres are labelled with GFP]

Review utilizing Sylvius

An access code came with your book
Launch Sylvius , Launch Visual Glossary
and we will use it for various views of :
Broca's area, Wernicke's area, motor cortex, auditory cortex
Brodman's areas, famously 4 (precentral gyrus=motor cortex), 17 (visual cortex)
Occipital lobe
Postcentral gyrus
Spinal cord (including cervical and lumbar enlargements of gray matter for fore- and hind-limbs
Striatum
Substantia nigra

Brain imaging techniques

(Box 1B - three pp. 18-19) MRI

Suggested readings

Marcus E Raichle (WashingtonUniversity Radiology and Neurology) The brain's dark energy, Scientific American March 2010 44-49. Current research on brain imaging, mental function and disorders.

Thomas R. Insel (National Institute of Mental Health) Faulty circuits, Scientific American April 2010 44-51. About mental disorders and brain circuits.

Alumnus research in neuroscience

Adrian A. Epstein, SLU class of 2002, took this course from me in 2002 (and introductory biology earlier). After that, he went to Washington University and was a research assistant in biological imaging (in the Department of Radiological Sciences). He is first author of several abstracts (convention presentations) and is coauthor of J. S. Shimony et al., Diffusion tensor imaging reveals white matter reorganization in early blind humans, Cerebral Cortex, 2006. Here, they use a specialized technique called diffusion tensor imaging to trace tracts (hence DTT= diffusion tensor tractography) to compare the visual projection in normal and blind subjects. Now he is in the MD-PhD program at Nebraska.

Some useful information and links

As of January, 2014, Neuroscience in SLU's A&S College is a contract major (with limited enrollment and no funding) web site. Neuroscience at SLU's Medical school is in the Center of Anatomical Science and Education and Department of Pharmacology-Physiology. Outlines from my signal course in biology might be helpful sometimes. Dr Buchanan in Psychology works in cognitive neuroscience of stress. Dr Kirchhoff's neuroscience interests are briefly encapsulated in the SLU Psychology site. 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. 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:
A professor I had my first year in graduate school has an extensive web site on Biology of the Mind
Society for Neuroscience
Neurosciences on the internet

***Neurons and glia

from Purves et al., Chapter 1, Figures from Chapters 3, 6, 16, 22, Appendix

Diseases of the nervous system are significant
in the overall health care system
and in fulfilling the optimum quality of life

Examples: Boxes

Neurons

Fig. 1.3A p. 6
Typical neuron (Nerve cell) soma, perikaryon
nerve cells have typical organelles, nucleus, rough ER, Golgi apparatus, mitochondria
axon hillock, dendrites

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

Fig. 1.4 E p. 8 Dendrites have protrusions (spines) tubulin is labeled
Fig. 1.4 F p. 8 spines, actin is labeled

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

Fig. 16.5 p. 365 (shows how motor nerve branches to innervate all the muscle cells of one "motor unit" collateral)

Fig. 5.5 p. 83
Cytoskeleton
important and, in neurons, have unique properties
microtubules 25 nm diameter
Axon transport as fast as 400 mm/day
discovered by Paul Weiss (American) in 1940's - based on microtubules
kinesin moves toward + end of microtubule, anterograde (orthograde)
put radioactive proline in eye - use autoradiography for neuroanatomy
dynein moves toward - end, retrograde
herpes and rabies viruses ascend by retrograde transport
Slow (1 mm / day)

Glia

Fig. 1.5 ABC p. 9 astrocyte, oligodendrocyte, microglial cell
astrocytes - support, repair, grouping, regulate ions, neurotransmitters
microglia -> macrophages (Virchow noted phagocytosis in pathology)

Fig. A20 p. 741 (Appendix) Astrocyte end feet involved, along with capillary endothelium, in blood brain barrier
central nervous system is well sequestered from the immune system

Fig. 22.12 AB p. 502
Fig. 22.13 A p. 504
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 p. 6 myelin
also
Fig. 1.3G p. 6 node of Ranvier between adjacent patches of myelin
Fig. 1.5 B p. 9 oligodendrocyte
Fig. 1.5H p. 9 myelin is red, lots of channels at node of Ranvier green

Fig. 3.13 A,B p. 53
Myelin - cytoplasm squeezed out - multiple layers of membrane, high resistance, high capacitance
Channels at nodes of Ranvier

Here is an osmium tetroxide "stained" transmission electron micrograph of the many layers of membrane in myelin

nodes of Ranvier 1-2 micro meters (microns), Schwann cells 1 mm
"Saltatory" (leaping) conduction
oligodendrocyte myelinates several axons

Here is a classic diagram of an oligodendeocyte. Note that the cell myelinates several axons. Note also that the major dense line is where the cytoplasm was squeezed out and the minor dense line is where the outsides of the membranes fuse.

Recent reading: J. K. Huang et al., Glial membranes at the node of Ranvier prevent neurite outgrowth, Science 310, 1813-1817, 2005. A protein called OMgp (oligodendrocyte glycoprotein) is associated with a decrease in axonal sprouting after injury. This protein is not in myelin but in "oligodendrocyte-like cells" that make a wrapping around nodes of Ranvier. This understanding may be important in therapy and relates to the long standing dogma that there is no regeneration in the mammalian CNS.

Myelin diseases

Chapter 3 Box D multiple sclerosis

Polio (poliomyelitis) is a viral disease that damages myelin in peripheral nervous system causing paralysis; then the nerve cell degenerates.
Salk (1955, injected) then Sabin (eat sugar cube) vaccines in the 1950s, before that, only passive immunity from gamma globulin from people who had polio.
Serious cases required an iron lung.
FDR had polio.
Neuron's trophic effect on muscle is seen as muscle (not directly diseased) deteriorates.

It is thought that there is some recovery where motor neurons branch more (they already branch to innervate all of the muscle cells [fibers] of one motor unit) so that surviving neurons innervate muscle cells "abandoned" by lost nerve cells.
But at middle age, there is increased fatigue, pain and weakness (post-polio syndrome).
Cause: those sprouts are lost.
L.S. Halstead Post -polio syndrome, Scientific American, April 1998 42-47

Multiple sclerosis (MS) (Anette Funicello, Montell Williams, Richard Prior, "the president" in West Wing) damages myelin in the central nervous system
Might aflict motor function, vision, or others
Hits people 20-40, with deterioration but sometimes episodic, i.e. with remissions
Animal model - EAE (experimental allergic [autoimmune] encephalitis) to myelin basic protein.
Such a disorder used to happen with rabies vaccination when virus was grown in brain (before it was grown in eggs).
As you see from the box, there is lots of speculation as to the cause
Guillain-Barre syndrome peripheral myelin immune attack lose sensation and have weakness, sometimes severe, sometimes goes away, comes after illness, difficult to diagnose, controversy over whether it came after immunization for swine flu in Ford administration
Gina Kolata, Flu: The story of the great influenza pandemic of 1918 and the search for the virus that caused it, New York, Farrar Straus and Giroux, 1999.

In 2006. graduate student Matthew Hulvey gave a presentation on MS, and here is a pdf of his power point show

"Literature humanities"

Garrett Oppenheim (my uncle), The Golden Handicap: A spiritual Quest: a polio victim asks "why?" and turns his life around. Association of Research and enlightenment Press, 1993. An autobiography concentrating on what it was like to have that handicap and how people should treat someone with such a handicap.

AUTISM

Suggested readings

Nancy Shute, Desperate for an autism cure, Scientific American October 2010, 80-85. Now thought to affect 1/110 children, "No cause, no cure." Parents grope for expensive and "dubious therapies" (snake oil).

N Lang and C J McDougle. Help for the child with autism, Scientific American October 2013, pp 72-77. Since communication and eye contact are lacking, they do not learn. Identify them early and give them intensive training, and oxytocin (here called the cuddle chemical)

TV

In the television series Boston Legal, Jerry Espenson (portrayed by Christianson Clemenson) is a lawyer with Asperger syndrome and Tourette syndrome, closely related to Autism.

Suggested Link

1998 finding (Andrew Wakefield) linking MMR (measles, mumpa, rubella) vaccine with autism was recently considered to be fraudulent. Also, evidence suggesting link of thimerosal (a preservative in vaccines) with autism is very debatable. Thimerosal was removed from childhood vaccines in 1999.

Charcot-Marie-Tooth (CMT) disease,

a peripheral neuropathy, see Wiki link. I plan to introduce a friend of mine, JH, who will chat briefly about his case. According to his neurologist, he has type 2A or 2D, axonal (not myelin) types. He has long had high arches and hammer toes. He has very thin calves. He was well along before he really had symptoms, not only motor loss, but also now some sensory loss, and now affecting the hands as well as the legs. CMT was in the 2013 presentation by graduate student Ian Hakkinen (PodCast).

***Bioelectric

Bioelectric potentials, Ion pumps

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

Personal Reflection

I was first exposed to some of this material as a senior in 1969. Tom Ebrey had a background in physics. He was young, and since he is still living, but retired, I was happy to lunch with him in July, 2007 where he lives (Seattle) since we go there now and then to see my son and his family. see:
R Crouch et al, A tribute to Thomas Ebrey, Photochem Photobiol, vol 82, 2006.

Overview

Excitable membrane has resting and action potentials
Ions are dissolved in water and are pumped using ATP -> ADP for energy
These ion gradients establish "batteries" as ions can flow through channels
Other than channels and pumps, membranes do not pass ions well
For resting potential, Potassium (K+) channels dominate
For action potential, Sodium (Na+) channels open (activate) then close (inactivate)
Toward the end, a different type of K+ channels open (activate) then close (passively, they do not inactivate)
Action potentials are all-or-none big depolarizations
Synaptic (graded) and sensory (generator) potentials are smaller.
They can be of variable size and can be depolarizing or hyperpolarizing.

Electrophysiology

I use a Narishige PD-5 (Tokyo) horizontal puller with controls for an early magnet, a heater, and a late (stronger magnet).

The heater glows red while the first magnet pulls gently.

A microswitch with a shim detects the melt and the early pull to kick in the harder pull.

After the second pull, two electrodes are made.

Over the history of micropipettes, many tricks have been developed to get the very narrow tip to fill. Currently, a capillary tube with an inner filament has magic filling properties.

First you back fill the butt end a little with a spinal tap needle.

The electrolyte (I use saturated NaCl for ERGs) is carried to the tip. Then, you can finish back filling the elecrode with the syringe.

If equipment is dumping current into ground in various locations, then there is a circuit with voltage differences despite the infinitesimal resistance through ground. The result is ground loop noise. Thus it is wise to hook all grounds to one central ground tree. I hook this to water pipe ground with a big braided wire and bypass all the equipment grounds, connecting to the tree instead.

In the set-up, a dissecting microscope can be swung into position. The probe from the amplifier is in the Faraday cage (painted flat black) near the fly. A micromanipulator allows the electrode to be advanced toward the eye. The cage should not be cluttered by electrically noisy stuff, but a microscope illuminator is necessary.

A hydraulic microdrive (Kopf) [stepping motor driving water syringe on left and controller on rignt] driving a slave syringe helps to get the electrode into the eye.


An electrometer serves as the differential preamplifier

In the old days, this could feed into a polygraph, a penwriter that graphs voltage as a function of time, limited for speed by the momentum of the pen

Also somewhat outdated is the oscilloscope

A permanent record can be made with a camera, and the most famous is the Grass camera

Nowadays, the computer is used for an oscilloscope. Here is a PowerBase 180 from Power Computing (Mac work-alike) feeding into an Optiquest monitor using the PowerLab 410 from AD Instruments as the interface

Fig. 2.2 A p. 27
Insertion of stimulating and recording microelectrodes

Fig. 2.2 B p. 27
Voltage as a function of time ("graph") - resting and action potentials
Depending on direction of stimulation, passive potentials are depolarizing or hyperpolarizing
Threshold to trigger action potential is shown
Square wave (stimulus) leads to exponential curve (recording) because of capacitance

Fig 2.1C p. 26
shows action potential again (unconfounded with other information) from axon of spinal motor neuron

Fig 2.1 A&B p. 26
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. 2.4 p. 29
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 2B p. 36 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. 2.7 A&B p. 35
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 p. 59
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 p. 64
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
Circuits (equivalent circuits)
Battery, anode:+, anions:-, Cathode:-, cations:+
Current = i (Amps), defined as + to - (Benjamin Franklin)
Potential (potential difference): V or E (Volts)
(1) Battery (source of electromotive force, EMF)
(2) Current flow through a resistor
battery and resistor in circuit
E = IR (Ohm's law), R in units of Ohms, W
G is conductance, 1/R, "mho" = Siemens (S)
I = gV

Fig. 2.2 B (again) p. 27
note delay in depolarizing or hyperpolarizing membrane
Membrane capacitance (not emphasized in book)

see pdf again
RC circuits
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. 2.4 (again) p. 29
shows elementary properties of pump

Fig. 4.9A p. 72
Na+-K+-ATPase
Uses 1/3 (2/3 if high electrical activity) of cell

Fig. 4.10B p. 73
"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. 4.11AB p. 74
(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. 4.10A p. 73
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

See pdf

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 p. 35
ion gradients for mammalian neuron:
K+ in 140, K+ out 5
Na+ in 5-15, Na+ out 145

Fig. 2.5 C p. 32
shows dependence on external K+

Fig. 2.8 AB p. 37
also shows this

See pdf

Goldman equation
David Goldman, 1943
assume constant field

Vm = 58 log PK[K+]out + PNa[Na+]out + PCl[Cl-]in
PK[K+]in + PNa[Na+]in + PCl[Cl-]out

Cole and Curtis use AC bridge to show resistance of membrane decreases as action potential goes by

Kirchoff's laws

Such a membrane model seems to suggest a confusing circuitry, simplified by several simple concepts.

Kirchoff's first law: at any junction, sum of currents is zero.

Kirchoff's second law: sum of changes in potential around loop is zero.

There is a pdf to illustrate a problem and its solution using Kirchoff's laws.

The solution involves 3 equations with 3 unknowns (high school algebra)
[or determinants, slightly more advanced high school algebra].

***Action Potentials

Action Potentials


Purves et al., Chapters 3 & 4 (review figure from chapter 2)

Summary

Fig. 3.8 A p. 48
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)

See pdf
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. 2.3 DEF p. 28
An action potential is non-decremental

Alumnus research in neuroscience

Joel Geerling, a chemistry major, took this class (and also graduated) in 2000. He went to Wash U for an MD-PhD. Related to the importance of sodium (covered throughout this course and in this outline) is the hormone aldosterone from the adrenal cortex and its regulation of sodium in the kidney. It is well-known, especially by athletes, that a sodium deficiency leads to increased sodium appetite, Joel's work, in the 4 papers referenced below, addresses this issue at the level of the brain. They illustrate the importance of understanding techniques such as confocal microscopy, as well as brain anatomy.
JCGeerling et al., Aldosterone target neurons in the nucleus tractus solitarius drive sodium appetite. J. Neurosci 26, 411-417, 2006
JCGeerling et al., Aldosterone-sensitive neurons in the rat central nervous system, J Comp Neurol, 495, 515-527, 2006
JCGeerling & ADLoewy Aldosterone-sensitive neurons in the nucleus of the solitary tract: Bidirectional connections with the central nucleus of the amygdala, J. Comp Neurol, 497, 646-657, 2006
JCGeerling & ADLoewy Aldosterone sensitive neurons in the nucleus of the solitary tract: Efferent projections, J Comp Neurol 497, 223-250, 2006
NOW (2012), Joel is doing a neurology residency at Beth Israel / Harvard in Boston

Passive spread of potential along axon

Fig. 2.3 ABC p. 28
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 p. 27 (again)
TERMS: threshold, generator potential, all-or-none, refractory, unidirectional
NOTE also the membrane acting as a low pass filter

Fig B Box 2A p. 31 shows exponential decay and space constant (lambda)
Fig C Box 2A p. 31 shows exponential charging of capacitance and time constan (tao)

Cable equation
see pdf

Personal reflection. My fellow graduate student, Paul Kottler, and I took Warren Dennis's course (Physical chemistry of cell systems) together; we also studied for our PhD exam together. My mentor, Jerry Wasserman, had been famous for asking a question about the speed of the action potential and asking it each subsequent year because he was never satisfied with the answer. We resolved to retire this question since we knew that our coverage on the cable equation was much more than Wasserman would expect. When I found out that I passed, I asked Wasserman how he liked my answer and he replied that "it was ok, a little theoretical." So Paul and I decided we had done our duty for posterity, retiring the question, by answering it with a derivation that involved differential equations.

Summary:
(1) an action potential at one place depolarizes the membrane ahead of it to threshold.
(2) the spread is passive.
(3) current down the axoplasm leaks out through membrane resistance and capacitance.
(4) solving, space constant varies with square root of radius, time constant independent of radius.
(5) that is why invertebrates use giant axons for fast propagation.
(6) myelinated axons also have faster propagation for larger axons.

Coding
frequency of action potentials, not size since they are all-or-none
sometimes action potentials come in bursts
or at beginning of depolarization because of "adaptation"

Hodgkin Huxley experiments

Fig. 3.10 p. 50
Propagation of action potential (spike) shown with opening and closing of Na+ and K+ channels drawn in

Note relative opening and closing of channels
"sodium pump" already established the ion gradients
oscilloscope essentially graphs voltage as a function of time
action potentials can also be listened to on a loud speaker
activation, inactivation, voltage gating

Fig. Box 3A p. 42
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 p. 44
voltage clamp data
voltage clamp - change voltage then pump and monitor current needed to keep it there
I - t curves

Fig. 3.3 p. 44
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 p. 45
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 p. 61
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 4C p. 63
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 ABCD p. 4.5
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. 4.6 Ct o F p. 67
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. 4.8
Human K+ channel, includes detailed structure and model
tetramer
shows where K+ is when it is opened

Fig. 4.6G p. 67
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 p.67
Sodium channel, now diverse (human 10 genes)
electric eel Electrophorus electricus 600 V
Huge - 1820 amino acids - "pseudotetramer"
S4 - gating - positively charged (basic) arginine (R) or lysine (K)

Fig. no longer in book
rotation of S4
Pore between 5 & 6 (not hydrophobic)

Fig. 4.1AB p. 4.1
Patch clamp
low current (1-2 pA)
low conductance - 10 pS
stopper to inactivate.

There are different types of Na+ channels, and some are targets of local anesthetics benzocaine and lidocaine.

Potassium channels (lots of them, 100)
Leak (resting potential) 20 pS
Delayed rectifier (repolarization of action potential) 10 pS
Anomalous rectifier - maintain depolarization - cardiac, fertilization
HERG human ether-a-go-go related gene

Calcium channels
16 genes
Ca2+ regulation by parathormone, calcitonin and vitamin D important
Ca2+ channel in synaptic terminal vesicle release - very important, also many others
Ca2+ channel is receptor for IP3 (inositol trisphosphate "second" messenger) on smooth endoplasmic reticulum
Ca2+ channel in muscle sarcoplasmic reticulum
Ca2+ channel in t- (transverse-) tubule in muscle

Box 4B p. 62
Toxins
Tetrodotoxin puffer fish (saxitoxin dinoflagellates) block Na+ channel
scorpions
and many others

Fig. Box 4D p. 70
genetic diseases of channels
myotonia (stiffness from too much excitation) from Cl- channel defect

Fig. Box 4D p. 70
paralysis from Ca2+ channel defect
CSNB from Ca2+ defect Congenital (i.e. genetic) stationary (as opposed to degeneration) night blindness (would affect rods)

Fig. Box 4D p. 70
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. 4.7 p. 68
Structural studies on bacterial K+ channel - it takes a lot of protein to do X-ran crystallography

Fig. 4.7 p. 68
selectivity by pore size
interesting that non-hydrated ion passes.
Hydrated - size is inverse
Li > Na > K > Rb > Cs (lyotropic series)

Fig. 4.6 (again) p. 67
There are a lot of configurations of channels

***Synapses

Synapses


Purves et al. Chapter 5

Major point

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

Fig. 5.1AB p. 78 "electrotonic synapse"
Figure of chemical synapse is like Fig. 5.3 p. 80 (only simpler)
Vesicles, spine, receptors (the ionotropic type, i.e. channels) are shown

Alumna

Johnnie Moore took this course in 2002. She published this paper: Moore et al., Stable gene silencing of synaptotagmin I in rat PC12 cells inhibits Ca 2+-evoked release of catecholamine, Am J. Physiol Cell Physiol 291, 270-281, 2006
Topics to discuss:
confocal
synaptotagmin
NGF
calcium
PC

"Electrical synapses"

Fig 5.1A B p. 78

Gap junction is an exception to the above generalization in that cells are coupled electrically with cytoplasmic continuities (small ones).
Gap junctions are used in crayfish escape,

"Landmark" paper EJFurshpan and DDPotter, Mechanism of nerve-impulse transmission at a crayfish synapse, Nature 180, 342, 1957 and J. Physiol. 145, 289, 1959. "Landmarks" was a department in The Journal of NIH Research, includes interviews. (ref=vol 8, Oct 1996, 51-57)

They are also used to connect myocardial cells electrically at intercalated disk.
Conductance is high - 120 pS.

Fig 5.1C p. 78
Gap junction is patch of hexamers forming big channel in register with adjacent cell.
Proteins, called connexins, are very diverse.
They are often named with a number that represents the molecular weight.

Recent paper CDLandisman & BWConners, Long-term modulation of electrical synapses in the mammalian thalamus, Science 310, 1809-1813, 2005. There are gap junctions with connexin36 (Cx36) in thalamic reticular nucleus (TRN). There are chemical synapses using metabotropic glutamate receptors (mGluRs) from neocortex. Activating this corticothalamic path causes long-term decrease in electrical synapse strength. This is like long term depression, a model for learning at the level of the chemical synapse.(Each item of terminology that might be unfamiliar to you now will be covered later.)

Pore is big enough to give cytoplasmic continuity for medium sized molecules (dyes).
In addition to electrical coupling, there can be communication by molecules.
In EM, membranes appear very close but not fused
Extracellular tracers (heavy metal Lanthanum) proves there is extracellular space.

History

In 1906 Sir Charles S. Sherrington (England) published Integrative Action of the Nervous System and later (1932) won the Nobel prize for "functions of neurons." He coined the term "synapse."
In studies of the spinal reflex, he determined that the spinal motor neuron was the "final common pathway" (for integrative action of the nervous system). Spinal reflexes were studied in spinal animals in which the spinal cord was transected to prevent descending cortical influence. There are no inhibitory neuromuscular junctions in vertebrates, so whether the spinal motor neuron fires, based on summed inhibitory and excitatory influences, is the last chance to integrate neural influences.

Fig. 5.4 p. 81
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. 5.22AB p. 103
Sir John C. Eccles 1963 Nobel (with Hodgkin & Huxley) EPSP & IPSP
Excitatory or Inhibitory PostSynaptic Potentials (Eccles, using spinal motor neurons)
Excitatory and Inhibitory integrate in cell, and axon hillock "decides" whether to fire.

Fig. 5.21A p. 102
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 5.21BC p. 102
GABA (gamma amino butyric acid) is the inhibitory transmitter
IPSP - hyperpolarize (unless clamped negative to reversal potential)
increase potassium and chloride conductance
inferred because reversal potential negative to resting potential (in voltage clamp)
and by changing Cl- gradient by using ion specific electrodes to inject Cl-

1970 Nobel Sir Bernard Katz (England) Ulf von Euler (Sweden) Julius Axelrod (US) "humoral transmitters...nerve terminals....storage release inactivation"

Fig. 5.7A p. 86
classic experiment by Katz showing that the transmission at the neuromuscular junction is "quantal." Quantum is one vesicle. EPP (end plate potential) is reduced to meep's (miniature end plate potentials, 0.4 mV) by lowering extracellular Ca2+ ion, and nerve stimulation elicits responses the size of 0, 1, 2, or 3 meep's according to the Poisson distribution. "end plate" potential is big and effective in generating muscle action potential. Usually 200 vesicles give 40 mV potential.

Fig. 5.8 A p. 87
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. like Fig 5.3 p. 80 (only simpler)
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 5.13B p. 91
There is a protein called dynamin that helps pinch off vesicles. It is the product of the temperature sensitive Drosophila paralytic mutant called shibire. At restrictive temperature, there is a block in endocytosis of vesicles (another view).

vesicles and T-shaped ribbons in Drosophila

Here is a transmission electron micrograph of a synapse

Vertebrate - inputs to cell or dendrite (spine)
Invertebrate - cell is usually away from action surround "neuropil(e)." Here is a picture from my work on Drosophila, retina (compound eye is off top, cartridges of synaptic connections are at bottom, cell bodies of post-synaptic neurons are between.

Vesicle release

General: vesicles are interesting, transmitter is very concentrated, there are pumps to move transmitter "up hill" (against gradient) into vesicle, sometimes part of synthesis is in vesicle.

Fig 5-13, p. 91
very modern, interesting and detailed
also, interesting Box 5B, pp. 93-95, on diseases and toxins that affect neurotransmitter release
there are vesicle membrane proteins, target (presynaptic) membrane proteins, and cytoplasmic proteins
Ca2+ in through Q or N type voltage gated channel
(N stands for "neither," as opposed to T=transient or L=long lasting, the N channel is blocked by omega toxin from Conus [snail genus])

Vesicle proteins:

Synaptobrevin / VAMP (vesicle-associated membrane protein) = v-SNARE (SNAP receptor)
Botulinum and Tetanus toxin (clostridial toxins) are proteases which cleave synaptobrevin
Botulism (Clostridium botulinum) anaerobic, improper canning (need to heat to kill spores) - block release
When I ws 10, in the Cold War, we discussed, at the dining room table, how 1 teaspoon in the reservoir would kill the city. Now. 45 years later, people take it (injected) to get rid of face wrinkles.
Tetany is term for sustained muscle contraction based on twitches adding up.
Tetanus toxin cleaves synaptobrevin in inhibitory interneurons.
The disease is contracted in deep (because it is an anaerobic bacterium) dirty puncture wounds.
You would die with muscles contracted, called "lock-jaw."
There is a vaccine and boosters every 10 years are suggested.

Synaptotagmin - binds calcium
synapsins get phosphorylated (by CaM Kinase II and PKA) interact with actin
rhabphilin receptor

Target membrane proteins:

Syntaxin = t-SNARE = unc-18 (uncoordinated C. elegans roundworm mutant)
Neurexin - black widow spider venom (alpha Latrotoxin) causes too much release
Neuroexins bind to synaptotagmin

Cytoplasmic:

NSF - N-ethylmaleimide sensitive factor (ATPase activity when complex dispersed)
SNAP - soluable NSF associated protein
Rab3 (like ras, small GTP binding protein) (lots of rab's, specific for transport)
rabphillin

Summary:

Fig. 5.14 AB p. 92
SNAREs and SNAP (docking)
In addition to SNAREs and SNAP, Ca binding synaptotagmin is for fusion

Fig. Box 5B pp. 93-95
BoTX and TeTX sites.

***Transmitters

Neurotransmitters


Purves et al., Chapter 6 and selections from Chapters 5, 17 and 21 (for autonomic nervous system)
Sylvius (there are many places where you might want to look up the structures discussed)
This outline will focus on transmitters. Although transmitter receptors will be mentioned, they will be covered in more detail on the next outline.

Alumna

Michelle Lugus (nee Li) took this course in 2006. I am showing you one of her papers, Li et al., Electroanalysis 17, 1171-1180, 2005. A microchip-based system for imobilizing PC 12 cells and amperometrically detecting catecholamines released after stimulation with calcium.
Topics to discuss:
PC 12 cells
microchip
why calcium

Background

Synaptosomes
After gentle homogenization, pre- and post-synaptic membranes stick together, and membranes seal back up; all the chemicals of the synapse can thus be found in one centrifuge tube layer.

Figure
Box 5A (Chapter 5) p. 84
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 p 111
Fig 6.1 p. 110
Chemical synaptic transmitter substances:
Monamines (acetylcholine, catecholamines, serotonin, histamine, octopamine)
Amino Acids (GABA [gamma amino butyric acid], glutamate, glycine)

Figure 6.17 p. 134
Peptides (many)

gasses like Nitric Oxide (NO), see below

Purines - ATP (and AMP and adenosine) excitatory transmitters (not much to say)

endocanabinoids (see below)

General aspects about synthesis

(Fig. 5.5 was shown earlier, in the context of axon transport)

Fig. 5.5A p. 83
synthesis for small molecules in terminal
enzymes transported by slow axonal transport

Fig 5.5C p. 83
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. 6.16 AB p. 1\3
Further processing, especially cleavage (common for many peptide transmitters and hormones)

vesicles

Fig. 5.5 B p. 83
40 nm (small) electron lucent vesicles and just a few large dense core

Fig. 5.5 D p 83
somewhat larger dense core are catecholamines or peptides
100 nm diameter granules are secretory
Importantly, transporters concentrate transmitters into vesicles

General

Fig. (like Fig. 5.3, p. 80, only simpler)
Here, I show a typical synapse figure (again).
Receptors in this figure are channels

Fig. 5.16 A p. 97
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. 5.16 B p. 97
There is another kind of receptor, the G-protein-coupled receptor.
For cholinergic transmission, the muscarinic receptor is an example

Monamines

Fig. 5.4 p. 81 (again)
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 p. 112
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 p. 125
Adrenergic

Landmark paper
(1970 Nobel Prize) Julius Axelrod, Noradrenalin: Fate and control of its biosynthesis, Science 173, 598-606, 1971. Science publishes Nobel Prize papers.

Reflection, I saw Axelrod (twice) and he gave great talks, in an easy-going manner, said everything that was known.

tyrosine hydroxylase - rate limiting and regulated by end-product inhibition
calcium activates
it is DOPA quinones which polymerase to make melanin
substantia nigra is pale in Parkinson's disease => synthesis overlap
DOPA decarboxylase - gets rid of l vs. d
in insects, dopamine quinones "tan the hide"
dopamine beta hydroxylase - adds optical asymetry back again
interestingly, within vesicle
ATP is released with NE, ATPase turns to adenosine
Important agonists and antagonists and other drugs
PNMT (phentolamine N-methyltraansferase)
interestingly, in cytosol, necessitating transport out then in vesicle

Table 6.1 p. 111 (again)
"Metabolism"
Most removal is by transporters, but there is breakdown
MAO - monamine oxidase intracellular, inhibitors (MAOI's) are antidepressants
on outer mitochondrial membrane
COMT - catechol O-methyltransferase extracellular, but there are no inhibitors)
but reuptake most important

Autonomic n.s.

Motor system for smooth muscle and glands, covered here because of acetylcholine and norepinephrine involvement

Part of Fig. 21.1 (left side) p. 455
Parasympathetic, cranio-sacral, ACh (nicotinic and muscarinic), ganglion near target

Part of Fig. 21.1 (right side) p. 455
Sympathetic, thoraco-lumbar, ACh (nicotinic) then NE, ganglion near spinal cord
Many targets are "push-pull" like heart
Some are unique like arterioles (sympathetic only) -- close in peripheral vascular beds (make hands cold), open in muscle (hyperemia).

Fig. 21.2 A p. 459
arrangement of sympathetic output from lateral horn neuron -> white ramus -> sympathetic ganglion -> gray ramus

Fig. 21.3 B p. 460
Simpler for parasympathetic, i.e. from brain stem nucleus...

or ...

Fig. 21.3 C p. 460
lateral horn in sacral cord to parasympathetic ganglion

Fig. 21.4 A p. 462
called "enteric" for gut. Contribution of neural network (plexus) to circular and longitudinal muscles to mediate peristalsis. Parasympathetic allows digestion, sympathetic puts it on hold. Atropine (I'll talk more about atropine in next outline) blocks muscarinic synapses and is in anti-diarrhea medications to slow motility.

Fig. 21.8 p. 470
heart as an example. Automaticity at SA and AV nodes (spread from myocardial cell to next myocardial cell). Sympathetic speeds heart, parasympathetic (via vagus, X) slows, and relaxed heart rate is slower than automatic rate.

Male sexual function as an example.

Fig. 21.9 p. 471
Important aspect of quality of life

Robert F. Furchgott, Louis J. Ignarro, Ferid Murad Nobel 1998 "for their discoveries concerning nitric oxide as a signalling molecule in the cardiovascular system"

A few years ago, I wrote, "This is the only place where parasympathetic affects arterioles, dilating them in corpus cavernosum for erection. Sympathetic contributes to ejaculation."

Then I read a paper by Ignarro and then his Nobel "speech." Actually, for erection (relaxing arteriole smooth muscle), adrenergic (via alpha 1 receptors) contracts smooth muscle, cholinergic (via muscarinic receptors) inhibits adrenergic-induced-contraction (resulting in relaxation); more than cholinergic and adrenergic, a little mentioned autonomic component, the NANC (nonadrenergic noncholinergic) system, mediates relaxation.

In the 2003 movie Something's gotta give, Jack Nicholson has a heart attack while having sex, and the docs ask if he is on Viagra as they are about to give him nitroglycerine. (also listed in advertisements for ED (erectile dysfunction) medications because of interaction and resulting low blood pressure)

People take nitroglycerine for angina (chest pain), and it releases NO (nitric oxide) and relaxes the coronary arteries

Nitric Oxide (NO), made by endothelial nitric oxide synthase (eNOS), unusual in that it diffuses across "postsynaptic" membrane to affect guanylyl cyclase (GC) involved in making cGMP.
NO was endothelial derived relaxation factor (EDRF), mediator of parasympathetic nervous system's dilation of arterioles in corpus cavernosum. Viagra (sildenafil) inhibits the PDE that breaks down cGMP

Serotonin

Fig. 6.14 B p. 131
Serotonin = 5-HT (5-hydroxy tryptamine)
tryptophan hydroxylase
l-aromatic amino acid (5-HTP) decarboxylase
Serotonin from Raphe nucleus ispread widely and involved in sleep (discussed later in the semester). Tryptophan in turkey blamed for sleepyness after Thanksgiving dinner.

Alumnus interview relates to SSRIs
SSRIs (selective serotonin reuptake inhibitor)
Prozac (fluoxetine)
Paxil (paroxetine)
Zoloft (sertraline)
There is new controversy about whether these increase the incidence of suicide, now that they are given to teenagers, but there was also controversy overr a decade ago. The other side of the argument is that it is given to depressed people.

LSD (lysergic acid diethylamide) agonist of 5HT receptors in Raphe, cause decreased output to brain (as in sleep).

People used to take tryptophan, but bad batch caused eosinophilic-myalgia syndrome so FDA banned it in 1990.

The melatonin story

2 more steps after 5-HT to make melatonin (sleep promoting hormone, higher at night) in pineal
N-acetyltransferase (regulated) and hydroxy indole O-methyl transferase.
High at night, low during day, relates to biorhythms, see lecture later in the semester.
In animals where light can reach the pineal, it has photoreceptors.
For us, eye to suprachiasmatic nucleus of hypothalamus to pineal.
N-acetyltransferase is rate limiting step.
Melatonin sales went wild in mid-1990's after books stated that melatonin was a "wonder," "miracle" or keeps you young.
Thought to restore sleep cycle after jet lag.
Melatonin controls reproductive cycle in seasonally reproductive species.
Here is the diagram used in the Mizzou Physio lab on endocrinology.
Testes of short-day hamsters are smaller than long-day hamsters (Mizzou Physio Lab)
Melatonin was used at high doses for birth control by women in Holland

Amino acid transmitters

Fig. 6.5 p. 118
Glutamate
Central excitatory - like inputs to hippocampus - maybe half of CNS synapses
Synthesis is simple from glutamine (from nearby glia) by glutaminase.
Prof Bode in my department has a special interest in glutamine transport.
Affected by many toxins, for instance poison from mussels - domoic acid, and plants (Box 6B).
Involvement in ALS (Amyotrophic lateral sclerosis [Lou Gehrig's] ALS) and possibly Alzheimers.
Excitotoxicity - Box 6C - too much glutamate causes a cycle of Ca2+ influx.
May be involved in ischemia - induced injury.

Fig. 6.8 A p. 122
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 p. 122
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. 6.14 A p. 131
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 p. 127
Fig. 6.13 B p. p. 130
1960's technique of histochemical fluorescence allowed chemical anatomy -
Expose sections to vapor of paraformaldehyde
neurotransmitters have widespread effects but come from defined locations
Dopamine from substantia nigra
Norepinephrine from locus coeruleus
Serotonin from Raphe

Parkinson's
(mentioned here because of dopamine)
Miclelle Li, graduate student in 2006 class, gave a presentation on Parkinson's

Fig. 18.9A p. 408
degeneration of substantia nigra (left) relative to control (right)
Box 18.A p. 410 in Chapter 18
1817 Shaky palsey
Degenerate dopaminergic input to striatum from substantia nigra
Cells that survive have inclusions called Lewy bodies.
Aflicted have bradykinesia, akinesia, rigitystilted gait, tremors, walk in shuffle, stone (expressionless) face, loss of affect.
1% of people over 50 years old
Lateral hypothalamic lesions make thin rat and some motivational defects, dopamine in medial forebrain bundle toward basal ganglia.
Dopaminergic neurons degenerate, animal model - 6-OHDA uptake makes peroxide, cells die.
Cannot give dopamine because it coes not cross the blood brain barrier.
Give l-DOPA (in large doses because l-AAAdeCOOHase is everywhere); give decarboxylase inhibitor carbidopa. Jill Smith, Ph.D. 2005, in Dr. Fisher's lab (Bio, SLU) worked on this.
Extrapyramidal motor syndrome also comes from long term administration of antipsychotic phenothiozines such as chlorpromazine (brand name Thorazine).
(Chronic use of these drugs also cause a corioretinopathy.)
There was a bad batch of street drugs with an impurity called MPTP which gave its users a Parkinson's like disease.
The commonly used insecticide rotenone, and other insecticides, are like MPTP.
There had been some experimental cell transplant therapies - controversal.
Arvid Carlsson made contributions here and shared 2000 Nobel Prize in Physiology and Medicine.
Several famous people have Parkinson's - the late Pope, Mohammad Ali, Michael J Fox.
Mostly it is "sporatic" (not genetic), but familial cases have been interesting.
Alpha-synuclein, Parkin and DJ-1.

Psychiatry

Personal reflection.
I took abnormal psychology when I was an undergraduate at Columbia College in New York in the 1960's. We were sent up the the Psychiatric Institute at Columbia Physicians and Surgeons to see a psychiatrist interview patients for two classes. That part of New York is hilly, and the ground floor of PI was the 9th floor. An odd coincidence was that we had all read Dante's Inferno recently in literature humanities. The first patient was an 18 yr old kid who played chess instead of basketball who was being fed a shovel full of chlorpromazine every day. After he left the room, the doctor asked the class what was wrong with the kid and we all looked in the pony for the abnormal psych text and said things like "paranoid neurotic" etc., and the doctor said "you guys are far too cerebral, this kid's a schmuck, he has the schmuck syndrome." The next week we saw a person more normal than any of us who seemed to think an appeal to the class was his only means of escape. We were all happy to get out of the PI without being sent down to one of the lower floors (Dante's inner circles) and chained to the wall.

Alumnus interview relates to Psychiatry
Box E biogenic amines and psychiatric disorders.
Psychosis - severe.
Neuroses not so severe.
Schizophrenia (dementia praecox= early loss of intelligence) (paranoid, catatonic, etc.), real thought disorders, progressive and degenerative, used to be the cause of more "hospitalization" than everything else put together.
They were called "insane asylums" (These were the days before political correctness.)
Borris Karloff old movie "Bedlam" is about insane asylum.
It is popular to mistrust psychiatry, for instance the movie "One flew over the cuckoo's nest" with Jack Nicholson (1975), but people with schizophrenia are really crazy without a doubt.
Reserpine storage blocker, used for hypertension (for NE [andDA, 5HT]) for psychosis; 1950s - revolutionized psychiatry (nowadays, the disparaging phrase is "went off his or her meds").
There was a 1960s radio advertizing slogan "mental illness [again before political correctness] is no longer hopeless" (that kids used to say to each other).
There was a book, D.W.Woolley, The biochemical bases of psychoses (subtitle - the serotonin hypothesis about mental diseases (New York, Jhhn Wiley and Sons, Inc., 1962), and the understanding that LSD affected serotoninergic transmission fit in.
It seems every time a neurotransmitter was characterized, there was a band wagon of attributing everything to it, a catecholamine (norepinephrine) theory of affective disorders (partly attributed to Stein (J. J. Schildkraut and S. S. Kety, Biogenic amines and emotions, Science, 156, 21-30, 1967), and this fit in with the idea that amphetamine caused psychosis (Amphetamine stimulates NE release); this is before dopamine was appreciated as a transmitter.
Methedrine (speed, drug of abuse, MO (Jefferson Co famous for manufacture, explosions, fires), dexedrine (once used as a diet pill, recently, oddly, used for ADHD [attention deficit hyperactivity disorder]) [works on explorer, not netscape], and benzedrine (mild uppers, abused by students cramming for exams); now ritalin used for ADHD; I repeat that is it odd that stimulants would help hyperactivity; it is also controversial and troublesome how many kids are given such drugs. (Later in the semester, we will talk about "amphetamine and cocaine regulated transcription factor."
Now thought to be over-activation in dopamine pathway.
Dopamine receptor blockers (antagonist) - haloperidol, chlorpromazine are antipsychotics.
Chronic chlorpromazine treatment causes chorioretinopathy and Parkinson's tremors.
Incidentally, a controversal 1971 book (D. Rosenthal, Genetics of psychopathology, New York, McGraw-Hill Book Co) suggested an underlying genetic predisposition for schizophrenia, now widely believed.

Depression, unipolar, bipolar ("manic depression is a frustrating mess" - Jimi Hendrix)), involutional melancholy (in elderly) - great suffering.
Bipolar seems to run in families, treated with lithium salt, my theory is that, since Li+ can replace Na+ for the action potential but not in the Na+ pump, action potentials would be smaller.
Unipolar Tricyclic antidepressants (desipramine) blocks NE (and other) reuptake.
SSRI's covered above.
Antidepressants MAOI's (phenylzine)
After electroconvulsive shock (ECS), patients seem much happier; sounds barbaric, but still used and, with correct control medications, it is not cruel; Interestingly, there is a memory loss for the time before the shock, and ECS fits in with the idea that correctly reverberating neural circuits are important for memory consolidation.

Anxiety - Tranquillizers - benzodiazepines (chlordiazepoxide = Librium, diazepam = Valium) enhance GABA-A receptors

Treat panic with MAOI's, also serotonin receptor blockers, also benzodiazepine alprazolam (Xanax).

Peptides

substance P - 11 amino acids known for 60 years, named after "powder"
involved in pain

Landmark paper CBPert and SHSnyder, Opiate receptor: Demonstration in nervous tissue, Science 179, 1011, 1973, see also J NIH Res 2, 73-79, 1990
Tritiated naloxone, opiate antagonist, binds to places in the brain and is displaced by opiates in parallel with their strength.

Table 6.2 p. 135
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. 6.18 p. 136
Box G p. 137
Cannabis sativa

Recent paper R. A. Nicoll and B. E. Alger, The brain's own marijuana, Scientific American, pp 68-75, Dec 2004.

BoxG p. 137
THC used to treat anxiety, pain, nausea, obesity, glaucoma.

BoxG p 137
Affects hypothalamus, basal ganglia, amygdala, brain stem, cortex, hippocampus, cerebellum.

A. C. Howlett, 1988, SLU, receptor CB1, later CB2 was found.
G protein coupled receptors.
Presynaptic CB1 prevents GABA release to block glutamate excitation

Fig 6.18A p. 136
Anandamide

Fig. 6.18B p. 136
2-arachidonoyl glycerol (2-AG)
2-AG released from postsynaptic cell

***Alumnus e-interview

Alumnus e-interview


Robert Marietta, MD (SLU-2000) was a Med-Scholar 1992-1996. He did  several courses from me including this course.

He completed a Navy residency in Psychiatry and served in Okinawa. Now (2012), he is a
practicing psychiatrist in Virginia

This "e-interview" is from 2006



Q:  Prozac and related drugs have revolutionized the treatment of
depression.  From the outset and recently, they have been implicated, by
their detractors, in suicide and homicide.  How do you address these issues?

A:  People with depression have a higher incidence of suicide than
people without depression.  Is suicide caused by depression, caused by
the drug or both?  If you look at the rate of suicide for the entire US
population over time you will see that it dropped around the time
anti-depressants came on the market.  The current consensus in
psychiatry is that anti-depressants are safe, effective and reduce
suicide when used appropriately.  Just as a drug could make someone feel
better it could also make them feel "too good", more agitated or
irritable.  This is especially true in the case of a bipolar patient
presenting in a depressed phase.  An anti-depressant used alone might
flip such a patient into a mania and result in agitation or suicidal
ideation.  The way the clinician addresses this is through the process
of informed consent.  We tell patients the risks and benefits of a drug
and let them decide if they want to take it.  We warn patients to look
out for the potential side-effects and to stop the medication and call
us if they arise.

Q:  Depression, and medication for depression, is now a big issue in
children in teenagers.  What are the appropriate and ethical approaches?

A:  To my knowledge there was only a single study that suggested a small
increase in suicidal IDEATION (not the incidence of completed suicide or
suicide attempts) in children on anti-depressants.  Given the dramatic
and litigious nature of our society, the story was sensationalized and
developed a life of its own.  The study was quickly debunked and
disregarded by child psychiatrists.  The proper approach again is
informed consent.  To provide informed consent the pediatrician or child
psychiatrist has to have a firm understanding of the literature
surrounding issues like this so they can competently talk about the risks.

Children are very dynamic just like the wiring in their brain.  They
tend to have different and more transient symptoms than adults.  For
example, a depressed child might be irritable compared with an adult who
feels sadness and decreased energy.  Many symptoms in children represent
prodomes for disorders that will occur later in life.  The big
difference between the standard of care for treatment of children and
adults is that they require more frequent follow-up.  It might be
appropriate to start and adult on an anti-depressant and wait a month
for follow-up.  However a child patient requires a follow-up after the
first week of starting a medication.

Q:  In the early days of treatment for hyperactivity, it seemed odd that
an amphetamine (dexedrine) should be used. How can it have such
different effects, calming hyperactivity in youth and acting as a
stimulant in adults?

A:  ADHD is divided into 2 main symptom clusters including inattention and hyperactivity.  It is possible to have inattention alone, hyperactivity alone or a mixed presentation.  Approximately half of children with ADHD continue to have the disorder as adults.  It could very well be that these symptom clusters share a similar genetic mechanism of action.  For example, the serotonin transporter gene and dopamine receptor.  Recent neuroimaging studies like the PET scan show that different areas of the brain light up in patients with ADHD vs. normal controls.  There might be separate areas in the brain responsible for attention and impulse control affected by the same genes.  The "genetic load" or number of mutated genes in addition to the severity of the mutations is important to consider.  Regardless of the precise cellular mechanisms one could see how increasing the amount of dopamine or norepinephrine might act on both areas to improve attention because these areas of the brain are stimulated.

Your question is a reminder that for as much as we know about medications including what neurotransmitters they act on, we really don't know the exact mechanism of action for how they alleviate people's symptoms.  For example, we know that norepinephrine and dopamine improve concentration.  At the same time, it might not be accurate to say ADHD is caused by a "deficiency" of these neurotransmitters.  Besides acting directly on neurons, stimulants might increase blood flow to certain areas of the brain.

Q:  Nowadays, Ritalin is widely prescribed and hyperactivity is called ADHD. Tom Cruise, and the Church of Scientology, have been outspoken critics. Answer them on the reality of ADHD and the usefulness of medications.

A:  When neuroimaging studies suggested the possibility of differences between ADHD and control subjects the Church of Scientology claimed that the medications themselves were resulting in brain damage.  A follow-up study was performed that compared neuroimaging studies of patients with ADHD on medication and control subjects with ADHD without medication.  As I recall, the results were the same or better for subjects on medication.  The fact is regardless of the cause of the disorder, stimulants are very effective for ADHD.  There are other non-stimulant medications such as buproprion and atomoxetine that have also been proven effective for the treatment of ADHD.  Neuroimaging, genetic studies and that fact that patient's symptoms improve by drugs affecting specific suggests that our biology plays a significant role in ADHD.  To accept the notion that ADHD doesn't exist and that medications are harmful or ineffective means ignoring all this scientific research.  It is irresponsible and harmful for these parties to make such unsubstantiated claims and I question their motives.  

Q:  Brook Shields was criticized for receiving treatment for her post-partum depression.  Answer this criticism.

A:  There is a clear relationship between hormones and depression.  A disorder called premenstrual dysphoric disorder has been described in the literature where women experience clinically significant depression at a predictable point during their monthly cycle.  Similarly, birth control pills are known to cause depression.  Pregnancy and the post-partum period is a time when hormones are changing rapidly.  There is strong evidence for a biological etiology for post-partum depression.

If someone falls down they are experience pain.  Suppose they were doing something foolish that caused their fall.  Does that make a difference as to whether or not they deserve an effective treatment?  If we suggested withholding medication that would effectively treat the pain that would be unethical and immoral.  The same thing applies to patients with depression.  Even if a patient had a 100% psychological etiology for depression medications could still be considered an effective treatment.  Medications might improve the new mom's mood, energy level and sleeping pattern.  This might benefit the child by improving the mother's ability to bond with her child.

Q: Although it sounds barbaric, electroconvulsive (ECT) shock has played a role in treatment for depression. How useful was it and is it still used?

A: At some point the clinical observation was made that patients with epilepsy
have a lower incidence of psychiatric disorders. Around 1940, someone tried
generating a seizure in a patient with severe psychiatric problems and
reported good outcomes. The problem with a seizure is that it causes
muscular contractions all over the body. In modern ECT, patients are given
a paralytic agent such as succinylcholine prior to the procedure. They are
also given an anesthetic to make them unconscious. The psychiatrist then
connects usually two leads or sometimes one lead ("unipolar") to a machine
and generates a seizure. Unipolar ECT is used with people with dementia and
depression to reduce the chance of memory loss. The leads are connected to
an EEG so that the psychiatrist can make sure an adequate seizure was
generated. ECT is generally administered 1 to 3 times per week for several
weeks and then less frequent for maintenance treatment. ECT is very
effective for mood disorders such as depression and bipolar disorder. It is
unique in that it results in a very rapid improvement of symptoms where
medications act at the cellular level and take weeks to work. I suspect the
mechanism of action has to due with release of neurotransmitters. A
definitive mechnism of action is unknown. ECT has a unique utility for
elderly patients who can't tolerate medications. ECT can result in limited
memory loss and generally has few adverse side-effects.

Q:  Any other thoughts?

A:  One of the biggest areas of research in psychiatry is psychosis
because of the impact on society and costs involved.  The psychotic
disorders especially schizophrenia are considered to be very much a
biological illness.  Probably the number one prognostic factor in this
disorder is compliance with medication.  The neurotransmitter in
psychosis is dopamine.  The medications used for treatment of
schizophrenia block dopamine receptors.  Too much dopamine or overactive
receptors could mean psychotic symptoms like hallucinations.  Cocaine
causes release of dopamine and results in psychotic symptoms sometimes.  
The dopamine receptor subtypes are very important.  Block them all like
the older "typical" anti-psychotic agents and you can get tardive
dyskinesia and a Parkinson like movement disorder.  Block only certain
subtypes with the new "atypical" antipsychotics and you get relief of
symptoms without the movement disorders.  There is a newer class now
that has partial agonist and antagonist effect on dopamine receptors:  
keep them active at a low level but block the rest.

***Neurotransmitter receptors

Signalling


Neurotransmitter receptors and Second messenger systems
Purves et al., Chapters 6 & 7

Channels

Nicotinic receptors


Fig. 6.3 A, B, C, D p. 113
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.

Fig. 6.7A p. 120
some channel proteins, AMPA receptor shown here, span 3 times
Protein (nicotinic receptor subunit) spans the membrane 4 times.
M2 likely lines the pore.
Nicotine is an agonist; but it seems somewhat like an antagonist because it blocks transmission at autonomic ganglia by depolarization blockade.
There are pharmacological antagonists (curare, a plant alkaloid from Clondodendron tomentosum).
Important for mechanisms of muscular relaxatants used in surgery (like succinylcholine).
Must relax muscles in surgery but must prove that anesthesia is adequate.

Recent paper
Beverly A Orser, Lifting the fog around anesthesia, Scientific American, June 2007, 54-61
Obviously, analgesia (absence of pain) is paramount
Unconsciousness (hypnosis)
Immobility
Interestingly, amnesia (loss of memory)
Dentist William Morton used ether in Boston in 1846
These days, drugs that keep GABA-A channels open (benzodiazepines like Valium also affect these)

Some additional points about nicotinic receptors:
Developmentally, when nerve-muscle junction is made, diffuse receptors cluster.
Acetylcholinesterase, by contrast, is all over the place.
Receptor molecules are very concentrated at n.m.j. crest, 20,000 - 30,000 per square micron (about as tightly packed as possible in contrast with punctate voltage gated sodium channels).
Probably water filled pore.
All 4 subunits needed in expression systems to get functioning receptor.
10 to the 6th ACh molecules from one a.p. into n.m.j. cleft.
2.5 x 10 to the 5th channels transiently open.
400 nA n.m.j. end plate current.
1 ms open time.
10,000 Na+'s flow through each channel in this time.
Channel conductances of 25 pS

Box B (Chapter 6) p. 117
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. 6.3 F p. 113
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. (like Fig. 6.6 C p. 119 only older and simpler)
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 A p. 123
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. 6.3 F p. 113)

Landmark paper RADixon et al. (RJLefkowitz) Cloning of the gene and cDNA for mammalian beta-adrenergic receptor and homology with rhodopsin, Nature 321, 75, 1986, see J NIH Res, 9, 45-52, 1997.

Fig 6.4 AB p 116
7 transmembrane domains called G protein coupled receptors.
By hydrophobicity, they all cross membrane in 7 alpha-helices.
Rhodopsin was the prototype, followed closely by the beta adrenergic receptor.
Then many neurotransmitter and hormone receptors were found.
In the early 1990's, olfactory receptors were found to be G protein coupled receptors, and there are lots of olfactory receptors; Richard Axel and Linda B. Buch won the 2004 Nobel prize for this work.
In summary, there is an enormous diversity! Superfamily (>1000 in mammals).
N terminus outside cell, glycosylation
C-inside (heptahelical) -phosphorylation,
2nd and 3rd loops and C terminus for interaction with a subunit of G protein

Fig 6.4 C p. 116
Here's the example of the huge list for transmitters.
Many types mGluR1-8, NE alpha (6 types), beta 1 , 2, & 3, D1-D5, GABA-B(1&2), 5-HT-12 types, Purines 12 types
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 p. 144
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 p. 145
G protein so named because it (alpha subunit) binds GTP
AGGilman and M Rodbell, Nobel 1994
heterotrimer alpha, beta and gamma
alpha and beta are about the same size, gamma is smaller
alpha and gamma linked to membrane by fatty acid
alpha subunit affects effector and is GTPase

Fig. 7.6 p. 146
cascades with different second messenger (signalling) systems (effectors)

For beta adrenergic receptor, Gs (stimulatory) activates adenylyl cyclase, to make cAMP, which, in turn, activates protein kinase (PKA) for phosphorylation (more below)

For glutamate, Gq (q is designation here) activates Phospholipase C (PLC) or PLA2.
(more below)

Recent paper SKEKoekkoek et al., Cerebellar LTD and learning-dependent timing of conditioned eyelid responses, Science 301, 1736-1739, 2003, see also D. J. Linden, From molecules to memory in the cerebellum (Perspectives), Science 301, 1682-1685, 2003.
LTD=Long term depression, a model for learning.
Conditioned eyelid response is a paradigm for learning.
Transgenic with a Purkinje-specific promotor was used to express a molecule to inhibit PKC.
These mice lack LTD for this learning.

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

The phosphoinositide cascade

Fig. 7.7D p. 148
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 p. 151
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 p. 148
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 p. 152
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 p. 156
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 taught).

***Neuroanatomy

Neuroanatomy


Purves et al. part of Chapter 1, Appendix, the Sylvius CD, Box A in Chapter 19 for prions, Figure from chapter 22

Resources

Here is a site I found on mouse brain anatomy

I found these pictures of stereotaxic 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.

Acknowledgements
In 1970-1971, I was assigned to be a teaching assistant (TA) in Physiological Psychology at the University of Wiscconsin - Madison for Prof. Richard Keesey. Without the help of the senior TA, Norm Ferguson, I do not know how I would have survived. A few years later, Norm published "Neuropsychology Laboratory Manual" (Norman B. L. Ferguson, San Francisco, Albion Publishing Company, 1977), with good coverage on anatomy. The slide collection I present to you is mostly the slide collection I was given to use as a TA. For the first time in recent years, a student dissection of the sheep brain is being incorporated into this course. The dissection guide, which we will follow, and the glossary of neuroanatomical terms, which is entertaining and informative, is from the course I TAed. This lab was prepared and added to the Neuro curriculum for Spring 2005 mostly from the efforts of Christine Zelle, Lab coordinator for upper division biology labs. 2006 revisions included (1) labeling the slides, (2) simplifying the dissection guide from its original version, and (3) hyperlinking to slides from the guide; some of these revisions were suggested by 2005 students in their course assessment.

The Prion Lecture

Chapter 19 Box A p. 427
Prion diseases - this is in the cerebellum chapter because cerebellar ataxia is one of the characteristics of the diseases; I put it here as a warning for obvious reasons.
Creutzfeldt - Jakob Disease (CJD) "Spongiform" (brain turns to sponge) degeneration.
There were seemingly esoteric* cases of spongiform encephalitis.
* for instance afflicting Jews in Lybia who thought raw sheep eyeballs were a delicacy.
Kuru was a disease in New Guinea among cannibals.
D. Carleton Gadjusek (1976 Nobel Prize) thought it was a slow virus.
Scrapie in sheep so named because they roll around with intense itching.

Personal reflection. Since we did a sheep brain dissection in physiological psychology lab at Hopkins, I wondered if rubber gloves were necessary. Since Baltimore was close to Bethesda, I called. Gadjusek was away, studying some remote tribe, but I spoke with his coworker (Gibbs) who thought formaldehyde might not kill the virus. Then I got on their mailing list and, once a month or so, got an inch thich envelope full of case studies of diseases in far away places. I had to move to Missouri (in 1979) to make it stop.

Stanley Pruisinger 1980's proposes "prion" (protenaceous infectious particle).
That a disease could be transmitted without virus or bactera was heresy at the time.
But he had strong evidence and won the 1997 Nobel Prize.
Normal protein (PrP-C [control]) is altered by altered form (PrP-Sc [scrapie])
In the 1990s when the term "mad cow disease," was applied to observations in Britain, it seemed like a joke.
Now "BSE" (bovine spongiform encephalitis) is no laughing matter.
In meat industry, having matter from other animals in the feed is really bad.
Can disease spread from animal to animal? (probably)
Can disease spread from animal to human? (probably)
Cases in Canida, mainland Europe, and even in the US are in the news.
Should "downers" ("cows" that have dropped to the ground) be slaughtered for food?
How is it that meat from one downer can be sold in many different states and, only later, the announcement is made that it had BSE?

To supplement the above material, please view the 2006 graduate student presentation on prions.

Background

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

Fig. 1.6 EtoH p. 11
cellular cytoarchitecture - 2 mm thick cerebral cortex
6 layers, top (I) = molecular (without cells)
Brodman made areas (from cytoarchitecture), famous:
4 motor
17 vision

Fig. A1 [A,B] (Appendix) p. 718
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. A10A p. 728
Fig (more detail) from Atlas, p. 746
Overall external anatomy viewed laterally
Shows brains of mammals (cortex = "bark")
cerebrum senses - hemisphere controls contralateral
cerebellum (little brain) - hemisphere controls ipsilateral
Landmarks:
Central Sulcus divides
postcentral gyrus (primary sensory projection)
17 vision
precentral gyrus (primary motor area) Brodman made area 4 motor
Lateral (Sylvian) fissure
Brainstem

Fig. A3 p. 720
frontal lobe - planning behavior
parietal lobe - attending to stimuli
temporal lobe - recognition
occipital lobe - visual analysis

Figure, (not in book anymore, but relates to Fig. 22.3 p. 482)
Developmental introduction to neuroanatomy
(there is also a development chapter, chapter 21)
Prosencephalon
Mesencephalon
Rhombencephalon
Each of the above develops further. note (especially):
Telencephalon -olfactory bulbs, cerebral cortex, basal ganglia, hippocampus, etc.
Diencephalon is thalamus (sensory & motor "relay") and hypothalamus (visceral function)
Mesencephalon - tectum -> superior and inferior colliculi (vision and audition respectively)
Metencephalon - cerebellum, pons
Myelencephalon - medulla - auditory, somatic, gustatory

Table A2 (appendix) pp. 724-725
and

Fig. A7 (appendix) p. 723
Fig. More detail from atlas p. 747
and figure from sheep brain dissection
another figure from sheep
yet another
ventral view of brain
cranial nerves.(some are tracts)
sensory vs. motor, somatic vs. visceral (autonomic)
I olfactory
II optic
III occulomotor - goes to 4 external eye muscles, pupil, accomodation, eyelids
IV trochlear - to superior oblique muscle
V trigeminal - somatic from face, chewing
VI abducens - to external rectus muscle of eye
VII facial - facial muscles, lacrimal and salivary glands, taste
VIII auditory / vestibular
IX glossopharyngeal - taste from back of tongue, sense from pharynx, carotid baroreceptors
X vagus - autonomic, sensation, vocal cords, swallowing
XI accessory - shoulder & neck muscles
XII hypoglossal - tongue movements

some other ventral landmarks:
pyramids- of pyramidal (corticospinal tract) (decussation is caudal to this) (vs. extrapyramidal)
mammallary body, pons, inferior olive (motor control), rhinal fissure, etc
optic nerve, chiasm and tract
cerebral peduncles - axons between brainstem and cortex

Fig. A14 p. 734
Fig (Magnetic resonance) from atlas, p. 748
neocortex (found only in mammals),
hippocampus (archipallium) (one cell layer) (seahorse shaped)
and olfactory cortex

Fig A12 p 730
Fig, more detail, from atlas, p. 746
human midsagittal
sheep
close up
tract dissection
thalamus, hypothalamus, midbrain, pons, medulla
(subthalamus is between, concerned with motor function)
corpus callosum, anterior commisure, cingulate sulcus and gyrus, etc.
optic chiasm, infundibular stalk, pituitary, mammallary body, pineal, colliculi, etc.
some of these are in limbic system (chapter 29)

Fig. A8 p. 724
sheep
dorsal view of midbrain and brainstem
Cerebellum has 3 peduncles
superior and inferior colliculi
many important nuclei, principally of cranial nerves, are drawn in

Fig. A14A p. 734
coronal section
this view is especially good for the basal ganglia and internal capsule
striatum = caudate + putamen

Fig sheep
Fig Magnetic resonance p 752
horizintal section

Prep for dissection
A
B
C
D
E
F
G

Fig. A2A p. 719
spinal cord - cervical thoracic lumbar and sacral nerves
Cauda equina branches out toward bottom

Fig. A21
meninges (as in meningitis)
(1) dura (2) arachnoid (3) pia
subarachnoid space has cerebrospinal fluid (CSF)
So do ventricles.
sheep

Fig. A23
ventricles
the CSF is "isolated" by the blood-brain-barrier (BBB)
and is secreted by the choroid plexus

***Touch and pain

Touch (somesthesis)


Purves et al., Chapter 9 (the somatic sensory system) and Chapter10 (pain)

General and historical
A very compelling sense, from the pain of a tooth ache to the ecstasy of an orgasm
considered in domain of "Physiology"
(vision and audition are more in the realm of psychology)
There has been an emphasis on submodalities (qualities such as pain vs. hot), where modalities refers to different senses like vision and audition
von Frey (turn of the century) - punctate sensitivity - touch forearm with pencil, sometimes feels cold, sometimes feel pressure.
This approach overemphasized correlation of histoloogical receptor type with sensory experience.
It fit in well with Muller's (mid-1800's) "doctrine of specific nerve energies" - in which, if the ears were made to feed in through the optic nerve, sounds would be experienced as visual sensations because the quality comes from the nervous system not the physics of the stimulus.

The present view of receptors and axons depends more on nerve type and adaptation, and the central projection (axon type [A myelinated, C unmyelinated] pathway [dorsal columns = lemniscal vs anterolateral = spinothalamic]) is critical.

Receptors and axons

Tables 9.1 p. 193 & 9.2 p. 195
Much information here - I will emphasize different sizes of myelinated (A) axons, alpha biggest and delta is smallest, and unmyelinated (C) axons.

Fig. 9.5 p. 194
Skin (glabrous, there is also hairy)

The different types of receptors (in general, free nerve endings and encapsulated):

Free nerve endings
for pain, temperature and crude touch
the axons are C fibers (unmyelinated) and A delta, also slow

Landmark paper: MMendelson & WR Loewenstein, Mechanisms of receptor adaptation, Science 144, 554, 1964 (see also J NIH Res., vol 8, 41-45, 1996.
Here is the work attributed mostly to Loewenstein in which he shows that the Pacinian corpuscle is rapidly adapting because of the layers surrounding the nerve ending (by dissecting off these layers).
Also, there is an electrical adaptation preventing continued spikes after stimulus onset.

Pacinian corpuscle - rapid adaptation
A beta axons
Lowenstein - peel to show layers make rapid adaptation
very sensitive, very large receptive field (area which, if stimulated, will affect the receptor [or higher order sensory nerve])
vibration - 250 - 300 Hz

here is a Pacinian corpuscle from our histology course

Meisner's corpuscles are fast but not as fast as Pacinian
encapsulation is with Schwann cell layers
most common receptors of fingers, palms and soles
A beta axons
smaller receptive field
"feeling" - active touch - would use fast as finger moves across textured surface

Merkel's disks are slow and have a small receptive field and are for light touch
finger tips, lips and genitals
A beta axons
static discrimination of shape

Ruffini slow - large receptive field -
sensitive to stretching in deep skin, ligaments and tendons
A beta axons

also Krauss in lips and genitals (dry vs mucous skin)

Fig. 9.7A p. 197
Proprioceptors -
muscle spindles (nuclear bag fibers)
muscle spindle tension presets readiness for reflex, gamma motor neurons to intrafusal fibers
Ia sensory axon
also Golgi tendon organs Ib afferents

warm and cold
a person can feel a difference of 0.01oC
relation to body temperature
(cold have additional peak at high temp - paradoxical cold - "pins and needles")

Personal reflection My interest in Drosophila vision started with an undergraduate project in 1968. In graduate school, I learned that several scientists had isolated mutants with abnormal vision. DJCosens and AManning (Nature 224, 285-287, 1969) published "Abnormal electroretinogram from a Drosophila mutant." I met Cosens one and only one time in 1978 and asked him "How did you find that mutant?" He told me it had abnormal mating. By about that time, Baruch Minke, a leader in that work who I met in 1974, had named the mutant trp (transient receptor potential) on the basis of its ERG. It is amazing, with hindsight, what happens when somebody decides to breed that fly and study its progeny.

Recent progress on determining channel properties
C. Seydel, How neurons know that it's cold outside, Science 295, 1451-1452, 2002.
D.E.Clapham, Hot and cold trp ion channels, Science 295, 2228-2229, 2002
cold related to menthol

Fig Chapter 10 Box A p. 212
hot related to capsaicin

Fig Chapter 10 Box A p. 212
Both involve VR-1 channel with homology to transient receptor potential (trp) originally discovered in Drosophila because of difficulty in using visual cues in mating and found not to have sustained photoreceptor potentials.

Fig. 10.2 p. 211
Pain is faster in A delta fibers than in C fibers
Nociceptors
A delta mechano and mechano-thermal, and C fiber polymodal

Fig. 10.7 p. 221
Some mediators of pain are in bee and wasp sting venoms (serotonin, histamine, acetylcholine).
Also tissue damage substances (Table 9.1): , serotonin (platelets), prostaglandins, leukotrienes,
Histamine from mast cells, substance P
Bradykinin from blood borne precursor - enzyme from injury

Fig. 10.7 p. 221
In summary, nociceptor is really a chemoreceptor
Nociceptors are in many places, but not in brain, hence brain surgery under local anesthesia used in mapping studies in humans by Penfield.

Input

Fig. 9.8A p. 199
input into spinal cord

Fig. Box 9A p. 191
segmental organization of spinal cord - the dorsal root ganglion where input is
translates into dermatomes - which place is innervated
herpes zoster "shingles" reactivated virus - localized to one sensory ganglion

Fig. 9.8B p. 199
face & head enter via trigeminal nerve

Lower limbs are handled medially in gracile tract.
Upper limbs are lateral in cuneate tract.
ipsilateral projection
First nucleus is in lower medulla
There is a cross-over, and then the next nucleus is in the thalamus.
This lemnicsal system is evolutionarily "new" (reptiles and above) and is for localized touch.

In projection to the brain, there is processing - lateral inhibition to sharpen spatial localization.
(This is the first mention of lateral inhibition, a fundamental mechanism of sensory processing.)
If you tap your forearm, there are big waves but you feel localized touch.

Fig. 10.6A p. 219
spinothalamic with synapse and decussation at entry point.
There are separate tracts in spinal cord.
The lateral portion is for pain and temperature.
The ventral (anterior) part is for gross tactile sense.
Hence the nomenclature "anterolateral."
Sharp pain can inhibit inhibit worse pain (example: a hard touch to a door knob makes an electric shock less annoying)
Jargon -
"neospinothalamic" (more recently evolved) A-delta
"paleospinothalamic" (more ancient) C fibers
A small injury to the former can lead to intractable pain, so "psychosurgery" can be helpful.
Dull pain (paleospinothalamic, C fiber) has more diffuse projection (see below) and thus is less localized.

Fig. 10.4 p. 215
A half spinal cord injury would cause contralateral loss of spinothalamic below injury and ipailateral loss of lemniscal.
Brown-Sequard syndrome include motor (ipsilateral impairment)

Fig. Box B, Chap 10 p. 214
referred pain for viscera is interseting
heart attack in neck and left arm
notably, bladder stretch receptors localize pain to genitals

Fig. Box C Chapter 10 pp. 215-216
Interestingly, visceral pain goes in dorsal columns.
Very useful since midline myelotomy for palliative treatment in terminal and painful cancer.

Fig. 9.8B p. 199
sensation from face - trigeminal
Cell is in trigeminal ganglion and first synapse is in a nucleus at the mid-pons level.

The diving reflex, that we study in undergraduate physiology lab, is mediated by the trigeminal sensory input. There are 3 branches that can be individually manipulated (pick nerve # V, of course).

Fig. 10.6B p. 219
pain from face - trigeminal

Thalamus and cortex

Fig. 9.10 p. 202
VPL of thalamus to Postcentral gyrus- S1 = areas 1, 2, 3a & 3b
arranged in columns - a vertical electrode penetration same submodality
each S1 nerve responds to only one receptor type

Fig Box B Chapter 9 p. 203
In sensory map of cortex, all cells as electrode penetrates vertically are from one area (Mountcastle)
(a) Ocular dominance coumns for vision (Hubel and Wiesel) Nobel 1981
(d) Woolsey - (box) "barrels" from vibrissae (whiskers)

Fig. 9.3 p. 192
two point threshold
2 mm fingertips, 30 arm, 70 back
this relates to the cortical projection (next:)

Fig. 9.11 p. p. 202
sensory magnifications
Penfield - homunculus

TRANSPARENCY (from intro book)
Here is the more traditional way those data are presented

Box D, Chapter 10 p. 222
Phantom limbs and phantom pain
hand maps on face - => plasticity, in that there is a rearrangement in postcentral gyrus and hand is near face

Higher areas
now thought to be multiple maps not just association area
=> parallel rather than serial processing

Fig 10.8 A p. 225
Pain modulation includes an efferent system
periaqueductal grey (PAG) enkephalin

Fig 10.8 B p. 225
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
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

Brain and Vision

Purves et al., Chapter 12 (and bits of Chapters 11 and 24)

Projection to Brain

Fig. 12.1 p. 258
Overall Visual Projection
Eye -> LGN (Lateral geniculate nucleus, genu= knee, part of thalamus) -> striate cortex
Temporal retinal field = nasal visual field stays ipsilateral at chiasm
Nasal retinal field = temporal visual field crosses to contralateral side at chiasm
From LGN to striate cortex = area 17 = V1
Retinotopy (like somatotopic organization) is preserved
*Eye -> pretectum - pupil size (iris) and control of lens (accomodation)
Eye -> superior colliculus - eye and head movements (Chap. 19)
Eye -> hypothalamus - to regulate circadian rhythms (see, in chapter 27)

*Fig. 12.2 p. 259
pupillary reflex
Pretectum -> Edinger-Westphal nucleus -> cranial nerve III->ciliary ganglion ->parasympathetic fiber.
Note connection to both ipsilateral and contralateral sides after pretectum, so pupillary reflex should be bilateral.
Kids, go ahead and try this.
Important test in neurology.

Fig. 12.13 A & B p. 268
Thalamus
Cells have center - surround receptive fields like ganglion cells
1, 4, 6 contralateral -- thus 2, 3, 5 ipsilateral

Fig. 12.15A p. 269
large and small retinal ganglion cells
Magnocellular - large receptive fields for processing movement - connect to LGN 1 & 2
Parvocellular cells connect to layers 3, 4, 5, & 6 and process color, also for acuity

Cortical processing

Landmark papers

DHHubel & TNWiesel, Receptive fields, binocular interaction and functional architecture in the cat's visual cortex, JPhysio, 160, 106-154, 1962
TNWiesel, DHHubel & DMKLam, Autoradiographic demonstration of ocular dominance columns in the monkey striate cortex by means of transneuronal transport, Brain Res 79, 273-279, 1974 (see also J NIH Res, 5, 61-67, 1993)
DHHubel & TNWiesel, Brain mechanisms of vision, Scientific American September 1979 (vol 241, #3), pp 150-162.

Tom Yin's home page, follow links, Simple cell is a good video to show how work was done

Fig. 12.8 A & B p. 264
cat (monkey) looks at screen, cell responds best to line at angle
Striate cortex - physiology and anatomy
Hubel & Wiesel share 1981 Nobel for "information processing in the visual sytem"

Fig. 12.11 p. 266
there are vertical columns of preferred angle (just like in somatosensory system)
presumably, to prefer line at angle, cell receives inputs from from alligned center surround cells
these are called simple cells
complex cell - line at algle moving in direction
hypercomplex cells - line has end - corner
vertical electrode penetration gives cells with all the same preferred angle
an oblique penetration tracks different angles
Note that there are 6 layers of cells, IV has inputs from LGN

"Philosophical question" -- does processing get to more and more levels of complexity until you find "grandmother cells" which recognize, specifically, your grandmother's face?

Fig. (like 12.13 B & C) p. 268
experiment to determine ocular dominance columns (0.5 mm wide)
There are cortical cells with input from one eye, from the other eye, and, in between, from both eyes.
Binocularly driven cells should be necessary for stereopsis, the kind of depth perception which relies on the focussing of both eyes.

Fig. 12.14 p. 269
Apparently, cells can preferentially respond to disparity from fixation
depth-perception
stereopsis

Even higher order visual processing

With all that color processing in the LGN, it seemed odd how far the work on the cortex got without any mention of color

Fig. 12.16A 272
V4 - color but not movement
MT (middle temporal) - direction of movement but not color

Fig. 12.18 p. 274
parietal stream - spatial vision
temporal stream - object recognition

This relates to Andrew Laguna S.J.'s presentation on the binding problem (pdf) (PodCast)

Development of visual connections

Fig. 24.4 p. 545
If a radioactive amino acid is injected into one eye, labeled proteins cross synapses at LGN and mark ocular dominance columns in cortex; this is detected by microscopic autoradiography.
Binocular cells connect up correctly at first

Fig. 24.5 p. 546
Then there is a sensitive (critical) period in the first few months of life during which patterned visual input from both eyes is necessary to maintain binocular input to cortical cells.
Thus early visual defects like cataract or strabismus (cross-eyes or lazy eye) need to be corrected right away.

Here are autoradiographs. A of normal visual cortex, nd B after monocular deprivation from 2 weeks to 18 months in monkey

Recent Literature

*P Sinha Once blind and now they see, July 2013, 48-55. Blind from birth Indian children get surgery, takes a while to learn to see. Hard to put things together. SK was 29, had congenital aphakia (rare). "not particularly thrilled" Motion helped

*BPeak Seeing is feeling (letter to the editor) Nov p 6. Book ­p; Pilgrim at tinker creek (1974 by Annie Dillard) she quotes  Space and Sight (1932), patient could name a cube by feeling it but, after cataract surgery could not name it if (s)he saw it



***Neural Development

Development


Purves et al., Chapters 22-23, one figure from Chapter 11

Pep talk

The overall theme relates to "plasticity." In that regard, learning and memory are considered to be continuations of development, so the boundary line between development and memory is not clear.
Dogma is that invertebrate nervous systems are hard-wired with little plasticity or learning (though there are lots of exceptions) and that vertebrate adaptability relies on rewiring, alterations, and learning.

Prof Schreiweis taught a course in embryology (BL A344, Fall, 5 credits, lecture plus lab). He retired summer 2012. 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)

Famous molecules

Fig. 22.5, p. 486
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.

Stem cells

Box 22A, pp 479-480
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 collaborated 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.

Recent paper

SSHall, Diseases in a dish, Scientific American, March 2011, 40-45. Take skin of elderly person who has ALS in the family, make stem cells, turn them to neurons, watch ALS develop, test drugs
Time Line
1998 James Thompson (University of Wisconsin - Madison)
2001 (Aug) George W Bush restrictions
Harvard, Columbia, Stanford - labs with private funding
2002 TMJessell, HWichterle et al (Columbia) how to get embryonic stem cells to be motor neurons
2006 SYamanaka (Kyoto) how to get stem cells from skin2009 Obama relax restrictions
2010 court banned NIH support

Review

Know from earlier this semester:
No regeneration of neurons in the (mammalian) CNS. Interesting regeneration in olfactory and taste receptors.
Hubel and Wiesel (1981 Nobel) (and others since) - need for patterned vision during critical period to maintain visual cortical binocularity and feature (contrast) detectors (this will come up in chapter 24)
Wiring in cerebellum is disrupted in mutants (Chapter 19)

Drosophila Embryology

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

Fig. 22.4, p. 483
a lot has to do with segmentation

Fig. 22.4 again
Maternal means that the gene was transcribed in the mother; that is how bcd (bicoid) was deployed
zygotic genes have the order of action as shown in Fig.
gap such as kr (kruppel), pair-rule such as h (hairy), and segment polarity such as wg (wingless)

TRANSPARENCY
Imaginal discs are structures in larvae destined to become structures in the adult (entomologists call the adult the "imago")

Fig. 22.4 still
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. not in 5th edition
(I put more information below than is in the book)
How do > 750 ommatidia with some 19 cells develop?
(receptors (R1-6, R7 & R8, cone cells, bristles, pigment cells)
Development in the eye imaginal disk.
In sev (sevenless) mutants, the R7 precursor becomes cone cell.
(I wrote the paper that introduced sevenless, see here)
Sevenless is a receptor tyrosine kinase, and signalling involves ras = small G protein.
Sequential addition of receptor cells in Drosophila eye: R8, R2 & R5, R3 & R4, R1& R8, R7
Boss = bride of sevenless is 7 transmembrane domain ligand

Fig. 22.5 C p. 486
sevenless is receptor tyrosine kinsae -
2 transmembrane subunits, 2 extracellular subunits
expressed everywhere except R2 R5 and R8
It is a topic of intense present interest how this signals across membrane
Drk = downstream of receptor tyrosine kinase
which is a small SH adaptor protein, SH = src homology
src = oncogene of Roux sarcoma virus
Sos = son of sevenless, a GNRP (guanine nucleotide releasing protein) to exchange GTP for GDP on ras
ras = rat sarcoma [viral ras oncogene of normal protooncogene]
other steps -> signalling to nucleus
MAPK = mitogen activated protein kinase
alias ERK = extracellular signal regulated kinase

Embryology

Fig. 22.1AB, p. 478
Neural plate forms from ectoderm -> neural groove -> neural tube to make CNS

Fig. 22.1C, D
One area remains outside CNS - neural crest gives rise to PNS structures like sensory ganglia

Fig 22.2 p. 481
Different cells migrate to make (1) sensory ganglia, (2) autonomic ganglia, (3) adrenal, or (4) non-neural tissues like melanocytes

Fig. 22.11C, p. 499
Factors on how neural crest progenitors turn into specific PNS types
(more on factors later)

Brain subdivisions

Fig. 22.3AB, p. 482
Prosencephalon -> telencephalon and diencephalon
Mesencephalon
Rhombencephalon ->Metencephalon and myelencephalon
Note, "optic vesicle" signifies that retina is outgrowth of CNS

Fig. 11.4, p. 233
Induction from optic vesicle makes lens form from ectoderm

Histogenesis

Fig. 22.7A p. 491
Cell divisions in monolayer with nuclear migration (mitosis near neural tube lumen (ventricle) and have S-phase near pial surface)

Fig. 22.12A, p. 502
Fig. 22.13, p. 504
Then cell migrates out along tracks made by radial glia
Recall Weaver mutant mouse in which cerebellar granule cells are missing:
Bergman glia screwed up - granule cells not migrate, die

Fig. 22.8, p. 493
then each layer (e.g. V) migrates past previous (e.g. VI)

Axon pathfinding

Retinotectal projection in frog


Fig. 23.7B
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. 23.2C, p. 510
These are drawings from Ramon y Cajal
There are these growth cones (enlargements) at the tip of an extending axon which extend and retract filopodia, feeling their way along.

Fig. 23.2B, p. 510
growth cone, confocal microscopy
SEM growth cone

netrin elicits axon growth from explant from spinal cord
Although, netrins (Sanscrit "to guide") serve as chemoattractants, Sperry's neurobiotaxis idea was overly simplistic:

Fig. 23.4, p. 514
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. (not in 5th edition)
Synaptogenesis at neuromuscular junction
agrin & its receptor cause aggregation of AChR

Trophic factors

Inductive interaction is important - like trophic effect of nerve on muscle (in polio, nerve disease leads to wasting away of muscle)

Fig. 23. 10, p. 525
This would also work in reverse, those nerves deprived of muscle vanish, or if extra limb, there are more spinal motor neurons.
Thus, there are too many nerves at first, then those which do not connect degenerate.
This would rely on programmed cell death (apoptosis), not really emphasized in chapter.

Rita Levi-Montalchini 1986 Nobel Prize "discoveries of growth factors"
NGF (nerve growth factor) is from targets like glands.

Fig. 23.13, p. 529
Here is a dorsal root ganglion (somatosensory ganglion) without (A) and with (B) NGF making it obvious, from the neurite outgrowth in B, why it is named NGF (work of Rita Levi-Montalchini)
Take-up makes sympathetic (and other nerve cells, like certain sensory nerves) survive.
Antibody to NGF kills sympathetic nervous system.
Oddly, one good source of NGF is male salivary gland.
Cytokines include:
Neurotrophins like NGF, BDNF (brain derived), NT-3, NT-4/5
Hematopoietic factors (like interleukins)
Growth factors like EGF, FGF, TGF, IGF

Fig. 23.16, p. 533
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 c, 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.)

***Memory at the cellular level

"Learning"


Purves et al. Chapter 24 "Modification of brain circuits as a result of experience"
and Chapter 8 "Synaptic plasticity"
(Figs from chapter 19 and 23)

Introductory remark

There was a famous textbook in the late 1940's by Donald Hebb which proposed that there were loops of neurons with excitation, "reverberating circuits," and that excitation alters synapses. Imagine looking up a phone number and repeating it in your mind until you dial the phone, but, if you use it often enough, you will remember it always (like your friend's number from when you were a kid).

Fig. 23.11, p. 526
One example involves a story from last chapter on synaptogenesis at neuromuscular junction.
Overlapping connections of multiple spinal motor neurons onto multiple muscle cells is sorted out after birth.

Development of visual connections

repeated
from Vision and the brain lecture)

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

Fig. 24.4, p. 545 (not shown again)
If a radioactive amino acid is injected into one eye, labeled proteins cross synapses at LGN and mark ocular dominance columns in cortex; this is detected by microscopic autoradiography.
Binocular cells connect up correctly at first

Fig. 24.5, p. 546 (not shown again)
Then there is a sensitive (critical) period in the first few months of life during which patterned visual input from both eyes is necessary to maintain binocular input to cortical cells.
Thus early visual defects like cataract or strabismus (cross-eyes or lazy eye) need to be corrected right away.

Here are autoradiographs. A of normal visual cortex, like Purves et al., Fig. 24.3, and B after monocular deprivation from 2 weeks to 18 months in monkey Purves et al., Fig. 24.6.

not covered before

Fig. 24.6 B, p. 547
Just 6 days of monocular deprivation right around one month of age has this effect.

There are columns early which get reinforced during early development.

Fig. 24.1, p. 538
Ocular dominance shift from deprivation sould be blocked if TTX (tetrodotoxin) were injected into the eye. In the experiment shown here, replacing activity in a synchronous way would maintain normal binocularity while asynchrouous optic nerve stimulations would let binocularity disappear. Thus alterations are activity dependent.

Fig. 24.9, p. 551
In strabismus (lack of fixation), lose binocular cells.

Recent literature
TKHensch & MPStryker, Columnar architecture sculpted by GABA circuits in developing cat visual cortex, Science 303, 1681, 2004
MFagiolini et al., Specific GABA-A circuits for visual cortical plasticity, Science 303, 1681-1683, 2004.
DFerster, Blocking plasticity in the visual cortex, Science 303, 1619-1621, 2004.
At birth, there is complete overlap, sort out in a few weeks.
Potentiating GABA inhibition with diazepam widens columns.
An agonist DMCMnarrows them.
GABA- A receptors with alpha 1, 2, and 3 subunits specifically (alpha 4 and 6 are insensitive to benzodiazepines and alpha 5 is insensitive to zolpidem, also used).

On the topic more closely related to what most people think of as learning

American Psychology dominated by Associative Learning - repeated pairings

(1) Classical conditioning
Pavlov - 1904 Nobel Prize "physiology of digestion"
UCS (e.g. food) -> UCR (salivation)
pair UCS (bell) with CS repeatedly
then CS -> CR (salivation)
(2) Instrumental conditioning from Watson's behaviorism
B. F. Skinner box response (bar press) paired with reinforcement (food, water)

Early attempts to determine cellular mechanisms of learning in mammals had problems (see memory lecture)

For that reason, some simple cellular responsivity changes which could possibly account for learning were demonstrated like:

Landmark paper
Donald Kennedy, Small systems of nerve cells, Scientific American May 1967.
Work on crayfish is in one of the early papers touting simple cell systems in invertebrates.
Kennedy has been presedent of Stanford and is now editor-in-chief of Science, the weekly journal of the AAAS (American Association for the Advancement of Science)

Aplysia

Landmark papers

ERKandel & LTauc, Heterosynaptic facilitation in neurons of the abdominal ganglion of Aplysia depilans, J. Physiol, 181, 1-27, 1965, Mechanism of heterosynaptic facilitation in the giant cell of the abdominal ganglion of Aplysia depilans. J Physiol 181, 28-47, 1965. (see also J NIH Res 2, 63-72, 1990).

Fig. 8.2, p. 165
(1) depression of responses during tetany in muscle cell; and
(2) post-tetanic potentiation.

Fig. 8.3 A, p. 166
Studies of Aplysia (a mollusc) by Kandel (Nobel in 2000)
Aplysia - habituation - nonassociative learning

Personal reflection - I was an undergrad student at Columbia College in New York when my physiology professor said "Come on with me, there's a neat seminar," when Kandel was new at Columbia.

Fig. 8.3 B, p. 166
The nice thing is that there are big identified cells.
(Recall that invertebrate neurons are on the outside of neuropil [where synapses are made].)

Fig. 8.3 C, p. 166
Lots of work in the 1960's to 1970's - habituation of gill withdrawal reflex
Habituation is a diminution in the response after repeated stimulus administrations which is not attributable to sensory adaptation or muscle fatigue.
It is one (motor neuron L7) synapse.
EPSP gets smaller - modification is at presynaptic level - Ca2+ channels less effective.

Fig. 8.4 AB, p. 168
There is also sensitization another nonassociative learning

Fig. 8.5 A, p. 169
short term sensitization
serotonin-induced enhancement of glutamate release
5HT -> cAMP -> PKA -> close K+ channel -> C2+ influx -> transmitter release

Fig. 8.5 B, p. 169
long term sensitization
CREB - cAMP response element binding protein, turn genes on
ubiquitin hydrolase break down PKA regulatory subunit, persistent activation
In Chemistry, Ciechanover, Hershko and Rose won 2004 Nobel for ubiquitin
(There are 2 main pathways in intracellular degradation, lysosomes and proteosomes, the latter involving ubiquitin.)
Several of biology"s new faculty are interested in ubiquitinization (Wang, Downes)

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

Drosophila

Fig. Box 8A, p. 170
(Earlier, there had been some shoddy work on learning, so researchers had to be more careful with controls [for sensitization], but it became clear Drosophila could be trained to avoid odors associated with shock.)
mutants Benzer and Quinn work in 1970's all involve cAMP
dunce - phosphodiesterase
rutabaga - adenylyl cyclase
amnesiac - peptide transmitter that stimulates adenylyl cyclase

Summary

Learning and memory are very complex
so simple "learning" and simple preparations predominate
but parts of the brain can be simple, if studied for simple "learning"

Hippocampus

Landmark paper

TVPBliss & TLomo, Long-lasting potentiation of synaptic transmission in the dentate area of the anesthetized rabbit following stimulation of the perforant path, J Physiol 232, 331, 1973 (see also J NIH Res 7, 59-67, 1995).

The hippocampus is involved in spatial learning (and lots of other things)

Brain slice technique
Cells can be reached by thin brain slice to keep metabolism (oxygen, nutrients) while having enough thickness (0.5 mm) to still have wiring

Fig. 8.6, p. 171
hippocampus is rather a simple neural circuit
Hippocampus anatomy: CA1 CA3 & Dentate gyrus
Long term potentiation is a simple form of learning
Input specific long-term potentiation (LTP) can last weeks
Perforant pathway (from entorhinal cortex) -> granule cell (mossy fibers) -> CA3 pyramidal cell (Schaffer collaterals) -> CA1 pyramidal cell

Fig. 8.7ABC, p. 172
train of stimuli make response to another bigger while in another (control) pathway, the synaptic efficiency is unchanged

Fig. 8.10, p. 174
NMDA receptor important, rise in Ca2+ is important, the same mechanisms of Mg2+ expulsion and spiral of ligand, voltage and C2+ activation which can lead to excitotoxicity is responsible for long lasting excitation

Box 8C, pp. 182-183
Epilepsy is a syndrome of sensitized excitation

Cerebellum

Fig. 19.9B, p. 424
recall simple wiring of few cell types in cerebellum from motor lectures
Purkinje cells use GABA for inhibitory output
climbing fiber from inferior olive makes big EPSP in Purkinje cell
yet many parallel fibers contact Purkinje cell each with one contact

Fig. 8.16BCD, p. 180
describes LTD (long term depression)
two synaptic activations must come at about the same time
decrease in effectiveness of glutamate AMPA receptor

(LTD was first mentioned on the second messenger system outline)

***Language and cognition

Language and Cognition


Purves et al., Chapters 26 & 27

General
Consider how much communication enhances the human experience.
Also think about how your thought patterns are guided (perhaps constrained) by language.

aphasia is loss of language ability
studies of brain damage (stroke) but some attempts to get at live brain function with imaging techniques

Fig. 26.1, p. 588
Localization of function - note that Chapter 26 refers to "association cortex"
some very interesting case studies of people with specific defects like:

Fig. 26.11, p. 596
prosopagnosia (-agnosia - not knowing) - face recognition deficit in right temporal lobe damage in patient L.H.
fMRI activity increase in right temporal lobe

Fig. 26.5A,B,C, p. 592
contralateral (hemispatial) neglect syndrome caused by:

Fig. 26.6 A, p. 593
damage to parietal, temporal and frontal areas.

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

Recent paper. MT de Schotten et al, Direct evidence for a parietal-frontal pathway subserving spatial awareness in humans, Science 309, 2226-2228, 2005 (see also DGaffan, Widespread cortical networks underlie memory and attention, perspectives, Science 309, 2172-2173).
In the old days, stroke victims were studied on autopsy.
Neurosurgeons (removing cancer for instance) still test awake subject.
Electrical stimulation will temporarily inactivate small areas.
(If there is a loss of function, that area will be spared.)
Here, tumors were in parietal area.
So do line bisection task.
Although gray matter had been implicated, superior occipitofrontal fasciculus (white matter) was found to be most important.
DGraffan (perspectives) argues for a relationship with memory in work on monkeys.

Fig. 26.2, p. 588
Brodmann areas- based on cytoarchitecture

Fig. 26.3, p. 589
6 layers in human neocortex, I-not really cells,
II & III - pyramidal cells send and receive input from other areas of cortex
IV - stellate cells receive input
V & VI - Pyrimidal output from cortex

Fig. Box 26A, p. 590
fewer layers in "archicortex" (hippocampus)
and
in "paleocortex" (pyriform cortex)
[These were terms used in the sheep brain dissection guide.]

There is a lot of emphasis on neural correlates (a nerve in such-and-such are of the brain that does so-and-so) like:

Fig. 26.13 B, p. 598
a face recognition neuron in the temporal lobe which does not respond as well to degraded or wrong images

Fig. 26.17ABC, p. 604
a neuron in the frontal cortex which responds specifically in a delayed task (planning)

Language

Recent literature

FOXP2 transcription factor defect leads to dyspraxia (cannot learn speech)
Use RNAi to show defect in zebra finch in area X of brain
("editors' choice," Science 318, 1835-7, 2007, summarizes work published PLoS Biol 5 e321, 2007)
FOXP2 knockout homozygous infants do not make ultrasonic cries when separated from their mothers
(in "Random Samples," CHolden, Science 309, 47, 2005, Gene knockout leaves mice squeakless)

Fig. 27.2, p. 611
Brodmann areas, Broca's area, Wernicke's area

Fig. 27.1, p. 610
Note that Broca's area and Wernicke's area flank the auditory & somatosensory/motor cortices
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

Box 27D (p. 617-618) also text p. 619
Wada procedure: inject sodium amytal to one carotid-
show that speech is on left even in most left handed people.

Fig. 27.3 AB, p. 616
Surgery to cut corpus callosum (to prevent the spread of epilepsy)
Here is the midsaggital close-up from the sheep brain dissection which view is predominated by a collosal body, the corpus callosum slide 10
There are 2 consciousnesses and the two sides of the brain have different capabilities
This work won Roger Sperry (who also did the eye to tectum regeneration in the frog and inferred neurobiotaxis) the 1981 Nobel Prize. Then the work was taken up by Gazzaniga.
Because of the orderly visual projections to the brain, it is possible to present visual stimuli to 1/2 of brain, and, if presented to the left half of the brain. the person can say what it is, but if presented to the right half of the brain, (s)he cannot say what it is but can pick it out (multiple choice) by touch.
Thus experiments distinguish comprehension vs. speech.

Box 27B, p. 611
argues whether language is actually unique to humans

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

Landmark paper RAGardner and BTGardner, Teaching sign language to a chimpanzee, Science 165, 664-672, 1969
American Sign Language (ASL) [used by deaf in North America]
22 months of training in a young female
paper lists 30 signs Washoe could use

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

Fig Box 27B
DRumbaugh and S Savage-Rumbaugh used computer type-writer

Landmark paper HSTerrace et al. Can an ape create a sentence?, Science 206, 891-902, 1979
Nim Chimsky (Noam Chomsky, famous MIT linguist who thought language is unique to humans)
criticized above approaches and created a controversy.

Fig. 27.8, p. 622
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).

***Biorhythms

Rhythms


Purves et al. Chapter 28

EEG

Fig. Box 28C p. 632-633
EEG (electroencephalogram) set of pooled potential waves recorded from head.
This is as opposed to the "evoked potential," evoked by some stimulus.
To get regular waves, there must be some synchrony in neuron firing.
Thalamus to cortex loop may contribute.
Reticular formation involved in arousal (reticular activating system) (RAS) may also contribute.

Fig. 28.6, p. 632
The relaxed EEG with eyes closed is 8-13 cycles per second (Hz), called alpha (not shown).
During arousal there is alpha-blocking, and with eyes open, 14-60 Hz (beta) makes it almost as if there were no rhythm.

Sleep

Landmark paper
EAserinsky & NKleitman, Regularly occurring periods of eye motility, and concomitant phenomena, during sleep, Science 118, 273-274, 1953 (see also J NIH Res, 4, 63-66, 1992).

Fig. 28.6 (continued)
There are various stages of non REM (rapid eye movement) sleep, as defined by the EEG.
Deep sleep - slow wave sleep- delta (and theta) rhythm-stage 3, 2 Hz - stage 4 (slow wave sleep).
REM is associated with dreaming.
There is an atonia (lack of muscle control) during REM sleep.
PGO spikes at onset of REM (pontine reticular formation -> geniculate -> occipital cortex).
Birds do not have REM sleep but most mammals do.

Fig. 28.7, p. 635
During a night of sleep, go back and forth
REM - heart rate, respiration, erection all increase.
Called "paradoxical sleep" because it seems like awake state.
Deprivation of paradoxical sleep makes a person or animal irritable.
Because of loss of muscle tone, a cat restrained over a dish of water will wake up when it goes into REM sleep.

Box 28A, p. 627
Dolphins sleep with one hemisphere at a time.

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

Landmark papers
Michel Jouvet, The states of sleep, Scientific American, February 1967, 62-72
Michel Jouvet- Biogenic amines and the states of sleep Science 163, 1969, 32-41

Hobson - raphe and locus coeruleus turned off in sleep. Note, the section which follows could have been placed in any of a number of places throughout this course, but, because of the involvement of several neurotransmitter systems in the wake-sleep patterns, it is here. Also, an important period of of historical excitement in the mid 1960's is underplayed in which Swedish workers (Dahlstrom and Fuxe) developed the techinique of histochemical fluorescence in which 5-HT, NE and DA pathways could be visualized since the products of transmitter reacted with paraformaldehyde vapor can be seen.

Transmitters in sleep

Table 28.1, p. 639
Ascending reticular activating system:
(1) Raphe (which means ridge or seam) nuclei uses 5-HT (serotonin)
The caudal part innervates downward, while the rostral part innervates upward.
Since it fires during wakefulness, it must be involved in sleep.
The hallucinogenic drug LSD (lysergic acid diethylamide) is an agonist of presynaptic raphe 5-HT receptors inhibits firing (like in sleep), working like peyote (cactus) Aztec and psilocybin (mushroom) Maya.
(2) The locus coeruleus (blue spot), bilateral in the pons, spreads NE around brain.
12,000 neurons (each) with lots (e.g. 250,000) of synapses.
Like sympathetic ganglion in brain- activated by sensory stimulation
(3)The pontomesocephalotegmental complex regulates thalamic sensory relays using acetylcholine.

Note that there are other systems which distribute acetylcholine in the brain:
septal area (->hippocampus)
basal nucleus of Meynert (->neocortex) [these cells die early in Alzheimer's disease]

Note that dopamine is also distributed via the nigrostriatal pathway, disrupted in Parkinson's and involved in the mesocorticolimbic (reward) system and from the tegmentum to the forebrain and limbic system.
Cocaine blocks DA reuptake, amphetamine blocks NE & DA reuptake, potentiating reward
Depletion by alpha-methyl-para-tyrosine blocks stimulant action.

Fig. 28.8, p. 636
Circuits
5HT & NE -> -> Glycine to spinal motor neuron to inhibit motor movement.
GABA to dorsal column nuclei to inhibit sensation.

Biological clocks

There are many rhythms in nature and man, for instance the 3/min Parkinson tremors, the 21 day cycle in manic-depression, the 28 day human menstrual cycle, circannual (about a year), ultradian (fast, less than a day).

Fig. 28.4, p. 628
photophase, scotophase, free-run, endogenous
Entrainment, zeitgeber (time giver)
biological rhythms, periodicity, biological clocks
circadian (about a day)
Note human volunteer goes to >24 hr.

Ashoff - light on - nocturnal increase period - like waiting for night
light off - diurnal increase period - like waiting for day

What is the photoreceptor (it can be extraretinal in sparrows and fruitflies)? Where is the clock? (These are different questions.)
The pineal is important in small-headed animals like lizards.

Light may even hit the pineal in birds, and old experiments with enucleated sparrows used India ink under skin in head to decrease light and feather plucking to increase light

Landmark paper
M.Menaker, Nonvisual light reception, Scientific American, March, 1972, 22-29.

In seasonally reproductive birds, testes size in affected by more light in reproductive season. The pineal has photoreceptors, rhodopsin and molecules of the phototransduction cascade.

Fig. 28.5C, p. 631
In higher (bigger headed) animals, the zeitgeber (time giver) is usually a light-dark cycle, most likely with eye as sensory system.

Recent Paper S.Panda et al., Melanopsin is required for non-image-forming photic responses in blind mice, Science 301, 2003, 525-527
Pigment may be a different opsin (melanopsin [expressed in melanophores]) (and may be in ganglion cells).

The suprachiasmatic nucleus is important - lesions in SCN disrupt rhythm.
There is a mutant (named "tau") in the hamster affecting the SCN with altered rhythm.

(The melatonin story was here but is now consolidated in the transmitter lecture)

Drosophila

Box 28B, p. 629
Drosophila have locomotory rhythm and rhythm of pupal emergence.

Some classic work
Action spectrum for entrainment drops off dramatically above 500 nm.
Deprivation of carotenoids does not decrease sensitivity for entrainment.
Suggests thqat the photoreceptive pigment is not rhodopsin.

Seymour Benzer at Caltech used Drosophila in "genetic dissection" of various systems, and, with Ron Konopka, found "period" gene.
Mutants: per=period, l=long, s=short, 0=arythmic, perl 29 hr, pers 19 hr, per0 - arythmic or fast rhythm.
Clock or photoreceptor were localized to brain.
There is also a rhythm in courtship song, an ultradian rhythm, and it is affected by per.

Fig. Box 28B
The early excitment, imagining a clock in the head coded by a gene, was too simple.
PER is a nuclear protein whose mRNA and protein cycle.

Recent paper
A Busza et al., Roles of two Drosophila CRYPTOCHROME Structural domains in circadian photoreception, Science 304, 1503-1506, 2004.
Cryptochrome is blue sensitive protein (relates to points above about the pigment not using carotenoids and being short wavelength sensitive).
PERIOD and TIMELESS dimerize and act as negative transctiption factor.
Interfere with action of CLOCK and CYCLE.
CRY binds to TIM, and they are degraded by proteasome.

***Emotion

Emotion


Purves et al., Chapter 29 (and part of Chapter 21) (and Chap 25 figure, Chap 17 figure)

General - historical

Darwin - Expression of emotion in man and animals - 1872
James-Lange theory: physiological changes -> emotional experience "we are afraid because we tremble" counterintuitive
Cannon-Bard theory: emotional experience is primary (Cannon coined "fight or flight") (and, of course, it is the sympathetic nervous system that prepares the body for both)

Hypothalamus

Fig. 29.1, p. 650
Bard did experiment implying that cortex inhibits hypothalamic (sham - directed at everything) rage unless the caudal hypothalamus is also disrupted.
Hypothalamus -> reticular formation for rage
Walter Hess (1949 Nobel prize) - rage or fear if hypothalamus stimulated.
(shared with Moniz who developed frontal lobotomy)
not in book: Electrical self-stimulation (Olds and Milner) - of hypothalamus is positive reinforcement in operant conditioning paradigm in a Skinner box

Fig Box 21A, p. 456
hypothalamus
surprisingly not in book: Lesions to ventromedial nucleus makes a fat rat, so older literature called this a satiety center, lesions to lateral hypothalamus makes a thin rat, so LH was once called a hunger center. There are problems with calling a small lesioned area a such-and-such-center based on the defect. Also, LH is where medial forebrain (reward) system goes (dopamine, covered repeatedly already).

Facial expression of emotion

Fig Chap 29 Box A, p. 648
Duchenne demonstration, electrical stimulation of face ("faradization") mimics emotional expressions
Photos to demonstrate
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.
Interesting story - voluntary facial paresis inability to volontarily move lower facial muscles on one side due to lesion [pyramidal smile]

Fig. (no longer in text) like Box29A p. 649
paresis

Fig Box29A p. 649
block diagram

Fig, box A, Chapter 17, p. 379
(related to moter coverage)

Brain areas

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

Fig. 29.3, p. 652
Fig. 29.4, p. 653
Limbic system
Papez (1937) circuit
Note that in sheep brain tract dissection, the fornix and mammillo-thalamic tract were shown in slide 11

rabies affects hippocampus - exxagerated fear etc.
tumors in cingulate cortex - fear & other emotions

Figs A & B, etc., Box 29B, p. 654
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) p. 656
Kluver-Bucy syndrome with amygdala lesion.
A terribly hostile monkey becomes docile with temporal lobe lesion (loss of fear) - hypersexuality, mouthing objects, etc.

Box D, pp. 657-658
Patient SM has degeneration of amygdala - cannot recognize or draw fear
Urbach-Wiethe disease (autosomal recessive)

Interesting stories:

Fig (no longer in text)
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, pp. 659-660 - Affective disorders
Lincoln "I am now the most miserable man living...I must die or be better, it appears to me,"
Depression (counting several categories) will affect 10 % of people.
Relieved by lots of drugs, fluoxetine (brand name Prozac) [serotonin uptake inhibitor] widely prescribed likened to "soma" in Aldous Huxley's "Brave New World" Late 1980's, now one of the most prescribed drugs. Also sertraline (Zoloft) and paroxetine (Paxil)
Depression more common in females
Other coverage of depression in transmitters outline
and in "alumnus e-interview."

***Neuroendocrinology

Sex and Neuroendocrinology

Purves et al., Chapter 30, Figure from Chapter 21

Hormones

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

Fig. 30.3A, p. 676
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

John -> Joan -> John (medical pseudonyms), actually Bruce -> Brenda -> David
Electrocautery mishap during circumcision of twin.
Sex change operation.
John Money (Hopkins) - theory that upbringing is as important as chromosomal make-up in gender identity.
Poorly adjusted, demanded to know truth at age 14.
Change back to guy eventually
Money's research seemed interesting at first but was infamous with hindsight

Fig. Box A Chapter 21, p. 456
Hypothalamus (peptides)
(1) Posterior pituitary (peptides
magnocellular neurosecretory cells
oxytocin (milk, delivery)
synthetic to induce labor
vasopressin (ADH), H2O and blood pressure
ADH action on kidney
alcohol, caffein inhibit anti [diuresis] hormone
also low blood pressure -> renin (kidney) ->
angiotensinogen (from liver) - renin -> angiotensin I ->II
affects kidney, blood vessels,
subfornical organ to lateral hypothalamus (for thirst)

Fig. Box A Chapter 21 (again)
(2) Anterior pituitary Master gland
portal system etc.
Hypothalamus parvocellular neurosecretory cells to anterior pituitary
releasing factors
inhibiting factors
Example: CRF-> ACTH->cortisol feeds back to body, hypothalamus, brain
Adrenal cortex - Glucocorticoids, metabolism, inflamation
negative feedback in stress response

Fig. 30.4B, p. 676
Thus (obviously) hormones (estradiol shown here) must bind to brain, and this has been known for a long time (note the reference to McEwen and Pfaff, famous names in this work from the 1970's

Fig. 30.4A, p. 676
recall that steroids affect transcription

Fig. 30.3A [again]
Hormone synthesis
note testosterone can have its affects as 17-beta-estradiol

androgen receptor mutation (androgen insensitivity syndrome [AIS]) -> testicular feminization, children think they are females until there is no menstruation

There are androgens from adrenal, so with Congenital adrenal hyperplasia, CAH, clitoris is large and behavior is "tomboy"

lack of 5-alpha-reductase -> "testes-at-twelve" (at puberty, testes descend, clitoris becomes penis etc when there is enough testosterone to overcome deficit) There is a pedigree in the Dominican Republic.

When I typed "five alpha reductase" or the like into my search engine, I got hits on hair loss, concerning male pattern hair loss (androgenetic alopecia) accelerated by DHT and alleviated by a drug, Propecia

Steroids are involved in photomorphogenesis in plants, and there is a mutant (in Arabidopsis) of a gene with homology to 5-alpha reductase.

Sexual dimorphism

Fig 30.2, p. 671
sex organ development
Sry gene on Y codes for TDF (testicular determining factor)
In female, Wolffian ducts degenerate and Mullerian ducts develop into oviducts, uterus, and cervix (default pathway).
In male, testes make testosterone and MIH (Mullerian inhibiting factor), Mullerian ducts degenerate, Wolffian ducts become epididymus, vas deferens and seminal vesicles (active, not default)
urogenital groove becomes external genitals

A lot of the chapter concerns neural dimorphism, surprisingly not mentioning (much) the original famous example of the part of the bird brain controling song which is male-specific

Fig. 30.5C, p. 677
motor neuron count in spinal cord of Onuf's nucleus controling perineal muscles which function differently in male and female rats
(This is in many ways parallel to the Fig. 23.9 example of spinal motor neuron count being influenced by limb bud ablation or supranumerary limb buds.)

Fig. (no longer in text)
INAH (interstitial nuclei of anterior hypothalamus) can be sexually dimorphic

Fig. (no longer in text)
in work by LeVay, the suggestion is made that homosexuals and heterosexual males differ and that homosexual males resemble more females in hypothalamic area

The book also covers some specific details in differences in cognitive function (a fairly controversial topic and one where it is sometimes difficult to get robust, unconfounded data)

Fig. 30.9, p. 682
(this could also be in another chapter)
cortical representation and receptive field of female ventrum changes during lactation

***Memory

Memory

"Throw Mama from the train a kiss, a kiss
And she throws one back from up high"
-Irving Gordon (Patti Page)


Purves et al., Chapter 31

Chapters 8 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 (and continuing to witness the events of our surviving loved ones' lives, see quote from Mama fron the train, above).
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.

Personal reflection

Here at age 66 (2013), I am still impressed with the memories triggered by things I see, hear and smell, and also the occasional flashbacks. Often these memories have not been opened for decades. I used to fancy that that was proof that dementia had not started. But how do I know whether other memories that might have been triggered last year are now forever lost?

Fig. 31.1, p. 696
Chapter emphasizes declarative memory (for facts, possibly involving language) and procedural (skill, practiced skills) memory.

Interesting stories:

Extraordinary memory of Luria's subject Sherashevsky.

Famous patient HM studied by Brenda Milner - lesion temporal lobe + hippocampus and amygdala at age 27 for epilepsy [grand mal seizures]- has anteriograde amnesia -after 50 yrs of study Milner still has to introduce herself - but HM can learn mirror drawing task (procedural memory).
Landmark Paper: WBScoville & B Milner, Loss of recent memory after bilateral hippocampus lesions, J Neurol Neurosurg Psychiat 20, 11, 1957, see also J NIH Res 8, 42-51, 1996

Another subject - NA, lesion [accidentally stabbed by roomate playing with fencing] of dorsomedial thalamus, mammillary bodies, right medial temporal lobe - amnesia like HM.

Another, RB, had ischemia with only loss of hippocampus, verified after his death.

Short-term memory-

presumably something electrical like Hebb circuits - easily disrupted, say, by electroconvulsive shock (used to treat depression).
Then there must be a consolidation for the sake of long-term memory which must involve permanent changes like changes in synapses. mRNA and protein MUST mediate change.
Retrieval is an important consideration.

Long term memory-

Biochemistry of memory got off to a terrible start

RNA

Classic (bad) papers

R. Thompson and J.V.McConnell (1955) Classical conditioning in planarian, Dugesia dorotocephala, J. Comp. Physiol. Psych. 48, 65-68.
Poor controls, not replicated
J.V.McConnell, (1962) Memory transfer through cannabalism in planarium, J. Neuropsychiat. 3 suppl 1 542-548 (eat RNA of worm that has learned, then worm knows it already)
very silly

Classic (spoof) paper

J. G. Nicholls, D. A. Baylor et al.. (i.e. the whole physiology department at Yale), Persistence transfer, Science 158, 1967:
...demonstrate the transfer of certain innate characteristics from one oscilloscope to another. Accordingly, a Tektronix Storage oscilloscope (RM 564)...was pounded with a Sears ball peen hammer (Cat. No. 28B4652) on a Fischer Lab bench (Cat. No. B158)...until all electronic components and the tube were reduced to sufficiently small pieces to pass through a filter made of 007-mesh nylon stocking (seamless). The storage oscilloscope fragments (SOF)...sprinkled over the chasis of a Tektronix 502 oscilloscope. The persistence of the afterglow was used as an index... In 18 of 33 experiments, there was an increase which was highly significant (,.001, t-test). While the average increase in persistence was not large - 3.2 msec - it nevertheless suggested that some change had been wrought in the recipient oscilloscope by the SOF. etc.

Hollywood

A book, (also a 1970 movie) Hauser's memory, describes events after a dead spy's RNA is transferred to gain his information.

Personal reflection.
One of the professors whose work I had to learn (to pass my Ph.D. exam) worked in this area. His graduate student was in my peer group. His research involved quickly dissecting the brain after teaching a rat in a T-maze and showing that RNA in the hippocampus changed. Before he was finished, his work was on control experiments showing that these changes might not be attributed to the maze learning experience.

In summary, RNA experiments were naively done with great optimism & poor controls

Protein

Landmark papers

B. W. Agranoff Memory and protein synthesis, June 1967 Scientific American, 115-122
long term memory must involve something like protein synthesis L. B. Flexner et al. Memory in mice analysed with antibiotics, Science, 155, 1967, 1377-1383
antibiotics like puromycin block protein synthesis
but return of memory with saline washout suggests interference with retrieval

How is memory stored in the brain?

Fig. 31.9 p. 706
Limbic system

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.).
The temporal lobe seems particularly important for establishment, but not storage.
Penfield - electrical stimulations


Working memory for spatial location

Fig. 31.10, p 707
Animal model of "working memory" - radial 8 arm maze put a food pellet on the end of each arm and rat uickly learns to visit each arm one time before any repeats - David Olton - rat has amazing spatial memory and hippocampal lesion disrupts that.
Personal reflection - he was an associate professor where I was an assistant professor; this demonstration, that became standard in many learning labs across the country, was the undergraduate project of Robert Samuelson, an undergraduate student, and was made by 2x4's thrown together in the wood shop. Although Scientific American was known to publish mostly articles invited from famous people, Dave broke the mold by submitting the paper (Spatial memory, June 1977, 82-98) that made their work known even in undergraduate courses across the country.

Alzheimer's disease

Box 31D - pp. 713-714
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.

More detail
several recent student presentations
Alzheimers
treatments

Recent paper G Miller Computer game sharpens minds, Science 310, 1261, 2005
Can mental exercise help?
Garden view care center activity based dementia care

***Synthesis

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

Of course it is happening inside your head, Harry, but why on earth
should that mean that it is not real?
JKRowling, Harry Potter and the deathly hallows


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.