***First Lecture

Introductory lecture


Reading assignment: Chapter 1 and other material specifically referenced

What is life?

Fig. 3.1
(Also TRANSPARENCY from an intro text)
showing a cell

If this were the first lecture for introductory biology, we would ask, "What is unique to life?" and we might argue that "Inside the cell is alive. Outside is not. The plasma membrane is thus the gate-keeper that separates the quick from the dead."(1) Then we would develop the following list:

#1. Life is very complex.
#2. Life has excitability.
#3. Life has development.
#4. Life utilizes metabolism.
#5. Life's processes are regulated by homeostasis
#6. Evolution is major unifying principle
#7. Reproduction is fundamental

In introductory biology (but not in physiology), we would concentrate on:
#1. Life is very complex and has complex macromolecules (DNA, RNA, protein).
#3. Life has development, growth, form
#6. Evolution is major unifying principle, and present-day organisms have an unbroken ancestry of 3 1/2 billion yrs
#7. Reproduction is fundamental causing us to define "survival" in biology in terms of reproduction and production of fertile offspring.

What is Physiology?

In Physiology, we will concentrate on:

#2. Life has excitability, movement and responsiveness (irritability, sensitivity)

Figure
Excitability - Copy of a page from a mathematically oriented text from 1971 text (2)

In the mid-1800's, it might be hard to distinguish a physiologist and a physicist, and Helmholtz made contributions in both disciplines.

Figure
Nervous system -Copy of a page from the book I used when I took physiology in 1969 (3), by Sir Bernard Katz, (Nobel Prize, 1970), one of many neuroscientists to win the Nobel Prize in Physiology and Medicine

#4. Life utilizes metabolism, and we will concentrate on:

Catabolic processes, for the production and delivery of energy. (However, we will not dwell on the bioenergetics coverage as much as "BL A302 Cellular Biochemistry and Molecular Biology.")

and

(to a lesser extent) Anabolic processes, involving build-up. (You have heard the term "anabolic steroids," such as testosterone and drugs of abuse among athletes.)

Perhaps, foremost, in Physiology, we will concentrate on
#5. Life's processes are regulated by homeostasis

Homeostasis: the thermostat
A fundamental example is the thermostat.
Negative feedback is sometimes referred to as a servo mechanism.
The thermostat works by negative feedback.
In house, "effector" would be furnace heat

Heat (energy) is what changes temperature.
1 calorie raises temperature of 1 ml of water 1 degree C
(the "calories" you "count" in a diet are kcal's)
Importantly, it takes about 540 calories to turn 1 ml of water to vapor.
Thus, for evaporation, we lose a lot of heat by panting or sweating.
This is called "insensible" water loss, not because it does not make sense but because you are not aware of it as you are for micturation.
Ectotherms "cold" (ambient) blooded.
Endotherms (homeotherms).

Figs. 1.3 and 1.4
"set point" 37oC
Humans - 98.6oF = 37oC
Reset thermostat's set point in fever (pyrogens).
Antipyretics (like aspirin) or hibernation lower set point.
Produce heat by shivering or increasing metabolism (with thyroxine, epinephrine)
Decrease heat loss: Arrector pili (smooth muscle) for piloerection (fluffing fur) , vasoconstriction (closing peripheral capillary beds).
Increase heat loss by panting [for dog] or sweating [for person] or vasodialtion.

Homeostasis: weight regulation

One of my favorite examples of regulation is weight regulation. My fellow graduate students and their professor in the early 1970's studied the hypothalamus, a part of the brain you will see in a few minutes, and its involvement in weight regulation. People actually regulate their food intake well. It is stated that no calories are lost (in feces or urine) [except that glucose is lost in urine of people with untreated diabetes]. Thus, you eat the same amount you need for energy catabolism (2000-3000/day) or else you gain or lose weight. I checked the calculations and found that 250 extra calories per day (1 cookie/day) would result in gaining 25 lb/yr (and very few people are gaining or losing weight that precipitously).

Levels of analysis

Levels of analysis (from introductory biology):
element - molecule - organelle - cell - tissue - organ - organ system - organism - population - biosphere

Levels of analysis (for this human physiology course):
cell - tissue - organ - organ system - organism

Integrating body functions

To make everything function in cooperation, systems of integration are needed:
(1) hormones (examples of homeostasis, next)
(2) nervous system (first major topic of the semester)

Fig. 6.29
shows these mechanism as well as paracrine (local hormone)
In both cases, a chemical is used.
Neuron uses small amount of neurotransmitter applied directly to target (muscle, nerve or gland)
Endocrine (ductless) gland (as opposed to exocrine gland with duct) puts a larger amount of hormone into blood stream where it can affect one or several target organs.

Homeostasis - hormones

TRANSPARENCY (review figure from introductory biology)
Here's the bottom middle of the brain, the hypothalamus.
Also, the pituitary to which the hypothalamus connects.
The anterior part of the pituitary puts out ACTH (adreno cortico tropic hormone).
["AC" refers to adrenal cortex, "T "refers to trophic effect, "H" stands for hormone.]
ACTH positively regulates the cortex of the adrenal gland (just north of the kidney).
The adrenal cortex puts out cortisol that feeds back negatively the anterior pituitary to decrease ACTH.
The Hypothalamus sends CRF (corticotrophin releasing factor) through the portal vessel to the anterior pituitary for ACTH release.
[Explanation of "portal" -- Mostly, the circulatory system is "wired" in "parallel," but for 3 systems, hypothalamus->pituitary, intestine->liver and kidney cortex->kidney medulla, the blood flows first to one then to the other, i.e. it is "wired" in "series".]
ACTH feeds back negatively to the hypothalamus to decrease CRF.

Fig. 11.16
[a similar example from your text]
TRH (thyrotropin-releasing hormone) (Note, "hormone" term, "factor" above.)
TSH (thyroid stimulating hormone)

Fig. 11.3
"Thyroxine" has two forms, T3, T4, formed from dimer of tyrosine (amino acid) with 3 or 4 iodines attached.

What everybody should know about thyroid hormone:

Fig. 11.25
Goiter insufficient dietary iodine

Fig. 11.24
Goiter

Figure 11.26
Hyperthyroid syndrome in adult

Cretinism hypothyroid in infant

Dietary iodine is from sea food. Now iodine is added to salt.
It is because of thyroxine that you should worry if there is a reactor leak (like 3 mile Island or Chernobyl), and the solution is taking lots of iodine so that any radioactive iodine you are exposed to will be competitively swamped out for thyroid uptake.

Roger Guillemin and Andrew V. Schally won the 1977 Nobel Prize for their discovery of these releasing hormones (factors), a heroc task because they are present in vanishingly small amounts (because of the efficiency of hormone delivery through the portal vessel).

References
(1) see p. 117, G. Audesirk & T. Audesirk, BIOLOGY Life on Earth (3rd ed.), New York, Macmillan, 1993.
(2) see pp. 48-49, D. J. Aidley, The physiology of excitable cells, Cambridge, University Press, 1971.
(3) see pp. 34-35, B. Katz, Nerve, muscle and synapse, New York, McGraw-Hill, 1966
(4) S. Freeman, Biological Science, Upper Saddle River, NJ, Prentice-Hall, 2002

***Membranes

Membranes


Fox, Chapter 6, plus some references back to earlier and later chapters and to Freeman

There's enough lipid to make two layers

Fig. 6.13
shows how red blood cells react to hypertonic, isotonic and hypotonic solutions.
Get a good source of membranes:
red blood cells (erythrocytes) from adult human have only plasmalemma.
Gorter and Grendel showed in1925 that there was enough lipid to make two layers.
Put red blood cells into distilled water, they burst from hyposmotic shock and become only "ghosts" - membrane only.
Blood cell counts, and geometry solves for membrane surface.
Extracted lipids on a surface have an increased lateral stability when they reach a monolayer which, when measured is twice the membrane area.
Here is a snapshot I took of oil on a road after rain - when oil is multiple layers, you see color, and layers slip, when oil is one layer, it is black.

Fig. 6.7
(To understand how hypotonic shock burst the erythrocyte, I introduce a fundamental concept, osmosis)
Osmosis - water moves passively from where water is at a higher concentration (for instance pure water) to where water is at a lower concentration (where organic chemicals are dissolved in it)
through a semipermeable membrane (i.e. a membrane which passes water but not the organic molecules).

Membrane structure

(Glucose transport across the cell membrane is so fundamental that it is in the introductory book)

TRANSPARENCY (Review from an introductory text)
glucose transporter

Fig 6.16
Glucose transporter from your textbook
shows bilayer of lipids with protein in it

Notice that the lipid molecules are drawn in this "cartoon" as a ball with two sticks.
Most membrane lipids are phospholipids with:
(1) a polar (hydrophilic) head group
and
(2) hydrophobic fatty acid (acyl) tails

Another example allows introduction of another fundamental molecule:

TRANSPARENCY (Review from an introductory text)
Here is a famous membrane protein, rhodopsin, the molecule we see with, and how 7 hydrophobic alpha helices of the protein fit into the hydrophobic part of the membrane (the milieu created by the fatty acid tails). For future reference, retinal is the chromophore, the component (chromophore) that makes the protein [proteins are otherwise not colored] into a pigment. Retinal is a derivative of vitamin A. Rhodopsin is in the membranes of rods and cones, visual receptor cells, shown in the diagram. Rhodopsin is the prototypical G protein-coupled receptor (GPCR), and GPCRs are used for hormones, neurotransmitterss, olfaction, taste and others.

Electron microscopy (EM)

Fig. 3.2, Fox
Robertson did work that led to earlier bilayer model.
He saw 2 "electron dense" (dark) lines in EM when stained osmium, an electron dense heavy metal. Davson and Danielli developed a membrane model from Robertson's vistas.
Fluid mosaic Singer and Nicolson the more modern version

Picture I made freeze fracture replicas with this apparatus. Specimen is prepared, frozen to liquid nitrogen temperature, put inside a vacuum, smashed with a razor (membranes break down the middle between the fatty acid tails), blasted from an angle with a platinum gun (to shadow protein with electron dense heavy metal), blasted from above with a carbon gun (to hold replica together), then the tissue is dissolved away.

Here, from my research, is an example of how things look. Picture shows visual membranes in Drosophila. High vitamin A flies have membranes full of protein (the same rhodopsin I mentioned above) while vitamin A deprivation decreases this protein.

Membrane biochemistry

Membrane lipids are composed of:
(1) Phospholipids such as phosphatidylcholine (lecithin)
I did some research on the phospholipids of the Drosophila head. Using radioactively lbeled phosphate, many different phospholipids are visualized after they have been separated on a TLC (thin layer chromatography) plate.
(2) Cholesterol
(3) Glycolipids such as one that accumulates in Tay-Sachs, a hereditary lysosomal storage disease,1/30 American Jews carry, recessive, fatal at 6 mo - 5 yr

Alexa B. Serfis in SLU's Chemistry Department studies membrane lipids and their proteins

Membrane physiology

Relevant to physiology, if the membrane had only lipids, it would have extremely high resistance. This is because the hydrophobic milieu in the center of the membrane does not allow water, a polar solvent, or ions which carry current. The membrane is only permeable because some of the proteins are channels that pass ions. Also, there is high capacitance. The concepts of resistance and capacitance will be dealt with shortly.

Membrane signalling

Lipid makes a barrier to anything polar or big like protein hormone or epinephrine (bind receptor).
(This receptor is the GPCR, mentioned above.)
Steroid hormones can go in

It used to be thought that lipids just sit there. In the 1980's it became clear that they turn over metabolically and that some products of membrane lipid turnover are important mediators of intracellular signalling. This is very fundamental and will come up repeatedly in later.

Fig. 11.9, Fox
Hormone -> receptor protein (GPCR) -> G-protein -> cascade makes second messengers (IP3 and DAG [diacyl glycerol, not in your diagram]) from the membrane lipid PIP2 [phosphatidylinositol-4,5-bisphosphate, not in your diagram], note that calcium ion Ca2+) becomes a next messenger in the cascade.

Important points that will come up repeatedly:
Phospholipase C is the enzyme [and I have a research interest in PLC]
IP3 is a "ligand" for a calcium channel.
Ca2+ is sequestered inside endoplasmic reticulum.
Inside a cell's cisterns is tantamount to outside the cell.
Ca2+ is high outside and low inside, like Na+ (sodium ion) unless deliberateluy increased intracellularly.
Ca2+ levels are so important that 3 hormones regulate blood Ca2+, parathormone, calcitonin and vitamin D.

Membrnne channels

Fig. 7.26
Nicotinic Acetylcholine receptor [More on this later])
Acetylcholine is a ligand (neurotransmitter), nicotine is a pharmnacological agonist.
This receptor is a channel (for ions, giving the membrane electrical conductance [g])
Channel is ligand gated.
Sodium (Na+) and potassium (K+) shown going through pore in membrane that can be open or closed.
Sodium, higher outside the cell, is likely to go in.
Potassium, high inside the cell is likely to go out.

The 1991 Nobel prize in physiology and medicine was awarded to prize was awarded jointly to: ERWIN NEHER and BERT SAKMANN; they developed patch clamping that allowed electrical recording from single channels.
In 1963 the Nobel prize was awarded jointly to: SIR JOHN CAREW ECCLES , SIR ALAN LLOYD HODGKIN and SIR ANDREW FIELDING HUXLEY for their discoveries concerning the ionic mechanisms involved in excitation and inhibition in the peripheral and central portions of the nerve cell membrane; Hodgkin and Huxley worked on the voltage gated channels of the axon's action potential and Eccles worked on the neurotransmitter gated channels at synapses.
In summary, the topic of ion channels is pretty fundamental.

Fig. 7.21
Also holes in membranes from one cell to another are important:
Gap junctions - 2 hexamers in register of connexin protein
This is a very big channel.
Important in many places, especially connecting one heart muscle (myocardial) cell to another electrically.

Membrane transport

Fig. 6.19
"sodium pump"
A large fraction of the cell's energy (ATP) goes to pumping ions (active transport)
This creates an ion imbalance, sodium Na+ high outside cell, potassium K+ high inside.
This gives rise to the membrane electrical potential (voltage) important in nerve and muscle cells.

Fig. 3.4
bulk transport:
phagocytosis - cell eating
pinocytosis - cell drinking
Receptor mediated endocytosis - clathrin coated pits turn to vesicles, clathrin is a protein that makes vesicles look fuzzy.
Receptor mediated endocytosis is important in clearing lipoproteins, LDL and HDL, from blood (later), and, of course, a receptor protein in the membrane is important in the transport.
From my research, a coated pit.

In summary,

Functions of membrane proteins
(1) transport
(2) many enzymes are on the membrane
(3) receptors for hormones, neurotransmitters and developmental signals are on the membrane.
(4) cells are joined by proteins
(5) cells communicate by proteins
(6) cells hook to extracellular proteins by proteins

Reference:

E. Gorter and F. Grendel, On bimolecular layers of lipoids on the chromocytes of the blood, J. Exp. Med. 41, 439-443, 1925

***Bioelectric potentials

Neurons


Fox Chapter 6 and 7. Note that web material is especially important for this lecture

TRANSPARENCY (from intro book)
Figure 7.1a
typical neuron
Connections, from other neurons, created graded electrical potentials at synapses, on dendrites and cell bodies.
Cell body integrates the synaptic excitatory and inhibitory voltages.
If there is net excitation, axon propagates the all-or-none, non -decemental action potential quickly over long distances.

Overview

Excitable membrane has resting and action potentials
Ions are dissolved in water and are pumped using ATP -> ADP for energy, Na+-K+-ATPase.
This "sodium pump" uses 1/3 (2/3 if high electrical activity) of cell
These ion gradients establish "batteries" as ions can flow through channels.
Other than channels and pumps, membranes do not pass ions well (covered before).
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.

History

1791 Luigi Galvani (Italy) (of Galvanometer fame) - nerve muscle electricity in frog
1850 Herman von Helmholtz - speed of conduction (40 m/s)

Walther Hermann Nernst (Germany) (1864-1941) 1920 Nobel in Chemistry.
Nernst equation says that ion gradient is equal and opposite to voltage difference.
(often misunderstood)
1902 (paper) Julius Bernstein apply Nernst, K+ permeability lost in action potential.
(insightful but short of the full story)

TRANSPARENCY (from R. D. Keynes, The nerve impulse and the squid, Scientific American, December, 1958).
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.

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)

Electrical concepts

Fig. 6.26, Fox
Sodium is high outside.
Potassium is high intracellularly.

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

delay in depolarizing or hyperpolarizing membrane
Membrane capacitance
Thus, this is a low (frequency) pass (high cut-off) filter
Typically, capacitance adds delays
There are also high pass filters

Derivation of Nernst potential

Fig. 6.26, Fox (again)
Because of the potassium gradient there is a resting potential of about -65-70 mV

pdf
Assume two compartments in communication
(ions like K+ or Na+ dissolved in each)
Free energy (of each system) = RT ln Ci + ziFF
chemical electrical
F is absolute potential, C is concentration, i is given ion, e.g. K+ or Na+
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

K+ in 140, K+ out 5
Na+ in 5-15, Na+ out 145

Fig. 6.27
Because of the potassium gradient there is a resting potential of about -65-70 mV
(like before but with voltmeter drawn in

Goldman equation

pdf

There is an equation that looks like the Nernst equation except that is has sodium (Na+), potassium (K+) and chloride (Cl-) and their relative permeabilities. Permeabilities change as a function of time.

David Goldman, 1943
assume constant field, this derivation is "beyond the scope of this course" (way too dificult)

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

(see pdf for equation drawn more neatly)

Note that in and out are reversed for Cl- since it is an anion while Na+ and K+ are cations.

There is a membrane model with 3 batteries (note that the sodium and potassium batteries are reversed because the gradients of these two cations are opposite).

The relative permeabilities are modelled by variable resistors (potentiometers) [where variable conductances, the inverse of resistances, are more analogous to variable permeabilities]

Wheatstone bridge

How to determine an unknown resistor
Use two knowns as voltage divider
use a variable and the unknown as another voltage divider
Use a galvanometer as a null detector between the two nodes

Cole and Curtis used an AC bridge to show that resistance decreased during the action potential

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].

Reference

R. D. Keynes, The nerve impulse and the squid, Scientific American, December, 1958

***Action Potentials

Action Potentials


Fox, Chapter 7 (mostly)

Spike propagates nondecrimentally long distances

Fig 7.4
Typical nerve
Most important information - axon is relatively long.
There are various shapes.
Top - this looks likes the input to the spinal, the cell is in the dorsal root ganglion
Middle - there are bipolar neurons in the retina
Bottom - this looks like the spinal motor neuron, cell in ventral horn of spinal cord gray matter.
In this multipolar neuron, synapses are on dendrites and cell body, axon carries action potential

Fig. 7.11
oscilloscope essentially graphs voltage as a function of time
The figure introduces the terms depolarization and hyperpolarization

Properties of the action potential

Fig. 7.13
(What everybody should remember about the action potential based on the background you are assumed to have.)
At threshold, Na+ channels open (then close), and Na+ diffuses in
After peak of action potential (spike), K+ channels open, and K+ diffuses out
The spike is all-or-none, as opposed to having variable sizes like synaptic potentials or receptor potentials.
After the spike, there is a refractory period (when another spike cannot be started), and this insures unidirectional propagation.
Note that the depolarization to threshold shows the membrane acting as a low pass filter.

Fig. 7.19
Spike depolarises the axon ahead of it to depolarize the membrane to threshold

Passive propagation

Introduction. "Action" potential refers to the active voltage-gating that opens the Na+ channel that allows nondecremental propagation. If that did not happen, propagation would be decremental based on the passive spread of current going down the axon and also leaking out the membrane.

Fig. 7.19
(look back, I already showed it)
Current going down axoplasm and leaking out membrane
The recorded potential gets smaller

pdf
Cable equation

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.

Myelin speeds up the action potential

Fig. 7.7
Transmission electron micrograph (TEM) of myelin.
Membrane is wrapped around and cytoplasm is squeezed out, leaving only alternating bands of electron density and lucency at high magnification.
Each layer of membrane has high resistance, and resistors in series block current flow through membrane.
Each layer of membrae has high capacitance which would leak current, but capacitors in series add reciprocally, decreasing capacitance and leakage.

Fig. 7.20
Myelinated axons have faster propagation.
Invertebrates do not have myelin, and that is why they have giant axons.
Here's why: action potential jumps from one node of Ranvier to next, "saltatory" (leaping) conduction

Myelin is invested by different cells in peripheral vs central nervous systems

Fig. 7.6
In PNS (peripheral nervous system), myelin is made from multiple membrane wrappings of Schwann cell.
One axon
Disrupted in polio (poliomyelitis)

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.

Recent literature
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

Fig. 7.8
In CNS (central nervous system), myelin is formed from oligodendrocytes.
Multiple axons, hence the prefix "oligo" (a few).
Disrupted in multiple sclerosis.

Multiple sclerosis (MS) (Anette Funicello, Montell Williams, Richard Prior, "the president" in West Wing) damages myelin in the central nervous system
Might aflict motor function, vision, or others
Hits people 20-40, with deterioration but sometimes episodic, i.e. with remissions
Animal model - EAE (experimental allergic [autoimmune] encephalitis) to myelin basic protein.
Such a disorder used to happen with rabies vaccination when virus was gron in brain (before it was grown in eggs).

Hodgkin Huxley Nobel experiments

Fig. 7.14
resting potential is based on predominant K+ permeability
then Na+ channels activate
then Na+ channels inactivate
then a late K+ channel activates

Channels

GENERALIZATION - action potential is based on Na+ and K+
there are MANY other channel types

Fig. 7.12
inactivation is "stopper" on chain

Tetrodotoxin puffer fish (saxitoxin dinoflagellates) block Na+ channel

***Synapses and transmitters

Synapses and transmitters

Synapses


Fox, part of chapter 7 (part of chapter 12) (a figure from chapter 8)

Major point

Cell theory (cells being separated) implies that cells must communicate with each other through an extracellular connections and most communication is through chemical messages
Golgi developed a special staining that highlighted individual cells among the zillions in the CNS but did not believe that cells were separate; Ramon y Cajal used this technique a lot and did develop a cell theory; both won the 1906 Nobel prize

Fig. 7.23
Synaptic terminal has synaptic vesicles that contain and release chemical transmitter.
Calcium coming in through channel is involved in transmitter release into synaptic cleft.

Role of synapses in reflexes

Fig. 12.28
Fig. 12.29
Fig. 12-30
reflexes
knee-jerk reflex - tap patellar ligament, spindle (stretch receptor), dorsal root ganglion, monosynaptic, alpha motoneuron to muscle
too much stretch monitored by Golgi tendon organ, act through inhibitory interneuron (two synapses, less excitation)

->1906 Sir Charles S. Sherrington (England) Integrative Action of the Nervous System 1932 Nobel "functions of neurons" coined "synapse" = "clasp"
spinal reflex - Spinal motoneuron - Sherrington - final common pathway (for integrative action of the nervous system)

Fig. 12.31
integrated reflexes, reciprocal reflexes, extensor activated then flexor inhibited
integrated reflex, crossed-extensor reflex, if flexor activated, opposite extensor will be activated to compensate for weight support

History

1926 Otto Loewi (Austria) 1936 Nobel Prize
Reportedly, he thought of this experiment in a dream
vagus-stuff slows heart (10th cranial nerve, parasympathetic)
take substance and show that it slows a heart in another dish, vagus substance = acetylcholine (ACh) a monamine transmitter


Inhibition, excitation and integration

Fig. 7.34
Sir John C. Eccles 1963 Nobel (with Hodgkin & Huxley) EPSP & IPSP
Postsynaptic potentials (Eccles, using spinal motor neurons)
EPSP - depolarize
increase sodium and potassium conductance
IPSP - hyperpolarize
increase potassium and chloride conductance
Excitatory and Inhibitory integrate before axon hillock "decides" to fire.

Structure

Here are some classic pictures, work by Heuser and Hueser and Reese, of vesicle release at the neuromuscular junction, a transmission electon micrograph and a freeze fracture electron micrograph

Chemical synapses
Presynaptic membrane, cleft, Postsynaptic membrane (intracellular density seen in EM [electron microscopy]), vesicle
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 body is usually away from the action, and cells surround processes where connections are made, "neuropil(e)"

Vesicle release

Fig. 7.23
again

General

Vesicles are interesting.
Transmitter is very concentrated, there are pumps to move transmitter "up hill" (against gradient) into vesicle.
Sometimes part of transmitter synthesis is in vesicle.
Ca2+ in through voltage gated Ca2+ channel
Note that figure shows that Ca2+ activates calmodulin which activates protein kinase and that "kinase phosphorylates synapsin proteins"
There are vesicle membrane proteins, target (presynaptic) membrane proteins, and cytoplasmic proteins

A lot of detail

Vesicle proteins:
Synaptotagmin - binds calcium
Synaptobrevin / VAMP (vesicle-associated membrane protein) = v-SNARE (SNAP receptor)
Botulinum and Tetanus* toxin (clostridial toxins) are proteases which cleave synaptobrevin
Botulism (Clostridium botulinum) improper canning - block release
BoTox
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

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

vesicle membranes are recycled

endocytosis is via coated pit, coated with protein called clathrin
coated pit from my work another (not related to synapses)
dynamin is protein required for pinching off coated pit
dynamin is product of temperature sensitive shibire mutant with paralysis at restrictive temperature
from my work, coated pits that fail to pinch off to coated vesicles in shibire

Neurotransmitters and neuromodulators

Fig. 7.24
Reminder how nerve works

Pharmacology was pivotal in discussing chemical transmission.
agonist - a drug that mimics the neurotransmitter
antagonist - a drug that blocks the neurotransmitter

Acetylcholine

Fig. 7.26
(shown before in the membrane lecture)
Nicotinic ACh receptor
Receptors in this figure are channels and this kind of transmission 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).
Channel opens and both K+ and Na+ conductance increase

Fig. 7.28
There is another kind of receptor, the G-protein-coupled receptor
For cholinergic transmission, the muscarinic receptor is an example

Aceylcholine metabolism
Dale 1936 Nobel "cholinergic" ("-ergic" used universally)
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. 7.30
Axelrod
Adrenergic
(1970 Nobel ) 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 (31, this is part of the table, note mistake for ACh, no this projected version but not in the book)
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

Parkinson's

(mentioned here because of dopamine)

Fig. 8.21
degeneration of substantia nigra
1817 Shaky palsey
Degenerate dopaminergic input to striatum from substantia nigra
Aflicted have bradykinesia, akinesia, rigitystilted gait, tremors, walk in shuffle, stone (expressionless) face, loss of affect.
1% of people over 50 years old
Lateral hypothalamic lesions make thin rat and some motivational defects, dopamine in medial forebrain bundle toward basal ganglia.
Dopaminergic neurons degenerate, animal model - 6-OHDA uptake makes peroxide, cells die.
Cannot give dopamine because it coes not cross the blood brain barrier.
Give l-DOPA (in large doses because l-AAAdeCOOHase is everywhere); give decarboxylase inhibitor carbidopa. Jill Smith in Dr. Fisher's lab (Bio, SLU) works on this.
Extrapyramidal motor syndrome also comes from long term administration of antipsychotic phenothiozines such as chlorpromazine (brand name Thorazine).
(Chronic use of these drugs also cause a corioretinopathy.)
There was a bad batch of street drugs with an impurity called MPTP which gave its users a Parkinson's like disease.
There had been some experimental cell transplant therapies - controversal.
Arvid Carlsson made contributions here and shared 2000 Nobel Prize in Physiology and Medicine.
Several famous people have Parkinson's - Pope, Mohammad Ali, Michael J Fox.
Mostly it is "sporatic" (not genetic), but familial cases have been interesting.
Alpha-synuclein, Parkin and DJ-1.

Signal transduction

TRANSPARENCY (from intro book)
peptide and small molecule hormones (and neurotransmitters) have membrane receptors
(steroids, covered later in the semester, bind intracellular receptor after crossing membrane)

TRANSPARENCY (from intro book)
Epinephrine activates a G protein signal transduction cascade

Fig. 7.31
1971 Nobel Earl W. Sutherland, Jr. (US) "mechanisms of actions of hormones"
Metabotropic neurotransmitter action, adrenergic, muscarinic cholinergic
G-protein-coupled receptor to heterotrimeric G protein
Alpha binds GTP (hence the name "G protein") activates adenylate cyclase converts ATP to make cAMP and that activates protein kinase A (PKA).
Alpha subunit eventually breaks down GTP to GDP and P ("inorganic" phosphate, i.e. PO4)
A kinase phosphorylates proteins.
Phosphodiesterase inactivates cAMP and caffeine inhibits PDE

More

There is so much more that could be said about neurotransmitters! The chapter does have more. Maybe we will get back to them. But we will stop with Adrenergic and Cholinergic for now to pave the way for the lecture outline on the Autonomic nervous system, so important in Physiology.

***Autonomic

Fox Chapter 9 (plus selections from Chapters 7, 8, 14 & 20)

Autonomic n.s.

It's a motor system


Fig. 8.28
Fig. 9.3
motor system for smooth muscle and glands
contrasted with somatic system innervating striated (skeletal) muscle
Autonomic has preganglionic and postganglionic output

Fig. 7.3
Another figure to show the same thing

Parasympathetic and sympathetic

TRANSPARENCY (From an intro book)
Parasympathetic = "rest and digest"
Sympathetic = "fight or flight"

Fig. 9.5 [Fox's version of this same classic figure]
Parasympathetic, cranio-sacral, ACh (nicotinic and muscarinic), ganglion near target
Sympathetic, thoraco-lumbar, ACh (nicotinic) then NE, ganglion near spinal cord

Acetylcholine and Norepinephrine

Fig. 9.7
(same material on next two lines)
Parasympathetic, cranio-sacral, ACh (nicotinic and muscarinic), ganglion near target
Sympathetic, thoraco-lumbar, ACh (nicotinic) then NE, ganglion near spinal cord

Fig. 9.10
(same material on next two lines)
Parasympathetic, cranio-sacral, ACh (nicotinic and muscarinic), ganglion near target
Sympathetic, thoraco-lumbar, ACh (nicotinic) then NE, ganglion near spinal cord

For NE (adrenergic), all receptors are G-protein-coupled-receptors
Alpha (vasoconstriction) phenylephrine (Neosynephrine, nasal decongestant) is agonist
Beta-1 in heart, why beta blockers like propranalol were given for high blood pressure
Beta-2 bronchioles, why asthma inhalers had epinephrine

Fig. 9.5 [again]
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).

Anatomy

Fig. 9.3
arrangement of sympathetic output from lateral horn neuron -> white ramus -> sympathetic ganglion -> gray ramus
Simpler for parasympathetic, i.e. from brain stem nucleus or lateral horn in sacral cord to parasympathetic ganglion
called enteric for gut. Contribution of neural network (plexus) to circular and longitudinal muscles to mediate peristalsis. Parasympathetic allows digestion, sympathetic puts it on hold. Atropine blocks muscarinic synapses and is in anti-diarrhea medications to slow motility.

Beautiful women

Clinical Box on page 253
Atropine muscarinic antagonist
Atropa belladonna (beautiful woman) [deadly nightshade]
SLIDE (Hess, Scientific American, Nov. 1975, p.111) Women are more beautiful with dilated pupils

Channels vs G protein-coupled receptors

Fig. 9.11
use nicotinic and muscarinic to remind you of ionotropic and metabotropic

Heart as an example.

Fig. 14.5
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.

Important aspect of quality of life

Fig. 20.22
(this is not quite true, see below)

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

***Muscle

MUSCLE

Fox Chapter 12 (plus references to chapters 5, 7 & 15)

How muscle works molecularly has been a real success story in cell-molecular biology.

Cell structure

Fig. 12.1
Skeletal ("striated" = striped) muscle cell ("fiber" = cell) 10- 100 microns [micro, 10 to the minus 6. meters] (huge) and long (from tendon to tendon)
There are smaller units within fiber called "myofibrils" (1-2 microns in cross section)
Thus 1000-2000 myofibrils/fiber

Fig. 12.6a&b
Sarcomeres are units along the length of myofibrils
Interestingly, the striped (striated) pattern of myofibrils is in register for all the myofibrils in the fiber giving the whole muscle fiber a striated appearance.
Within the myofibrils are the filaments
Actin - G (globular) polymerizes to F (filamentous) actin - the thin filament
Myosin - (2 heavy chains and 4 light chains) - the thick filament
I-band (isotropic - light), A-band (anisotropic, dark) based on actin and myosin, see figure

here is a picture from our histology course but watch out because the arrows for A, I, and H do not point accurately

Muscle proteins

Fig. 12.8 like last figure
Z disc where actins are joined in the middle of the actins
M line in the middle of the myosin
A (anisotropic)= where myosin is
I (isotropic) where actin is but not myosin
H (helle) (lighter) where there is myosin but not actin
This figure shows titin a gigantic protein that is elastic

"Clinical application" box on p. 356
Muscular dystrophy (Duchenne) X-linked recessive (sex-linked), affects boys
Lethal by age 20
"Dystrophin" protein associated with muscle cell membrane, binding cytoskeleton with extracellular matrix.

Sliding filaments

AFHuxley & RNiedergerke, 1954, Nature
173 971-973
Interference microscopy of living muscle fibers

HHuxley & J Hanson, 1954, Nature 173
973-976 (back to back!)
Changes in the cross-striations of muscle during contraction and stretch and their structural interpretation

Contraction of muscle was well-described in 1958 (H.E.Huxley, The contraction of muscle, Scientific American, Nov. 1958); he is not related to the other Huxleys, Thomas (zoologist and advocate of Darwin), Thomas's grandson, biologist Julian, Julian's brother Aldous, author of Brave new world, and Julian's and Aldous's half brother, Nobelist Andrew F. Huxley whose other work (with Hodgkin) we covered earlier.

Fig. 12.9a&b
Sliding filament explanation of muscle contraction

Fig. 12.21
The length tension curve shows that the optimum is when there is good overlap without the actin colliding (note, there will be an important difference for heart muscle.)

Involvement of ATP

Fig. 12.10
picture myosin as a boat rowing through a sea of surrounding actin molecules.

Fig. 12.12
Interestingly ATP binding unhooks myosin from actin. This can be remembered by thinking about rigor mortis (box p. 348) - a "stiff" in a detective show - has been dead long enough so that ATP has run out and actin and myosin are locked together. ATP -> ADP and a phosphate added to the myosin and this is like the rower back-stroking to get ready to take another power stroke. When the phosphate gets kicked off of the myosin, the myosin and actin bind, followed by the power stroke

Involvement of Ca2+

Fig. 12.14
Ca2+ ions are released to make muscle contract (explained later)
tropomyosin on actin
troponin has a Ca2+ binding site like calmodulin
Ca2+ binding to troponin pulls tropomyosin off of actin's binding sites for myosin

The neuromuscular junction

Fig. 12.3
here is a similar picture from our histology course of the neuromuscular junction
Action potential from nerve opens channels (nicotinic acetylcholine receptors) at "synapse" called the neuromuscular junction. (Notice that the nerve branches.)
This is a big "synapse" and it works.
Here is a transmission electron micrograph of a portion of a neuromuscular junction. Note the folds, increasing the area on the muscle cell. Note the space with electron density in the cleft. Note the numerous vesicles.

Bernard Katz shared the 1970 Nobel prize for using the quantal nature of transmission at the neuromuscular junction. The quanta are individual vesicles. The neuromuscular junction is like any synapse except bigger and easier to study. This information could fit equally well here, in the muscle lecture, or in the synapse lecture (but that was already crowded with Nobelists.

Box in Chapter 7 on page 183
Table 15.10
autoimmune diseases
Myasthenia gravis is an autoimmune attack on nicotinic receptors
Muscle weakness
Here's a picture I found on the web of the eyelid droop
Give AChE (neostigmine) inhibitor neostigmine to ameliorate symptoms

Table 7.5
nicotine is an agonist. 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.

The spinal motor neuron

Clinical applications Box on p. 380
Amyotropic Lateral Sclerosis (Lou Gehrig's disease affects spinal motor neurons)
some cases familial led to identification on chromosome 21
coper/zinc Super Oxide Dismutase (SOD1) reduces oxygen radicals
some famous baseball personalities, Lou Gehrig set consecutive games record until broken by Cal Ripken Jr.
Lou Gehrig's farewell speech

Fig. 12.4
(relative to the aforementioned "nerve branches") Motor units
(how many muscle cells per motor neuron)13 eye, 1730 calf

The muscle cell's action potential

Fig. 12.16
Then action potential goes down muscle cell. But cell is too big. So transverse tubules (T tubules) get action potential into cell at numerous locations (for each sarcomere and for each myofibril). Proximity with a specialized smooth endoplasmic reticulum called the sarcoplasmic reticulum causes release of Ca2+.
That "proximity" involves actual interaction of the types of Ca2+ channels in transverse tubules and in sarcoplasmic reticulum.

Fig. 12.19
1 - 1 spike, tetanus for sustained
Note that eventually, fatigue sets in.
A few years ago, in General physiology lab, one of the lab groups obtained the result shown Here. the result when tetanus was obtained by increasing the amplitude of stimulation.

In summary:

ACh to synapse Ecxitation to spike
Final common pathway - motor neuron carries integrated information from nervous system
action potential in membrane and t-tubules, t=transverse
Ca++ release from sarcoplasmic reticulum (ER)
T at A-I junction in Skeletal muscle but it is at the z line in cardiac muscle and in frog skeletal muscle

Types of skeletal muscle:

Difference obvious in turkeys
Fast twitch, strong, anaerobic, white meat
Slow twitch, enduring, aerobic, dark meat
capillaries (hemoglobin), myoglobin, cytochromes in mitochondria
can alter with training
It is possible to stain, in this case for ATPase, to show mixed muscle cells in a muscle (dark is slow, aerobic).

Metabolism:

Fig. 12.24
phosphocreatine (creatine phosphate [backup, battery]) makes ATP using phosphpcreatine kinase

Fig. 12.22
muscle uses glucose and fatty acids (from plasma)
and glycogen and triglyceride (from muscle)

Glycogen -> (glycogenolysis) -> glucose
Overall, 1 glucose can give up to 38 ATP's, a few from glycolysis and the rest from the mitochondrion
Without oxygen, make ethanol (yeast) or lactate (lactic acid).
Anaerobic glycolysis is used to deliver ATP quickly but wastefully (squandering glucose).
Make ATP's but need to regenerate NAD+ [from NADH] to make.

Fig. 5.6
Lactic acid contributes to fatigue in muscle and oxygen debt, and the liver eventually reconverts.
Anaerobic cellular "respiration" is needed in times of extreme exertion because the heart (cardiac output) is the limiting factor in delivery of oxygen to muscle.
Lactic acid is also made by bacteria in yogurt, sour cream, and cheese.

Fig. 16.37
Hemoglobin off-loads oxygen to myoglobin

Monitoring muscle stretch

Fig. 12.27b
remember reflex from synapse lecture
knee-jerk reflex - tap patellar ligament, spindle (stretch receptor, alpha motoneuron to muscle)
gamma motor neuron goes to nuclear chain fibers (intrafusal muscle) to set tone on spindle
sensory fiber wraps around nuclear bag fiber

Smooth muscle

In an undergraduate physiology lab, a piece of rabbit gut is connected to a force transducer. Rhythmic contractions are monitored. Drugs like atropine (see autonomic lecture) slow motility, and this is why it is in anti-diarhea medications. When I was a kid, a teaspoon of some terrible tasting stuff called paregoric cured a belly ache right away, but you can't get paregoric (tincture of opium) any more.

Fig. 12.35 b & c
smooth muscle - arterioles, gut, uterus - involontary, autonomic
actin and myosin are arranged differently (striations helped in sliding filament theory)

Fig. 12.36
Ca2+ comes across cell membrane, not from SR
activates myosin light chain kinase, phosphorylation
phosphorylation (and dephosphorylation) of myosin regulates cross-bridge

Fig. 12.37
regulated by autonomic neurons with varicosities and synapses enpassant
in single unit, autonomic activates then it passes from cell to cell
in multiunit, need to activate each cell

Dr. Fisher is our muscle expert, and he teaches a course in exercize physiology

***Energy

Energy metabolism


Readings
Fox selections from Chapters 2, 4, 5, 6, and 11

"He said science was going to discover the basic secret of life someday," the bartender put in. He scratched his head and frowned. "Didn't I read in the paper the other day where they'd found out what it was?"
"I missed that," I murmured.
"I saw that," said Sandra. "About two days ago."
"That's right," said the bartender.
"What is the secret of life?" I asked.
"I forget," said Sandra.
"Protein," the bartender declared. "They found out something about protein."
"Yeah," said Sandra, "that's it."

-Kurt Vonnegut, Jr. Cat's Cradle

Overview

We will not get very technical on biochemistry of metabolism, since this is a physiology course and not a biochemistry course.

Reminder
Metabolism is the general term for two kinds of reactions:
(1) catabolic reactions (breakdown)
and
(2) anabolic reactions (constructive)

Organic Chemistry is the chemistry of carbon (C) which makes 4 bonds.
In "Star Trek" (the first movie), people were called "carbon based units" by the alien.

Carbohydrate

Fig. 2.13a
Carbohydrate (Carbo-hydrate is also sort of a compound word, carbon, "hydrate" suggests water) - the general formula is Cn(H2O)n
Monosaccharides
Hexose (hex = 6 [carbons], "-ose" always means sugar)- glucose, the most famous monosaccaccharide, is good to illustrate that monosaccharides usually assume a ring structure

Fig. 2.15
Compound dehydration synthesis puts sugars together
Hydrolysis (hydro-water, lysis-breakdown) is the opposite.
In digestion, macromolecules are broken down to monomers.
Disaccharide - sucrose, lactose (milk)
Figure shows maltose and sucrose, and shows dehydration synthesis.

TRANSPARENCY from intro book
Polymerization Reactions: Condensation reaction and Hydrolysis

Fig. 2.14
Polysaccharides starch (plant), glycogen (glyco-sugar, gen-give birth to) (animal)
Energy storage:
In liver for whole body
In muscle for muscle use

Fat

Fig. 2.19
Lipids (fats) store more energy (2x sugar) 1 tablespoon of sugar is 50, fat 100 "Calories" = kilocaloriies
Glycerol & 3 fatty acids (16-24 C long) - triglyceride ester bonds , note the dehydration synthesis
The -COOH defines an organic acid such as a fatty acid, otherwise the molecule is a hydrocarbon.
C-C (single bond) vs. C=C (double bond) unsaturated (vs saturated with H's), with several, it is referred to as "polyunsaturated" PUFA = polyunsaturated fatty acid
Animal fats tend to be saturated, bad for arteries leads to atherosclerosis; vs vegetable fats better.
Polar phospholipids - we'll talk about that later, because our emphasis now is energy.
Steroids-cholesterol & hormones - we'll talk about that later, because our emphasis now is energy.
Salts of cholesterol are in bile (from liver) that acts like a detergent to emulsify fats to aid in digestion.

Protein

Fig. 2.27
short = "Peptides", medium = polypeptide, long = "protein" (hundreds, thousands of amino acids)
The general formula is NH2-CR-COOH - amino ( -NH2 ) and acid ( -COOH ).
Peptide bonds involves -NH2 and -COOH getting linked with a dehydration synthesis.
There are about 20 amino acids (alphabet of 20 letters)
R group varies, see figure.
About half of the amino acids are "essential" meaning that they cannot be made by metabolic conversion from other molecules and thus need to be eaten
Structure:
1. primary (the sequence)
2. secondary (alpha helix, beta pleated sheet)
3. tertiary structure (disulfide and other bonds)
4. quaternary structure (chains interact with each other)
Here is a really important example - hemoglobin - which has 2 alpha subunits and 2 beta subunits and a heme group.

Figure 5.16
Important to the topic of energy in physiology, amino acids can be used for energy, nitrogenous waste must be eliminated as urea.

Biological energy

Fig. 4.15
ADP plus phosphate <-> ATP involved in storage and release of energy [typo on transparency, but o.k. in book]
ATP made of Adenine, ribose and 3 phosphates, energy stored in 3rd phosphate bond
It is interesting to note that ATP delivers it's energy by transferring its phosphate to molecules (you will see this several times in diagrams throughout the semester)

Energy - kinetic and potential (discussing bioelectricity, potential will also be Volts)
BTU's (British thermal units, which can be converted to calories) imply that energy and heat are related.
Heat stored in energies of covalent bonds in kcal / mol
Free energy can be used for work = what is stored in bonds minus what is wasted as heat
cellular respiration C6H12O6 -> 6CO2 +6H2O + energy
the free energy is 686 kcal/mol
ATP to ADP
38 of them generated when respiration is complete
40.3% efficient, the rest is heat, usually considered as waste but useful in temperature regulation in warm blooded animals, homoiotherms, homeotherms.

Reminder - "count" "calories"= kcal
2000 per day for a sedentary adult woman
Important that we do not lose calories (through urine or feces) except through urine in untreated diabetes.
Marathon - 3000 Cal aerobic. 100 yd dash -anaerobic

We get our energy mostly from (1) glucose, (2) glycogen (glyco-sugar, gen-give rise to) in muscle for use in muscle and in liver for glucose release to blood, (3) amino acids (with NH3 as waste), or (4) fat (mostly fatty acids are chopped down 2 carbons at a time to give acetic acid into acetyl CoA in the Kreb's cycle).
Photosynthesis to make glucose, cellular respiration to release energy
Reaction [for glucose, C6(H2O)6]: C6H12O6 + 6 O2 -> 6 CO2 + 6 H2O
Overall, 1 glucose can give up to 38 ATP's, a few from glycolysis and the rest from the mitochondrion

Glycolysis and anaerobic glycolysis

Background
It is important to introduce NAD+ plus 2 H <-> NADH in oxidation - reduction reactions as a way to carry electrons.
lose electrons - oxidation (NAD+ is oxidized)
nicotinamide adenine dinucleotide
add electrons - reduction (NADH is reduced)

Fig. 5.3
Glycolysis is a compound word glyco-sugar, lysis-splitting. Glucose is split into 2 pyruvic acids
Use 2 ATP's make 4, net 2 make 2 NADH's plus 2 H+'s, the H+'s come from from "sugar"

Fig. 5.4
This was covered in muscle lecture
without oxygen, make lactic acid.
Anaerobic glycolysis is used to deliver ATP quickly but wastefully (squandering glucose).
Make ATP's but need to regenerate NAD+ from NADH to make.
Lactic acid contributes to fatigue in muscle and oxygen debt, and the liver eventually reconverts.
Anaerobic cellular "respiration" is needed in times of extreme exertion because the heart (cardiac output) is the limiting factor in delivery of oxygen to muscle.

Fig. 5.5
Polysaccharides
Glycogen - animal starch, polymer of glucose
High in muscle where it provides glucose for local use
High in liver where it provides glucose when fasting
Cellulose - cannot digest - "fiber"

Regulation by the hormone epinephrine (adrenalin)

Fig. 11.10
Epinephrine involved in stimulating liver to release glucose
Earl W. Sutherland, Jr. (from the US) won the 1971 Nobel Prize for mechanisms of hormone action.
It pertained to that beta adrenergic part and cAMP, a "second messenger" or part of a signal transduction "cascade."
So Sutherland is sometimes considered the founder of "signal transduction."
Note that there is a separate alpha adrenergic effect too

Glycolysis and the Kreb's cycle

Fig. 5.12
Pyruvic acids generate 2 acetic acids, become Acetyl CoA's.
Kreb's cycle = citric acid cycle = TCA (tricarboxylic acid cycle)
Takes place in the mitochondrion
A few ATP's are made plus NADH's and FADH2 are generated
CO2 is generated here.

The1953 Nobel prize in Physiology and Medicine was divided equally, one half awarded to: SIR HANS ADOLF KREBS for his discovery of the citric acid cycle and the other half to: FRITZ ALBERT LIPMANN for his discovery of co-enzyme A and its importance for intermediary metabolism.

sugar-H2 + NAD+ -> (DEHYDROGENASE) "sugar" + NADH + H+
(in other words, H is split to H+ and e-)
Electron transport and oxidative phosphorylation use oxygen
cytochromes - these are iron - containing pigments (iron is in the form of heme)
NADH and FADH2 give electrons to cytochromes and oxygen

Protons pumped, then flow down gradient making ATP's.
Something like an ion pump (we will covered that later in the semester) in reverse is how most ATP is made, H+ (pH, proton) gradient runs through that molecule, like water running through turbines generating electricity, to generate ATP

How does glucose get into the cell?

Fig. 6.16
Facilitated diffusion for glucose transport

Fig. 6.17
Insulin causes glucose transporters to be inserted to the membrane

Fig. 6.20
There is another kind of glucose transporter where Na+ (already pumped with ATP) drives it

Fig. 11.11
The receptor for insulin is a membrane spanning tyrosine kinase that dimerizes
Kinase means that the enzyme phosphorylates a protein
Tyrosine refers to the fact that phosphorylation is on tyrosine (an amino acid) residues.
Obviously, this would take place on the intracellular side of the membrane

***Metabolism

Control of metabolism
, Fox, Chapter 19 (also some other chapter figures, 11 and 3)

General considerations

Control of energy metabolism is so important that there are two major hormones (insulin and glucagon, proteins from the pancreas), as well as many others (thyroxine, epinephrine, and cortisol) to regulate it on short- and long-term bases.

In a lab...

...(BL A347, Fall, 2004), we injected insulin into mice, decreasing glucose, then injected glucagon, bringing it back up. Data: before: 157 mg/dl. after insulin 49, after glucagon 197.

More on insulin and glucagon

Fig. 11.29
In pancreas, which is largely a digestive exocrine gland, there are also islets of Langerhans (as shown in this picture from our histology course) which are the endocrine glands where the beta cells make insulin and the alpha cells make glucagon

Fig. (like 11.31a)
Pancreas Insulin- sugar uptake into cells (blood sugar down), make glycogen in liver

Fig. 3.23
2 peptides clipped from one chain held by disulfide bonds
(this sort of processing is common for signalling molecules)

Diabetes mellitus

Type 1 autoimmune disease beta cells are destroyed, young people, insulin dependent
inject insulin. protein, must inject
(vs steroid like "the pill" which can be taken orally)
Type 2, older people, genetic, correlated with overweight, non-insulin dependent
sugar in urine- can't pump back, in our physiology labs, we use these urinalysis strips which include a test for glucose in the urine. In the aforementioned endocrine lab, we introduced the students to this type of strip and meter for testing blood glucose.
Eye problems (too many new blood vessels - angiogenesis) and cardiovascular problems
Brain is not insulin-dependent - coma from too much insulin because no glucose for brain
Glucagon mobilize sugar to blood like adrenalin
sugar regulates insulin and glucagon

Glucose (and other calories)

Review


Fig. 19.2
Fat, carbohydrate and protein feed into metabolism
What you may not have seen before this figure is ketone bodies, produced from fatty acids in liver.
Low carbohydrate diet and diabetes can lead to ketosis, even ketoacidosis.
Note also that this figure shows that urea is the nitrogenous waste from using amino acids for calories.

Fig. 11.31
Blood glucose up, insulin up, glucagon down, cells use glucose
Blood glucose down, insulin down, glucagon up, glycogenolysis & gluconeogenesis (making of glucose from molecules like amino acids.

Fig. 19.10
The above is given in more detail relative to after meal vs fasting

What the liver does

Fig. 19.9
Here's what the liver does to release:
glucose (from glycogen and amino acids)
and
ketone bodies (from fat and amino acids)
When you fast, fat and muscle are broken down

Fig. 19.7
Opposite when insulin (and glucose) are plentiful:
Fat deployed (and not released) from adipose tissue
and
Glycogen deployed (and glucose not released) from liver

How glucose is monitored

Fig. 19.8
How glucose is monitored by a beta cell
glucose is transported in by GLUT2
metabolism makes ATP
ATP is ligand that closes K+ channel
cell depolarizes
voltage gated Ca2+ channel lets in Ca2+
exocytosis from vesicles with insulin

Signal transduction

Fig. 11.11
Insulin receptor is tyrosine kinase
a dimer
crosses membrane
binds insulin extracellularly
puts phosphates on tyrosine residues

Fig. 19.14
Like for epinephrine, receptor for glucagon is G protein coupled receptor
For the umpteenth time, I show you signal transduction cascade
One fact on this figure not shown before:
cAMP acts by binding inhibitory subunits and pulling them off catalytic subunits of PKA
The kinase phosphorylates enzymes, activating some and inhibiting some
end result, of course, is glycogenolysis in liver and lipolysis in adipose tissue

Glucocorticoids

Fig. 19.15
Glucocorticoids are also involved in stress (mobilizing molecules for catabolism)
Glucose, fatty acids, ketone bodies and amino acids in blood increase.
This is slower than for epinephrine

***Circulation

Circulation

Fox Chapters 13 and 14 (a figure from chapter 12)

Overview

In multicellular metazoan, need a vascular system (in terestrial plants above mosses, xylem and phloem)
Circulation : Cardiovascular system

Anatomy of the heart

TRANSPARENCY (Review, Introductory Biology)
Fig. 13.10
Chambers of heart
Birds and mammals have 4 chambers
Note that right is drawn on left as if looking into the chest of a supine subject (as I first mentioned when I lectured on Loewi's discovery of vagus stuff, acetylcholine)

Here is the circuit: LA - LV - Arteries (aorta, etc.) (blood pressure taken here) - Arterioles (regulate blood flow to muscles, brain, digestion, kidneys and skin) - Capillaries (near, exchange, WBC's) - venules - veins (no pressure, valves)- RA - RV - Pulmonary arteries - Lung capillaries - Pulmonary veins -

Heart valves and sounds

Fig. 13.11b
pulmonary valve (semilunar) feeds pulmonary arteries
aortic valve (also semilunar) feeds aorta
These valves snap shut from arterial back pressure at the end of systole to make second heart sound- "dub"
Superior and inferior vena cava feed right atrium -> ventricle via tricuspid (atrio-ventricular) valve.
Pulmonary veins feed left atrium -> ventricle via bicuspid (atrioventricular) valve.
Tricuspid & bicuspid snap shut at start of ventricular contraction to make first heart sound- "lub."
If there is backslosh through valves, this is called a heart murmur.

Blood vessels

Fig. 13.26
artery is like hose
blood flow to emptying into vascular bed: regulation by smooth muscle of arteriole
capillary is one layer of endothelial cells (fenestrated or continuous)

TRANSPARENCY (Review, Introductory biology)
Fig. 14.25
- blood spreads out as it goes from arteries -> arterioles -> capillaries and hence moves slower. Pressure goes down during movement arteries -> arterioles -> capillaries (bottom).

Fig. 13.29
Blood moves slowly and with very little pressure in veins. Movement in veins is mostly passive with a series of valves and where contraction of skeletal muscles helps

Fig. 13.36
Lymphatic circulation helps to percolate interstitial fluid back to circulation

Fig. 14.23
Shunts (arteriovenous anastomoses) help to regulate circulation through peripheral vascular beds.

Cardiac cycle and blood pressure

Fig. 13.16
cardiac cycle
Diastole (between heart beats), systole is during ventricular contraction, hence terms systolic and diastolic blood pressure.

Fig. 13.17
Ventricle fills during diastole.
Ventricle empties during systole.
Ventricular pressure builds during systole.

TRANSPARENCY Wiggers diagram
Relates ventricular pressure to arterial pressure.
Pulmonary pressure is lower than systemic.
Buildup of ventricular pressure opens valve and blood moves to aorta.
As ventricle relaxes, back pressure from artery snaps valve shut.

Ventricular filling

Fig. 14.2
Frank-Starling law.
The greater the ventricular filling, the greater the cardiac output.
This is good! -- recall that the tension length relationship for striated muscle had a peak, but, if the muscle got too long, less force could be generated.
This figure also shows that the sympathetic nervous system moves this curve up.

Measuring blood pressure

It is arterial blood pressure that is usually measured.

Fig. 14.30,
Fig. 14.31
close off artery, when it opens (systolic pressure), blood flow is turbulent and noisy (Korotkoff sounds), when it is always open (diastolic pressure), blood flow is no longer noisy
Blood pressure is measured in arteries
High blood pressure is called the "silent killer."
hypertension 45 million Americans - salt intake is still debated, >140/95 high 140/70 normal
high diastolic is especially bad

Explained by Wiggers diagram, if diastolic b.p. is high, then it takes higher ventricular pressure before valve opens and blood actually moves.

Regulation of blood pressure

Fig. 14.27
Blood pressure is regulated by sensory receptors in aortic arch and carotid sinus.
Goes to medulla oblongata of brain theh out to sympathetic and parasympathetic nervous systems.
There are also brain influences that come down via hypothalamus.

Myocardial cells

Fig. 12.32
Heart muscle cells branch and come together and are joiined at intercalated discs with gap junctions that spread the electrical signal from cell to cell.

cardiac muscle - automatic (explained below)
here is a picture from our histology course of heart muscle cells joined at intercalated discs
(like Figure 12.32)

Electrical activity of heart cells

Fig. 13.20
Electrical - SA (sinoatrial) node (or electrical pacemaker) - spread - automatic.
Sympathetic nervous system speeds it up, parasympathetic nervous system slows it down.
AV (atrioventricular node) is eventually stimulated.
If it were not, it is also automatic but slower and would generate a heart beat in the venticals.
Bundle of His, bundle branches, and Purkinje fibers get ventricular depolarization to happen almost synchronously.

Fig. 13.18
Pacemaker cells have depolarization during diastole because of slow Ca2+ channels.
Pacemake potential-HCN=hyperpolarization cyclic nucleotide (beta-1 adrenergic affects cAMP)
Spike is from Fast Ca2+ channels and Na+ channels
Repolarization uses K+ channels.

Fig. 13.19
Ventricular myocardial cells have long action potentials involving the specific channels shown.

The ECG

Fig. 13.24
Einthoven's triangle to show possible placement of EKG (ECG = electrocardiogram) leads.
Because a lot of cells in heart work together, and because extracellular fluid has high conductivity, electrical activity can be recorded non-invasively.

Fig. 13.22b
P is atrial depolarization.
QRS is ventricular depolarization.
T is ventricular repolarization.

Fig. 13.25
This figure relates EKG to pressure and sounds

Atherosclerosis


Fig. 13.26
(again)
Normally artery has
tunica externa
tunica media
tunica interna (endothelium and elastic layer )

Fig. 13.31
A layer of fat with cholesterol between media and externa
ulceration lining lumen
atherosclerosis - hardening of the arteries - plaques
atheroma with macrophages
Cholesterol is a problem

Heart attack

General:
Myocardial cells not regenerate (by mitosis in the adult). This is why heart attack is so damaging. The same is true for the nerves in the central nervous system where similar damage is called stroke.
Coronary arteries clog -> myocardial infarction - coronary thrombosis - ischemia (too little blood flow for oxygen delivery)
Angina, chest pain, and referred pain

Platelet aggregation - thrombus (local), embolism (from elsewhere) cause ischemia
tissue plasmogen activator (TPA) dissolve clots
streptokinase thru catheter dissolve clot
aspirin inhibits clotting, coumaden is a strong anticoagulant
catheter with balloon angioplasty insert stent

fibrillation - CPR (keep brain alive, needs O2)
In CPR (cardiopulmonary resuscitation) chest pressure keeps blood flowing a little and rescue breathing keeps blood oxygenated
1 million Americans die/yr reducing since 1971
bypass operations, replace coronary artery with vessel from somewhere else in the body, there are 100,000-200,000/yr operations - 30% may be unnecessary

"heart attack" - myocardial infarction
heart muscle is aerobic
anaerobic metabolism would build up lactic acid and cause pain (angina pectoris)
nitroglycerine relaxes smooth muscle (Viagra and other ED medications would be contraindicated)
heart muscle damage by necrosis (as opposed to apoptosis - programmed cell death)
can be detected in S-T of ECG
uncoordinated contraction of heart muscle - fibrillation
in atria fibrillation is not so important becaus atrial beat only addis a little bit to ventricular filling
in ventricles, it is fatal and hence the importance of defibrillators
re-entry of excitation as electrical signal takes long route around scar tissue after heart attack can contribute to poor ventricular coordination

Risk facrors for heart attack
(1) High blood pressure (the silent killer) -- Wiggers diagram --heart has to work harder to open semilunar valves.
(2) prior heart attack
(3) smoking
(4) diabetes
(5) family history - a dominant allele in hypercholesterolemia (and other genetic factors?)
(6) LDL-low density lipoprotein - made in liver - low LDL receptors help liver take up cholesterol
LDL receptors take out cholesterol which otherwise deposits
HDL may lower deposition - excercise good for this
(7) clotting, especially clumping of platelets) inhibited by aspirin (and coumadin) - hence term "coronary thrombosis" (in coronary artery)

Prevention -
(1) exercise - increase HDL (endothelial cells do not take up)
(2) antioxidants (oxidized LDLs in endothelial cells are bad)
alcohol in moderation (but people who die of cirrhosis rarely have atherosclerosis)
statins (box on p. 412):
(a) block rate limiting step in cholesterol synthesis in liver
(b) secondarily increase LDL receptors

Readings

S. Cohen J Leor Rebuilding broken hearts, Scientific American, November 2004, 44-51

infarct kills cardiomyocytes
noncontractile fibrous cells replace
adjacent healthy myocytes may die
(remodeling)
ventricle wall becomes thinner, distends, might rupture
heart failure
tissue engineering - must have scaffold for cells and blood supply
3-D sponge-like frame made alginate (from algae) frozen
progress so far- can prevent further damage
add controlled release microspheres of growth factors to help angiogenesis

Pacemakers (keep the beat) [working knowledge] M Fischetti, Scientific American, November 2004

wires run in through vein
tips have steroid reservoir to block early inflammation
that keeps contacts healthy
ICD - Implantable cardioverter defibrillator

***Respiration

RESPIRATION

Fox Chapter 16

"Plumbing"

TRANSPARENCY (review from introductory course)
Summarizes much of what will be said below, including the next transparency.
Nasal - moisture (smell) sniffing
Pharynx - larynx
Vocal cords larynx (laryngitis) "voice box"
Equal time to creationism : "Adam's apple"
Further down cilia sweep mucus, bacteria, dust up
(histology picture of cilia)
Cilia sweep from pharynx to esophagus (where you can swallow "crud")
Smoking paralyses ciliary sweep (more crud, less sweeping, famously asbestos is worse in smokers)

Fig. 16.4
Trachea - rings of cartilage to hold tube open like a vacuum cleaner hose
2 bronchi
Inflammation of the bronchi is called bronchitis.

Review chapter 9 material and note that sympathetic n.s. causes relaxation of smooth muscle (opening passageways) in lungs and parasympathetic n.s. constricts them (closing passageaways). The purpose is to regulate air flow.

Asthma caused by mast cells and eosinophils secreting leucotrienes, bronchioconstriction, use epinephrine to stimulate beta 2 receptors (note heart has beta 1 receptors). Epinephrine was in inhalers. Terbutaline is an anti beta 2 drug. Singulair is an antileukotriene. Because inspiration helps to open the bronchioles, breathing out (this is counterintuitive) is most difficult.

Alveoli 600 million in human 50 x skin area
Here is a picture from our histology course (like Fig. 16.18) showing how thin the cell layers of alveoli are.

Fig. 16.17
Emphysema - alveoli merge, often results from smoking, increased muscular effort in breathing- smoetimes they have a hunch back from using back to help breathe. These are the people older than they look pulling a dolly of oxygen around with them.

Fig. 16.20
[much like part of the figure from introductory course]
Air sacs (alveoli) are close to capillaries.
Note, red vs blue for arteriole vs venule is reversed for pulmonary circulation, obviously.
Recall, pressure lower in pulmonary circulation, and there is no regulation of flow to different areas as there is in systemic circulation.

Air Pressure

Fig. 16.18
Atmospheric pressure is measured in mm Hg

Fig. 16.19
Partial pressures of inspired air and alveolar air
Pressure relates to gas exchange.
In alveoli, H2O & CO2 higher and O2 lower for obvious reasons that we will chat about.

Fig. 16.22
Here is the cardio-respiratory system with blue blood (P O2=40, P CO2=46) and red blood (P O2=100, P CO2 = 40)

Lung volumes

Fig. 16.15 also here
Breathing in and out normally is called tidal breathing, volume about half a liter. There is an expiratory reserve, over a liter, and an inspiratory reserve, maybe 3 l. From the top of inspiration to the bottom of expiration is vital capacity. Even after you empty your lungs as much as possible there is a residual volume, over one liter.

A simple spirometer with a dispo tube to breathe into can be used cheaply to measure vital capacity, tidal volume and expiratory reserve.

A summary point: not all the air exchanges!

Ventillation

Fig. 16.7
Pleura, very slippery, and pleural cavity, slightly lower than atmospheric pressure, are important.
Pleurisy is inflammation of pleura, breathing is painful.
The low pleural pressure keeps the lungs open unless an injury lets air into cavity, "pneumothorax," collapses lung.

Fig. 16.14
Inspiration - pressure in lungs is lower than atmospheric, obviously, a word I seem to be using often, and expiration, pressure is higher.

Fig. 16.13
Muscles involved: intercostals and diaphragm mostly, and others as well.
Subtle differences for inspiration and expiration.

Fig. 16.11
Water's surface tension would tend to collapse (close) alveoli. Type II alveolar cells secrete surfactant (surface active agent), phosphatidylcholine plus phosphatidylglycerol, that decreases surface tension. RDS (respiratory distress syndrome) aflicts premature babies since surfactant production does not start until late.

Cystic fibrosis is from mutation in CFTR (cystic fibrosis transmembrane regulator), a chloride channel, results in viscous mucus.

Control of ventillation

Introduction: The receptors that are sensitive to changes in the concentrations of CO2 and H+ are located within the arterial system and the medulla of the brain. Excitation of these receptors trigger neural reflexes which alter the respiratory rate and depth. Additionally, other parts of the nervous system influence the basic ventilation pattern established by the respiratory center.

Fig. 16.24
Medulla rhythmicity center generates rhythm
Input from Pontine apneustic center (inspiration). Have you heard of sleep apnea?
Input from pontine pneumotaxic center counteracts inspiration.

Fig. 16.25
There are chemoreceptors in the aortic and carotid bodies, go to medulla in vagus (X) and glossopharyngeal (IX) respectively.

Fig. 16.26
This diagram adds a few items:
(1) Cerebral cortex over-rides. The funny thing about this information is that it is hard for you to think about how you breathe without you changinging how you breathe.
(2) There are important chemoreceptors in the medulla.

Fig. 16.28
Without the buffers that blood has, cerebrospinal fluid (CSF) on the other side of the blood brain barrier has CO2 and H2O -> carbonic acid generating H+ that affects receptors.

Summary. A common misconception is that variation in the O2 levels within the system cause changes in the ventilation rate. Actually, the O2 concentration, under normal conditions, has little to do with the determination of respiratory rate. The critical determining factor is the level of CO2 and/or the level of free protons circulating in the blood. For example, an increase in CO2 or H+ levels will induce changes which result in an acceleration of the ventilation rate and volume until these levels return to the normal range. Conversely, conditions associated with alkalosis and lower than normal CO2 levels depress the ventilation rate.

CO2 and CSF acidity are stimuli for breathing, and that is why oxygen given to patients has CO2 in it.

Fig. 16.28
Decreased breathing increases CO2 etc., resulting in a compensatory (there's that old negative feedback again) increase in breathing.

Fig. 16.27
Hyperventillation - blow off CO2 and desire to breathe less, can hold breath.

***Excretion

Excretion and homeostasis

Fox Chapter 17, one figure from Chapter 6

How the kidneys function is way more interesting than you may have thought. Summarizing, they throw the baby out with the bath water, then recover most of it.

Consider the work of the kidneys

Artificial kidney (dialysis) 10 hr 2 times per week
This is why transplant important, and there is difficulty getting a compatable donor.
Cell makes wastes that go into the plasma.
Heart pumps 7000 l/day (32 55 gal drums).
1/4 (8 55 gal drums) through kidneys
Glomerulus - Bowman's capsule passes (filters) 180 l/day.
And yet only 1 l of urine is produced per day.

Osmoregulation (for ions)

Review:
Hypertonic (concentrated), isotonic, hypotonic (dilute).
Nitrogenous waste (urea) is from catabolism of amino acids and nucleotides.
Ammonia (toxic) would be o.k. for small water animals where it can diffuse away.

Comparative biology

There is a tradition in undergraduate biology to emphasize comparative aspects:
Malpighian tubule in insects puts out uric acid and rectum recovers water and other molecules.
Uric acid is used in birds, reptiles, and insects, and water loss is minimized

The nitrogen story

Although 78% of the atmosphere is nitrogen in the form of N2, this is fairly unreactive.
Thus there are these important processes: N2 to NH3 nitrogen fixation, NH3 to NO3- (nitrate) nitrification, NO3 to NH3 (nitrate reduction) in plant roots.
Also nitrogen is recycled.
In Pacific, off the coast of Peru, the Humbolt current causes an upwelling of nutrients, anchovies thrive, bird droppings (guano) were used as fertilizer.
El Nino (the Child, named not for misbehavior but because it comes near Christmas) is a periodic climate misbehavior that disrupts this.

The uric acid story

In humans, mild accumulation of uric acid causes gout - crystals in joint cause inflammatory response which is treated by NSAIDS (non-steroidal anti-inflammatory drugs like prostaglandin inhibitors like indomethacin, ibuprophin, and aspirin). Enzyme is inhibited by chronic treatment with allopurinol. Genetically pathological uric acid accumulation which is Lesch-Nyhan syndome - children have bizarre self mutilation from HGPRTase (hypoxanthine guanine phospho ribosyl transferase) deficiency.

Functional anatomy

Fig. 17.1
kidney, ureter, bladder, urethra

Fig. 17.2
Kidney
Pelvis=basin; Medulla=marrow; Cortex=bark ("medulla" and "cortex" are terms used a lot, like in brain and in adrenal gland)
The blood supply is huge (1/4-15 of body at rest) and regulated (way less in stress)
Renal artery and vein branches near eachother
each kidney has 1 million nephrons:
Capsule, PCT, loop of Henle, DCT, collecting duct (this will be repeated in other figures)

Filtration

Fig. 17.5
Blood flow in glomeruli
Notice "afferent" (toward) and "efferent" (away from) arterioles, implies a portal system to next capillary bed iaround nephron and in medulla

Fig. 17.13
Glomerulus - Bowman's (glomerular) capsule
I picked just one figure, when the book uses several to develop the point gradually.
Blood pressure and osmotic pressure drives sieve
Green is protein that is too big to fit through.
Blue is all small molecules.
Na+ is actively transported, Cl- and H2O follow

Fig. 17.7
Fig. 17.9
Glomerulus - fenestrae (windows) in capillaries and slits between podocyte pedicels make up sieve.
here is a picture from the histology course
another picture highlights glomerulus by dye injected into artery
large molecules dye do not pass
- small molecules dye passes through
blood proteins and cells do not pass
urinalysis strips test if blood, cells or protein is present

Clearance test for filtration

Fig. 17.22
One test of kidney function, specifically filtration, is inulin clearance test
Inulin is an injected dye that is filtered but not resorbed.
Short of injecting inulin, an endogenous molecule, creatinine, can be assayed.

Resorption of glucose

Fig. 17.24
Proximal Convvoluted tubule - bring back amino acids, glucose note active (NaCl) vs passive (water) transport
Glucose is a special case.
(1) ATP is used in a Na+-K+ pump on basolateral cell surface
(2) glucose is cotransported with Na+ on apical cell surface
(3) Cells are joined so there are no other pathways
(4) recovery in capillary is by diffusion
Why an untreated diabetic has glucose in the urine is that this mechanism is saturated and cannot recover all of the glucose filtered from high blood glucose.

Resorption of salt

Kangaroo rat - metabolic water, hypertonic urine

Fig. 17.14
Ascending loop - salt resorbed but not water
Ascending loop of Henle - salt outward resorption is stimulated by aldosterone
Some passive water recovery is made possible because of high tonicity of interstitial fluid in the medulla.
This is called the countercurrant system

Fig. 17.18
A summary shows dilute in cortex, hypertonic in medulla

Secretion

Fig. 17.21
Kidney also secretes - pump out (penicillin)

Hormonal control

TRANSPARENCY (from an intro book)
ADH (vasopressin) makes water follow back into interstitial fluid which is hypertonic from salt
alcohol and caffeine inhibit ADH, hence diuresis (excessive urination)
affects water channels called aquaporins

Fig. 17.20
regulation of ADH by negative feedback (from hypothalamus to pituitary) and relation to thirst and water intake

Fig. 6.14
This same concept was covered way back in Chapter 6.
The relation of thirst to water conservation via ADH

Fig. 17.26
low blood pressure -> JGA (juxtaglomerular apparatus) makes renin

Fig. 17.27
Renin causes Angiotensinogen (liver) -> angiotensin II- closes arterioles
stimulates aldosterone

High blood pressure ->atrial natriuretic protein ->(-) aldosterone and renin

Sweat

Filter, resorb (salt and water)
Sweat pores not as good -which is why gatorade tastes good to athletes
especially bad in cystic fibrosis (salty sweat) molecular genetics shows a chloride channel defect

***Digestion

Digestion

Fox Chapter 18, figures from chapters 4, 6 & 19

Chemistry

TRANSPARENCY (From intro bio)
Fig. 18.1
break down long chain proteins, polysaccharides and nucleic acids into monomers
recall hydrolysis (opposite of dehydration synthesis) (hydro-water lysis-break apart)
if not broken down, proteins which are non-self would make a big antigen invasion

TRANSPARENCY (From intro book)
Tube - Alimentary canal

Input - output

Fig. 18.2
One emphasis will be on how the human digestive system invests many juices (hydrolases = enzymes which catalyse hydrolysis)
Some glands have ducts and these are called exocrine glands.
This is in contrast with endocrine glands (ductless, for hormones, which are also involved in digestion)

800 g food IN per day
1200 ml water
/
/ 7000 ml GLANDS
/
50 g solid OUT
100 g water

Overall anatomy

(from mouth to stomach)

Mouth - teeth, lubrication, salivary amylase to disaccharide maltose - starch tastes sweet (only starch in mouth)
-ase enzymes
Pharynx swallowing
Esophagus - bolus, peristalsis
Cardiac oriface

An integrative story

Rats cannot vomit (cardiac oriface cannot open for reverse peristalsis). They are very good at learning, in one trial, to permanently avoid tastes which make them sick. (You too may have developed a temporary dislike of foods you ate before getting sick.) They can only be poisoned by chemicals with a delayed reaction like Warfarin (warf = Wisconsin alumni research foundation) which is an anticoagulant. (It is also used in lower doses to prevent heart attack (coronary thrombosis).

Stomach

Fig. 18.5
Stomach - gastric mucosa - mucus protect

Fig. 18.6
from parietal cell: HCl kill bacteria
stop amylase
From chief cell: pepsinogen ---(HCl, pepsin))--> pepsin (proteolytic)
optimum pH for pepsin is 2
(Inactive forms called zymogens)
Heartburn, antacids, ulcer (although it is now known that a specific bacterium, Helicobacter pylori, is associated with ulcer)
very little absorption in stomach - exceptions: aspirin, alcohol

Fig. 4.4
The optimum pH for pepsin (proteolytic enzyme in stomach) is acidic while for trypsin (proteolytic enzyme in intestine) is slightly basic. And for salivary amylase, it is neutral.

Fig. 18.5 again
Pyloric sphincter regulates emptying of acidic gastric juice to duodenum.
In duodenum, bile from liver and bicarbonate and enzymes from pancreas add to enzymes from small intestine

Intestine:

enzymes - lactase, maltase, sucrase, others
mitosis - since cells digest themselves
absorption - food and water

Fig. 18.10
Villi (big) increase surface area. Note mitoses in crypts.

Here is a micrograph from our histology course dramatizing the tremendous increase in apical surface area of intestinal cells caused by the microvillar brush border.

Signalling by G-protein involving cAMP (covered earlier) is disrupted by cholera toxin - a life-threatening diarrhea, must replace fluids - salts and glucose (as in the electrolyte coctails athletes drink like Gatorade) facilitate water absorption

Fig. 18.12
The microvilli in the intestines have a special name, the brush border.
Protease (enteropeptidase turns trypsinogen into trypsin which, in turn, makes chymotrypsin and carboxypeptidase (and others)

Fig. 18.33
How proteins are broken down and absorbed is complex.
Trypsin and chymotrypsin are endopeptidases.
Carboxypeptidase, exopeptidase, cuts carboxy terminal.
Aminopeptidase (shown on brush border) cuts amino terminal.
Di- and tri-peptidases are intracellular.
Intestinal cells digest themselves, and their enzymes go into intestinal lumen.

Fig. 6.21
how glucose gets absorbed
same story as for kidney, and, in fact, notice "lumen of kidney tubule or small intestine"
apical, cotransport with sodium
basolateral Na+-K+ATPase plus glucose facilitated transport

Pancreas

Fig. 18.27b
Pancreas is responsible for dumping in many of the enzymes
Unit of this exocrine gland is the acinus
Zymogen refers to precursor of enzyme.

Table 18.4
"pro..." as in "procarboxypeptidase and "...ogen" as in "chymotrypsinogen" --a peptide fragment is cut off from a larger precursor protein to make active enzyme; there are many examples like this in biology, for instance prohormones cleaved to make active peptide hormones.
Pancreas puts out bicarbonate (alkaline) to neutralize stomach acid.
Optimum pH for for trypsin is 8.

Fig. 18.25
Pancreas and common bile duct (from liver and gall bladder) dumping into duodenum.
When I took organic chemistry lab (1966-7) we used gall stones for a cholesterol extraction.
Note: Islets of Langerhans (endocrine tissue) in pancreas where alpha cells make glucagon and beta cells make insulin.

Liver

Very few enzymes.
Emulsify fats.
Iron recycling.
Eliminate some wastes to feces.
Detoxify.

Detoxification

Portal blood veins (circulatory system "wired" in series is unusual, another famous example being the hypothalamus of the brain which feeds to the pituitary gland and kidney cortex to medulla). Via hepatic portal vein pick-up from small intestine is first delivered to liver cels. There, "microsomal fraction" (how biochemists view the smooth endoplasmic reticulum) has enzymes to detoxify. Enzymes like those that detoxify drugs like barbiturates are increased on exposure to toxins (inducible). Alcohol -(alcohol dehydrogenase (ADH) )-> aldehyde - (aldehyde dehydrogenase)-> acetic acid. With AcetylCoA, acetic acid can add to fatty acid chains 2 carbons at a time. There is a fatty metamorphosis of the liver from one binge. Continued heavy drinking leads to scarring and cirrhosis.

Fig. 18.22
Fig. 18.23
Erythrocyte iron recycling, bile pigment (bilirubin) ->urobilinogen turns feces dark.
Also colors urine.
Hepatitis (disorder which spills bile into blood) - turns skin yellow (jaundice) (feces are not as dark, urine is darker)

Fat digestion

Fig. 18.24
bile salts, salts of cholesterol, that emulsify fats

Fig. 18.35
Liver contributes to fat digestion

Fig. 18.34
Triglycerides are broken to monoglycerides and free fatty acids.

Fig. 18.36
Despite this breakdown, fats are reassembled, put in droplets with proteins and carried in lymph duct called lacteal.

Hormones

Table 18.5
Local hormones control digestion - Many found later in other places

Fig. 18.30
from stomach:
food stimulates gastrin which, in turn, stimulates gastric juice until there is a low (acidic) pH
from duodenum:
Cholecystokinin (CCK) - liver and pancreas
Secretin for bicarbonate release
Enterogastrones to slow gastric emptying

Appetite

It is worth mentioning that hunger and satiety are complex
In old work on brain lesions, LH (lateral hypothalamus) was called the hunger center, while the VMH (ventromedial hypothalamus) was considered to be the satiety center, but it never turned out to be so simple.
Hypothalamus is important in many motivated behaviors including thirst and sex drive.
Affect (the aspect of perception of goodness or badness of a stimulus) is linked through the nigrostriatal tract (bundle of nerve axons) which uses the neurotransmitter dopamine and which is deficient in patients who have Parkinson's disease.

Fig. 19.3
Now it appears that there is a hormone which is called leptin which is released by (well-fed) fat cells which causes the brain to decrease apetite.
Specific appetite for salt after adrenalectomy eliminates aldosterone.

Recent literature

Leptin

JKElmquist & JSFlier, The fat-brain axis enters a new dimension Science 304, 63-64, 2004 (Perspectives)

SGBouret, SJDraper & RBSimerly, Trophic action of Leptin on hypothalamic neurons that regulate feeding, Sci 304, 2004, 108-110

SPinto, AGRoseberry, HLiu, SDiano, MShanabrough, XCai, JMFriedman, TLHorvath, Rapid rewiring of arcuate nucleus feeding circuits by leptin, Sci 304, 2004, 110-115.

ob/ob mice are leptin deficient
arcuate nucleus of hypothalamus
orexigenic, Neuropeptide Y (NPY) and agouti-related protein (AgRP)
anorexigenic, proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART)
leptin regulates synaptic plasticity and axon guidance

***Hormones1

Hormones

Fox Chapter 11, part of chapters 2, 9, 19, 20

Introduction

Metazoans (animals with more cells than protozoans) require systems of integration
INTEGRATION: Hormones, paracrine (local) & nervous system
"endocrine" - ductless, into blood stream
vs. exocrine (like digestive - saliva etc.)

Three steps:
cells with blood vessels for release
hormone transported in the circulation
target cell with receptor

Two mechanisms
(1) receptor molecule on membrane
(2) enter cell and bind receptor

Overview

TRANSPARENCY (From intro bio)

Fig. 11.1
I. Traditionally, this material starts with a picture of the major glands

II. Then it covers Pituitary three ways
(1) posterior pituitary
(2) anterior pituitary as "master gland" (and the other glands it controls)
(3) anterior pituitary (affects not mediated through other glands)

III. Then it covers other glands (not controlled by the pituitary)

Based on feedback from the 2011 assessment, IV and V are covered in separate lecture outlines

IV. I will then give you a dose of "signal transduction" concentrating on steroids, thyroid and retinoic acid.

V. I will cover sex hormones in detail last (after glossing over them under II.(3) [above])

A later lecture outline, Reproduction, will take off beyond III. and V.

Posterior pituitary

TRANSPARENCY

Fig. 11.13
(related to kidney coverage)
neurosecretion from hypothalamus (peptides)
"suprachiasmatic" means over the optic chiasm
"paraventricular" means near the (third) ventricle
oxytocin (milk, delivery)
(synthetic to induce labor)
Covered in Excretion lecture: ADH action on kidney
vasopressin (ADH), H2O and blood pressure
alcohol, caffein inhibit anti [diuresis] hormone

Anterior pituitary

TRANSPARENCY

Fig. 11.15
Median eminence from hypothalamus to pituitary
Secretion of releasing (and inhibiting) hormones (peptides) at pituitary stalk
Portal system
Anterior pituitary and its hormones (peptides)

Fig. 11.14
(on right of figure) Master gland to show glands controlled by pituitary (thyroid, adrenals, ovary, testes) Trophic (tropins like "gonadotropins")
(on left of figure) not using other endocrine glands (Growth hormone and Prolactin)

Non-trophic hormones
(not where pituitary acts as master gland to control other glands)

GH - 200 a.a. -bone, muscle, not fat, -> liver to make somatomedins
GH - gigantism (bones grow long if too much GH when young), dwarfism (if too little GH when young), acromegaly (bones grow too thick if too much GH when already grown up, danger of GH abuse), abuse by body builders, dangers of extracts,, now available through recombinant DNA research

Prolactin - milk production, like GH (same ancestral gene)

Trophic hormones
(like gonadotropins) "Master Gland"
sex hormones from pituitary (more details later):
LH (female) = ICSH (male); (luteinizing) (interstitial cell)
FSH (follicle)
non-sex trophic hormones from pituitary:
TSH (thyroid)
ACTH (adrenal cortex)

TRANSPARENCY (again or still)
Review - same material, intro course

Thyroid hormones

(recall that thyroid was used as hormone example in first lecture outline)
Influence on metabolism, but not as obviously as epinephrine, insulin, glucagon or even glucocorticoids.

Fig. 11.25
Negative feedback with pituitary
Hypothalamus -TRF-> + Ant. Pituit. -TSH->+ Thyroid -> thyroxine-
- neck thyroxin (T4), triiodothyroxine (T3) iodine, sea food (and iodized salt)

Fig. 11.3 (also shown in an earlier lecture)
T3 and T4

Figs 11.24, 11.26
Goiter (thyroid overgrows if too little iodine in diet)
Cretinism if too little in infant, hypothyroid, hyperthyroid
Change in salmon during salt to fresh water change, metamorphosis in frog
Problem of radioactive iodine (like from reactor leaks) - helps to take large doses of non-radioactive iodine to compete

Adrenal gland

Fig. 11.20
Adrenal cortex - Glucocorticoids stimulate metabolism, inhibits inflamation.
JFKennedy had too little glucocorticoids (needed replacement therapy) which would create a situation of no feedback - too much ACTH (darkens skin like MSH).
pro-opiomelanocortin - big peptide cleaved to ACTH, MSH, endorphins, enkephalins
Emphasize regulation, negative feedback

Fig. 11.18
Zona glomerulosa - mineralocorticoids
Zona fasciculata and reticularis - glucocorticoids and androgens
Mineralocorticoids, the best known being Aldosterone helps kidney retain salt
Adrenalectomy causes salt loss and salt appetite.
Sweat glands are not as efficient at retaining salt as kidney.
That is why "Gatorade" (electrolyte) is used by athletes.
Salt is also lost in cystic fibrosis (mutation of CFTR (cystic fibrosis transmembrane conductance regulator)

Female reproductive cycle

good example of Regulation, Negative feedback
CHAULKBOARD DIAGRAM
Hypothalamus - RF's (peptides)
(chaulkboard diagram is also here, peptides in black, steroids in red)
Pituitary makes peptide hormones "gonado-trophic hormones" (gonadotropins, FSH and LH)
gonads (ovaries) make steroid hormones (estrogen and progesterone)
Feedback system plus effects on endometrium (lining of uterus)

FSH (follicle stimulating hormone) stimulates estrogen release from follicle
estrogen inhibits FSH
estrogen turns on LH (lutenizing hormone) release
estrogen begins buildup of endometrium
surge of LH causes ovulation
then follicle becomes corpus luteum that puts out progesterone
progesterone inhibits LH and FSH
progesterone also stimulates buildup of endometrium
to finish cycle, low FSH & LH which lets estrogen and progesterone go down
(corpus luteum starts to go away)
with low estrogen and progesterone, endometrium breaks down (menstruation)
with low estrogen and progesterone, pituitary is not inhibited so FSH starts
(if pregnant, HCG [human corionic gonadotropin] maintains corpus luteum
progesterone (from maintained corpus luteum) maintains endometrium
Here is a primary follicle, a growing follicle, the mature follicle, and the corpus luteum from our histology course.

Human corionic gonadotropin
Menstruation in primates
Estrus cycle - dogs heat 2x/yr, cats 3x/yr
Rabbits reflex ovulators
Pill Progesterone and Estrogen inhibit ovulation
28 day pill 7 duds: 1st 4 days, last 3
"combination pill"
Weight gain, circulation problems
lower proportion of estrogen
Rhythm - sperm viable 48 hr, ovum 15 hr: 3-4 day abstinance

The male pattern
FSH for spermatogenesis
LH (ICSH) to stimulate interstitial cells to release testosterone

Glands not controlled by pituitary

Adrenal medulla


Fig. 9.8
while on the topic of the adrenal gland,
Adrenal medulla (vs cortex under pituitary control)- Epinephrine, (alias adrenalin) - activates body
Autonomic (vs voluntary) motor control: sympathetic (vs parasympathetic)
Sympathetic nervous system uses norepinephrine at postganglionic synapses.
Sympathetic - "fight or flight"
Helps in metabolism to release glucose to blood stream
Muscles activity up, peripheral circulation and digestion inhibited
Heart rate goes up

Glucose (insulin and Glucagon) and diabetes
was moved from here to earlier

Calcium homeostasis

TRANSPARENCY (From introductory book)
Thyroid 2 glands (pituit - thyroxine TSH) vs:
Thyroid - thyrocalcitonin - blood Ca2+ down
Parathyroid - parathormone - blood Ca2+ up (from bones)
near thyroid gland in neck
Vitamin D sunlight, rickets, fish oil, hormone, absorption from gut
Osteoporosis - bone deterioration with age especially in women
Ca2+ very important, muscle (later), nerve (later)

Fig. 11.28
review, parathyroid hormone

Fig. 19.18b
PTH increases blood Ca2+
Osteoclast uses enzymes and acid to dissolve bone CaPO4

When calcium is needed a lot, bone depleted.
Osteoporosis, more common in women because of Ca2+ use in lactation.

Fig. 19.22
PTH effect on bone shown again here plus:
In kidneys, Ca2+ reabsorption is increased
and
In kidneys, 1,25-Dihydroxyvitamin D3 is made
(and that, in turn, increases intestinal absorption)

Working the vitamin D topic backward:

Fig. 19.21
kidney enzyme (1-alpha-hydroxylase) acts on 25-hyrdoxyvitamin D (from liver)

and

Fig. 19.21
Vitamin D from sunlight in skin
(plus liver and kidney shown in this figure)

Fig. 19.23
Calcitonin from the thyroid does the opposite

***Hormones2

Hormones2

Fox Chapter 11, part of chapters 2, 9, 19, 20

Steroids, etc

Fig. 2.23
structures of steroids
Structures of cholesterol, cortisol, testosterone, estradiol

Fig. 11.2
reactions of steroids
shows structures and locations of secretion
Interestingly, Cholesterol -> -> Progersteone (corpus luteum) -> ->Testosterone (Leydig cells) -> estradiol (follicles).

Fig. 11.5
steroid hormone receptor is protein that dimerizes
each receptor binds an HRE (hormone response element) (DNA sequence)
mechanism of hormone action is to activate gene transcription (into mRNA)

Estrogen

Menopause (pause in the menes) ["change of life" at about 50] - lack of estrogen.
(Some hysterectomy or ovarian cancer surgeries might also deplete because of ovarectomy).
Many symptoms, hot flashes most obvious short term effect.
Osteoporosis most obvious long term effect.
For me, this site worked with explorer, not netscape - estrogen (hormone) replacement therapy
Hotly contested (a lot of negative press lately), partly because estrogen increases chances of breast cancer.
There is a drug, Tamoxifen that blocks estrogen's effects, differently in different tissues.

Recent literature

J.L.Turgeon, D.P.McDonnell, K.A.Martin & P.M.Wise, Hormone therapy: Physiological complexity belies theraputic strategy, Science 304, 1269-1273, 2004
Estrogen and progesterone receptors in cardiovascular, neural, immune, gastrointestinal and musculoskeletal systems.
Menopause (average age 51) vasomotor flashes, vaginal dryness, urinary symptoms, osteoporosis, CHD (coronary heart disease.
Hence chronic estrogen therapy (ET) for CHD and osteoporosis.
A well intentioned study, WHI (women's health initiative) tested placebo, estrogen & estrogen-progestin.
Discontinued because of increase in breasst cancer, CHD, stroke and venous thromboembolism (but they did decrease fractures and colon cancer)
Human ovary: 17beta-estradiol.(E2) AND estrone (E1)
Study used conjugated equine estrogen (CEE) extracted from pregnant horse urine, many estrogens including sulfated estrogens.
Why this matters is that there are several types of estrogen receptors differentially activated by different estrogens.
Study used continuous oral administration, and hormone through hepatic portal system highly activates estrogen receptors in the liver, changing important proteins like angiotensin precursor.
Transdermal patch would be very different.
Women is study were fatter than usual.
Human progesterone vs study's medoxyprogersteone acetate (MPA), again affecting different receptors differently, also MPA activates glucocorticoid receptor.
There are several estrogen receptors, alpha and beta. and many ways they influence transcription.
"Antiestrogen" tamoxifen is antagonist in breast but agonist in bone and uterus, so now called SERM (selective estrogen receptor modulator).
Better SERMs are being found.

Androgens

Anabolic steroids - muscle growth, bone growth, increased hemoglobin
There is an androgen from the adrenal - DHEA dehydroepiandrosterone
Increased secretion of testosterone at puberty has many obvious effects including on larynx
Absence of androgens by castration decreases seminal vesicle and prostate
The whitish structure in this figure is the seminal vesicle
In this figure, the seminal vesicle of castrated and normal mice are compared

Fig. 20.13
Interestingly, many of testosterone's effects are mediated by estradiol-17beta, made by aromatase (in a process called "aromatization," note aromatic [in the organic chemistry sense] ring).
DHT (and several subsequent metabolites) made by 5alpha-reductase

Fig. 20.7
This step takes place in cells

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

Some wierd disorders

5alpha-reductase deficiency -> "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

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"

Signal transduction

TRANSPARENCY (From introductory book)
"gene"
sequence coding for protein (mRNA) is copied from exons with introns spliced out
"upstream" of gene, proteins binding promoter and enhancer regulate transcription

Fig. 11.4
steroid hormone
Carrier protein, receptor, DNA

Fig. 11.6
thyroid hormone
Carrier protein-T4, receptor-T3, DNA

Fig. 11.7
thyroid hormone
involves retinoic acid

Fig. 11.8
Remember signal transduction for G protein coupled receptor

TRANSPARENCY (From introductory book)
integrates the above point with epinephrine evolution of glucose

Prostaglandins, etc

Fig. 11.34
prostaglandins (mediators of inflammation) are derived from fatty acid (arachidonic acid, 20:4) using cyclooxygenase (COX)
Prostaglandins have different actions in different places; take platelet aggregation -- TXA2 stimulates clumping, PGI2 prevents them from sticking to walls of vessels; it is the TXA2 aspect that is why you take aspirin to prevent heart attack and should not take aspirin before surgery (etc.).
leukotrienes (mediators of inflammation) ... use lipoxygenase
NSAIDS (non-steroidal anti-inflammtory drugs) aspirin, ibuprofen, inhibit prostaglandin synthesis by inhibiting cyclooxygenase (COX-1 & 2) nonspecifically, problems in stomach
Celebrex, Vioxx, Bextra inhibit prostaglandin synthesis by inhibiting cyclooxygenase (COX-2); popular for arthritus, but Merck pulled Vioxx 10/04 for increasing cardiovascular problems, and later Bextra was pulled.
Aspirin is anti-inflammatory, anallgesic, antipyretic, anticoagulant, implicated in Reye's syndrome.

The Biology department's primary expert on endocrinology is Dr. Asa who is director of research at the St. Louis Zoo. As an adjunct Professor in SLU's Biology department, she teaches the popular course, "Introductory Endocrinology" BL A450-01

***Reproduction

Animal Reproduction and development

From speech of Aristophanes:
...The sexes were not as they are now...the primeval man...had four hands and four feet, one head with two faces...Terrible was their might and strength...and they made an attack upon the gods...Zeus...said: "Methinks I have a plan which will humble their pride and improve their manners; men will continue to exist, but I will cut them in two...After the division of the two parts of man, each desiring his other half, came together, and throwing their arms about one another, entwined in mutual embraces, longing to grow into one...
-Plato Symposium

Love (sweet Chloe) is a god, a young Youth, and very fair, and wing'd to flye... His power's so vaste, that that of Jove is not so great... For there is no med'cine for Love, neither meat, nor drink, nor any Charm, but only Kissing, and Embracing, and lying naked together.
-Daphnis & Chloe By Longus Translated out of Greek by George Thornley Anno. 1657


Fox Chapter 20

MALE

Meiosis and sperm


Fig. 20.15
Spermatogonia (mitosis and meiosis) - primary spermatocytes
- meiosis (both divisions) - spermatids (scrotum cooler)
Sperm (meioses throughout adult life) Seminiferous tubules
300 million/ ejaculation

Fig. 20.12
Testes - seminiferous tubules make sperm, stimulated by FSH, inhibin for feedback
Interstitial (Leydig) cells produce testosterone, stimulated by LH (ICSH), feedback

Fig. 20.11
Low mag section of testis, higher mag showing seminiferous tubule and interstitial cells
Testes in short day hamsters are smaller than in long day hamsters

Fig. 20.16
An even higher magnification showing Sertoli cell that supports spermiogenesis, has histology
(Here is a picture from our histology course)

Semen

Fig. 20.20
male anatomy
Semen:
Bulbourethral (Cowper's) gland (early overflow from sexual excitement)
Seminal vesicle - fructose, amino acids, mucus, prostaglandins (uterine contractions)
Prostate - alkaline (infection, cancer most men > 50)
Capacitation of sperm
Epididymis
Vas deferens - peristalsis -(vasectomy 100% effective- permanent long term effects unknown)
Urethra (of course, it is output here for which condom is a form of contraception)

The prostate story.

Recent paper

MBGarnick, The great prostate cancer debate, Scientific American Feb 2012, pp 38-43
Monitoring is used more, surgery is used less

Cancer in men >50, diagnosed by paplation
PSA=prostate specific antigen, 1 is low, 5 is high, but not specific to cancer, might be high after having sex
Several "remedies" including selenium
Surgery and radiation, etc.
Slowly developing cancer
Complications - incontinence (for #1, even #2), possibly impotence (ED)
For ED, Viagra, Levitra, Cialis

Fertilization

Many sperm attack one egg, only one fertilizes - fast (electrical) response prevents others

20.38
acrosome, nucleus, mitochondria (not go into egg), flagellum

Review:
Parasympathetic arterioles (unique, usu only symp.) - erection (sleep)
ACh - NO - smooth muscle dilate- viagra blocks breakdown enzyme
NO synthase in cavernous artery and corpus cavernosum
Robert F. Furchgott, Louis J. Ignarro, Ferid Murad Nobel 1998 "for their discoveries concerning nitric oxide as a signalling molecule in the cardiovascular system"
Sympathetic - ejaculation inhib erection

Fig. 20.20
Here is a picture from our histology course showing the spongy tissue of the corpus cavernosum which becomes engorged with blood to mediate erection.
rodents racoons walruses - bone
Sympathetic - ejaculation inhib erection

FEMALE

Review


Fig. 20.33
Here is the typical text book diagram depicting the menstrual (ovarian) cycle (covered earlier)

For convenience, I used the term "eggs" earlier, now I get more official

Meiosis, ovary, steroids

Fig. 20.31
I showed this to you before
primary oocyte in early follicle
secondary oocyte in mature follicle

Fig. 20.30
Here's how that relates to meiosis
Primary oocyte (2-4 million at birth, 1st meiotic prophase)
(400,000 at puberty, only 400 used)
(no oogonia after 3 mo)

Secondary oocyte + polar body
(Graffian follicle finish 1st meiosis) ovulation
if 2 ovulations - DZT - 2 amnions, 2 chorions
twins 1.2% of births, of these 70% "fraternal"
DZT run in family

Uterus, fertilization, and early development

Fig. 20.23
Review
I showed this to you before
anatomy of ovary, and relation of ovulation to fimbriae of uterine (Fallopian) tubule
Tubal ligation (laparoscopy) 100% effective. Reverse?
Cervix (diaphragm, cervical caps, foam, spermicidal jelly)

Fig. 20.41
Fallopian tube (fimbria capture ovulated egg - Sperm meets, 2nd meiosis makes ootid 3 polar bodies discarded nucleii
Division in Fallopian tubes
Blastocyst (trophoblast, blastocoel, inner cell mass)
(trophoblast - >chorion -> placenta)
(inner cell mass -> embryo -> fetus)
IUD prevent implantation, irritate, after previous child, not for everybody legal question
if inner cell mass divides, Monozygotic (identical) twins MZT (2 amnions, 1 chorion), 30% of twins

Fig. 20.43
Shows trophoblast, implantation and a little development

While I have this up, I will talk about "stem cell research"

This relates to cloning.

Cloning

(Not cloning as in cloning a gene, but cloning an organism)

1950's work on amphibians - Since all nuclei should have all the genes, any nucleus should work to make whole organism, taken out of, for instance, an intestine cell. But not all cells work, so put the nucleus into an egg where it is certain that the nucleus already there has been destroyed.

work to make sheep Dolly. Nuclear transfer by removal of egg nucleus followed by fusion with cell with diploid nucleus. Need to implant into a surogate mother.

Cloning has been extremely controversial, and human "reproductive cloning" is banned. Some scientists hoping to advance medical treatments would like to distinguish "theraputic cloning" from cloning to produce a person genetically identical with the donor. Some think the issue would be simplified by use of the term "nuclear transplantation."

Stem cell research

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 were collaborating to cure blindness in a mouse mutant with cells that started as embryonic and were induced to become precursors of nerve cells; identified by green fluorescent protein, here is a cell that has been put into the retina and is beginning to show a neuron-like phenotype.

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

Cursory overview of development

Fig. 20.45
trophoblast implants becomes chorion -
Chorionic villus biopsy - early genetic testing
Amniocentesis-later genetic screening
placenta - exchange, diseases like rubella, alcohol, drugs

Fig. 20.44
make HCG 2 wks - 4 mo (pregnancy test)
to maintain corpus luteum

Fig. 20.5
(not graphic)
2 sexes from 1 primordium
H-Y antigen = testes differentiating factor
then testosterone alters development
MIF (Mullerian inhibiting factor) contributes to development of male "plumbing" female pattern is the default pathway, clitoris is equivalent of penis

Prof Aldridge teaches several courses and does research on reproduction. Prof Ogilvie teaches developmental biology.

***Blood and the immune system

Blood and antibodies

Fox Chapter 15 (immune system)
also part of Chap 13 (for blood)
A figure from Chapter 20

Fig. 13.1

Overview of blood cell types

plasma and hematocrit (formed elements), Buffy coat between

I. Plasma - (serum lacks fibrinogen) fluids, nutrients, O2, CO2, ions
proteins (synthesized in liver except gamma globulins)(clotting)
Albumins
Globulins
Fibrinogen

II. Hematocrit
Erythrocytes 5-6 million/ml
Leucocytes 5-10 thousand/ml
Platelets 250,000-400,000/ml formed from megacaryocytes
(antibodies) ions, wastes, hormones

Blood clotting

Fig. 13.9
Platelets 250,000/ml from megacaryocytes
Clotting Platelet adhesion then fibrin (from fibrinogen)
Cascades
activated Hageman factor
prothrombin -> thrombin
fibrinogen ->fibrin
Hemophelia is famous disorder

Hemophelia (4 SLIDES)
Pix from Curtis and Barnes also Ritchie and Corola also Johnson et al textbooks long ago
pedigree
Victoria, family
Nicholas II & Alexandra - Alexis, Family
Rasputin
on X
problem with AIDS for clotting factor

Erythrocytes

Fig. 13.3
Red blood cells (corpuscles) (erythrocytes)
no nuclei
O2 transport, hemoglobin, anemia
last 120 days, made in marrow, recycled
iron recycling in liver is what makes feces dark (and skin yellow in jaundice [hepatitis]) - bile pigments

Polymorphonuclear granulocytes

There are non-specific responses to injury

White blood cells (leucocytes as in leukemia)
Polymorphonuclear granulocytes (phagocytosis, etc)
neutrophil (60-70%) phagocytosis
here is a picture from our histology course of a neurtophil showing the complex nucleus

Fig. 15.2
chemotaxis after 30-60 min
more synthesized especially in bacterial infection
reset thermostat (pyrogens)
eosinophil (1.5%) phagocytosis
allergic and parasitic inflamation
basophil (0.1%) histamine containing
like mast cells

Phagocytosis and review slides

Fig. 15.1
Phagocytosis (cell eating), fusion of primary lysosome, formation of secondary lysosome

SLIDES:
blood cells (SEM= scanning electron micrograph))
white blood cell engulfing bacterium (Light Micrograph) (Ritchie and Corola)
white blood cell engulfing bead (SEM)
Pix from Jaret paper, June1986 National Geographic
macrophage eating E. coli
macrophage - asbestos
fibrin SEM
fibrin LM (Ritchie and Corola)

Monocytes

Fig. 15.6
Mononuclear cells
monocytes (5%) (as in mononucleosis) (phagocytosis)
late chemotaxis become macrophages
alveolar macrophages in lungs
Kupffer's cells in liver

Inflammation

Fig. 15.5
Inflammation and phagocytosis
Triad redness, warmth, swelling
Histamine (from mast cells, platelets)

lymphocytes:

There are specific responses involving antibodies and other mechanisms

T-cells (80%) (thymus - near heart) cell
(transplant) cytotoxic, suppressor, helper (AIDS)
B-cells (20%) (bone marrow, actually bursa of Fabricius) (become plasma cells)
antibodies

Blood groups

Fig. 13.5
Blood groups
This topic is fundamental and a bit confusing.
genotypes IA IA or IA i have phenotype A, A antigens, anti-B antibodies
genotypes IB IB or IB i have phenotype B, B antigens, anti-A antibodies
genotype IA IB has phenotype AB, A and B antigens, no antibodies
genotype ii has phenotype O, no antigens, antibodies to both A and B
O universal donor, AB universal recipient
There are already antibodies since blood group polysaccharides are like those of bacteria even though there was no previous exposure to antigens. IgM not cross placenta

Rh factor

- mother and + fetus problem if blood crosses over (during delivery)
problem is next time since IgG crosses placenta
treat mother with antibodies (passive immunity) then she will not mount active immunity

Active and passive immunity

When I was a kid, nearly everrybody got measles, mumps, and chicken pox. We were presumably immune for life (active immunity). When we had the disease was part of out health record.

Vaccines - active immunity (like disease)
memory cells of immune system
Edward Jenner 1796 "encowment"
Farmers were less likely to get smallpox because they got a related disease, cowpox
When I was a kid, you could not enroll in school without the scar
Smallpox is so completely eliminated that one issue is whether to get rid of lab virus.

When I was a kid, there was (still) a polio epidemic.
A kid at a birthday party I went to got polio, so I went to the family doctor for gamma globulin, passive immunity
(1954 Salk vaccine injected, soon Sabin vaccine in sugar cube)

Fig. 15.13
lymph system and nodes

Antibodies

Humoral immunity - B cells

Fig. 15.21
clones of plasma cells and memory cells derived from B cells for specific antigens

Fig. 15.7
Another version of this figure

Fig. 13.4
(showing only erythrocytes)
Interesting continued development through life of monocytes, granulocytes and lymphocytes from stem cells
note, the bone marrow which makes blood cells is mostly in the head and ribs, the two most likely locations for X-rays which are dangerous

Fig. 15.8
Antigen (virus or bacterial coat, usually not self)
Antigenic determinant (epitope 5-15 anino acids)
IgD on B cells, antigen receptors

Fig. 15.8b
Antibody
2 long chains and 2 short chains, variable region at the end of all 4 makes it specific for antigen
An amazing mechanism where the gene is rearranged accounts for diversity.
IgG most abundant, monomer, cross placenta

Fig. 20.54
Antibodies cross placenta, also in mother's milk, and late weaning covers until child's own antibodies are formed.

Fig. 15.23
IgE allergy, bind to mast cells (histamine)

T-cells

Fig. 15.15
helper T cells express CD4
antigen presenting macrophage
MHC major histocompatability complex 20 genes 50 alleles each
Class II MHC only on macrophages (and B lymphocytes)
antigen presented by to B cell

Fig. 15.16
cytotoxic (killer) T cells express CD8
Class I MHC - actually on lots of cells (including the infected cellsshown here)
[try to match MHC (tissue typing) for transplantation]

Fig. 15.17
Interleukin-2 is released by helper T cells to cause killer and helper cells to proliferate***Touch and Motor

Sensory and motor systems

Text: selections from Chapters 8 & 10

Personal reflection

Though broadly trained, my Ph.D. and my first job (Assistant Professor) were in psychology. It was only in 1979 that I moved to biology. Long ago, I learned of certain brain studies after transecting the spinal cord in animals: the encephale isole, French for the isolated brain. This is much like the preparatioon the Nobelist Sherrington used for studies of spinal reflexes. I came to view studies above the transection as psychology and below as physiology. Thus, to me, the somatosensory system and the motor systems seem more in the jurisdiction of a physiology course than special senses such as vision & audition.

Review


Fig. 8.28
Spinal cord has white matter (myelinated tracts)
and
Gray matter (cells and synapses)
Dorsal root ganglion has cells for sensory input
Ventral root has output (motor) axons
Unit of behavior is reflex
In addition,
Sensory information goes to brain
and
Motor output comes from brain
and that is what this outline is about

SENSORY

Touch (somesthesis) and motor representations in the cerebral cortex


Fig. 8.6
"This is your brain. This (colorful diagram) is your brain in BL A260 class"
Brain, central sulcus with post-central gyrus (somatosensory projection)
and pre-central gyrus (motor area)
Many other aspects of "localization of function" for cerebral cortex are shown here:
auditory area, visual area, Broca's area (speech)
Note also the cerebellum, an area devoted to motor coordination.

General and historical

A very compelling sense, from the pain of a tooth ache to the ecstasy of an orgasm
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 (around 1900) - 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 in the skin

Fig. 10.4
Cutaneous receptors
The different types of receptors (in general, free nerve endings and encapsulated):

Free nerve endings
for pain, temperature and crude touch

Pacinian corpuscle - rapid adaptation
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 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
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
static discrimination of shape

Not in diagram

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

Krauss in lips and genitals (dry vs mucous skin)

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)
cold related to menthol
hot related to capsaicin

Nociceptors
some mediators of pain are in sting venoms
Also tissue damage substances: serotonin (platelets), prostaglandins, leucotrienes, histamine from mast cells, substance P , bradykinin from blood borne precursor
enzyme from injury, receptor is chemoreceptor
nociceptors are in many places, but not in brain, hence brain surgery under local anesthesia used im mapping studies in humans by Penfield

Spinal cord

Fig. 8.24
input into spinal cord
(does not include face & head which enter via cranial nerves [trigeminal])

LEFT SIDE OF FIGURE
Lemnicsal system is for localized touch.
Lower limbs are handled medially in fasciculus gracilis.
Upper limbs are lateral in fasciculus cuneatus.
ipsilateral projection
First nucleus is in lower medulla
There is a cross-over, medial lemniscus and then the next nucleus is in the thalamus.

In projection to the brain, there is processing - lateral inhibition to sharpen spatial localization
If you tap your forearm, there are big waves but you feel localized touch.

RIGHT SIDE OF FIGURE
spinothalamic for pain and temperature
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."
Touch can inhibit inhibit pain (a hard touch to a door knob makes an electric shock less annoying)

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)

referred pain for viscera is interseting
notably, blatter stretch receptors localize pain to genitals
heart attack in neck and left arm

Brain

TRANSPARENCY (from intro book)
Just to show you that the material in your next transparency can also be found in the freshman biology book.

Fig. 8.7

RIGHT SIDE OF FIGURE
sensory magnifications
Penfield - homunculus

MOTOR

Motor systems


LEFT SIDE OF FIGURE
topographic map of motor cortex- compare with corresponding sensory homumculus
work by neurosurgeon Penfield, note relative "magnifications"
toes (thought to curl with sexual excitement) in motor cortex across from genital projection in postcentral gyrus.)

Fig. 8.25
Pyramidal system with corticospinal tract
Corticospinal tract Pyramidal motor system (75-90% crosses) 10 to the 6th axons
named because it goes through pyramids on ventral medulla
(though it might have been named from pyramidal shaped neurons in layer V incl. Betz cells)
lateral and anterior pathways
Initiation of voluntary motor movements

output for face and upper body via facial nerve (and trigeminal, vagus, accessory, hypoglossal)

Basal ganglia (nuclei)

Fig. 8.11
Not just motor cortex, but huge parts of cortex feed to basal ganglia (and cerebellum).
Extrapyramidal (because it lies outside the pyramids)
caudate + putamen = striatum (striated because strands of internal capsule make it look striated)
putamen + globus pallidus = lentiform nucleus [lens shaped] (see sheep brain horizontal section)

Fig. 8.21
inputs to basal nuclei
substantia nigra (nigrostriatal dopamine system)
(also in medial forebrain bundle [through lateral hypothalamus] is the mesolimbic dopamine system.)

outputs from basal ganglia
The globus pallidus is a relay nucleus for the caudate and putamen and so is the subthalamus.
To VA/VL complex of thalamus to motor cortex

Disorders

Parkinson's see synapse lecture

Huntington's (1872) disease (chorea) choreoathetosis
Dominant late onset - many interesting genetic counseling issues. The Folk singer Woodie Guthrie died of Huntingtons. There is a big family tree derived from Venezuela near lake Maracaibo
On post-mortem, degeneration of putamen and caudate is observed.
It is on short arm of chromosome 4
1983 and since: cloning -CAG repeat (polyglutamine repeat), 15-34 (normal) -> 42-66 (Huntington's)
Other trinucleotide repeat diseases: fragile X syndrome, myotonic dystrophy, and others
sometimes they get worse from generation to generation (anticipation)
in some ways, Huntingtons is the opposite of Parkinsons in that circuit has thalamus increasing excitation to cortex.

Cerebellum

Dysmetria (cannot approach target), ataxia, intentional tremor if cerebellar damage
cerebellum highly developed in electric fish
cerebellum is involved in rhythmic activity and plasticity
An additional decussation makes it so that cerebellum controls the ipsilateral side of the body.

***Senses

The Senses

Fox, part of Chapter 10, figure from chapter 8

General

There are 5 "special" senses
touch (somesthesis) - already covered in previous outline
taste (gustation) - next (this outline)
smell (olfaction - after taste (this outline)
hearing (audition) - a big topic, next outline
sight (vision) - a huge topic, the outline after next

Taste (Gustation)

for chemicals dissolved in water
Gustation - chemicals - Many "flavors" are smell
Hanig (1901) - preferential localization:
sweet - tip of tongue
salt - front sides of tongue
sour - back sides of tongue
bitter - back middle of tongue

On tongue:
Papillae: Circumvallate (preference for quinine), foliate, fungiform (preference for sucrose)
also receptors in epiglottis
epiglottis via nerve X (vagus), circumvallate (9 of them) via IX (glossopharyngial), others via VII (facial)

Fig. 10.7
Several types of papilla including the circumvallate papillae on the back of the tongue, shown in this picture from our histology course
Within each papilla are numerous clusters of cells called taste buds shown in this histology picture. support cells and sensory cells

Note that there are taste "blindnesses" Ptc = phenylthiocarbamide, taster is dominant and nontaster
Use taste vs. non-taste to screen for G-protein coupled receptors (M. Barinaga, Family of bitter taste receptors found, Science 287, 2133-2135, 2000)

Fig. 10.8
generally, channel or G-protein linked receptor ultimately increasing calcium somehow for synapse
note receptor does not have axon

salt - Na+ channel opens (depolarization)

sour - pH sensitive channel closes (depolarization)

sweet - G-protein linked cAMP close K+ channel - depolarize

bitter -G-protein cascade

umami (glutamate) - and amino acids, channels as well as G-protein cascade

In each case, Ca2+ involved in vesicle release

Taste Projection
(much simpler than for olfaction)
Gustatory nucleus in medulla,
there to thalamus and then to sensory cortex, overlap to touch area - postcentral gyrus
also from medulla to hypothalamus

Smell- Olfaction

There are unusual primaries like aromatic and putrid , there may be many primaries, although mixtures give a single perception confounding the ability to define primaries
Relative to other senss, receptors difficult to stimulate
Even more than with the sense of touch, olfaction is related to motivational "affect"
The sense of smell is especially important in other animals (dogs)

Fig. 10.9
Anatomy of olfactory epithelium.
Note: the receptors are neurons with axons, unlike for taste
Receptors are ciliary, with cilia in mucus

Transduction - G protein coupled receptor via adenylyl cyclase
There is a specialized olfactory alpha subunit of the G protein (Golf)
Na+ - Ca2+ channel is like that of photoreceptor in that cAMP acts as a ligand to open the channel from inside the cell
Ca2+ opens Cl- channel
there is also a pathway involving PLC and IP3, but which is otherwise similar
in the background, there is a Na+/Ca++ exchanger

G-protein coupled receptor is very variable (there may be thousands, meaning that olfactory receptors contribute predominantly to diversity of G-protein-coupled receptors) and has specific variable regions
Axel and Buck won the 2004 Nobel prize (Physiology and medicine for this contribution)

Projection
Glomeruli - > Mitral cells -> lateral olfactory tract

Fig. 8.15
Olfaction is a complex sensory system in part because of the CNS projection to amygdala, hypothalamus, hippocampus) , areas called Limbic system

Also

There are senses outside the 5 special senses

Vestibular sense

Fig. 10.13
note proximity with cochlea (for hearing)
utricle and sacculus linear motions
3 semicircular canals - rotations

Fig. 10.15
stones (otoconia) provide mass for bending in utricle and sacculus

Fig. 10.16
cupula displaced as semicircular canal fluid is displaced

transduction

TRANSPARENCY Fig. 10.14
hair cells (also for audition) [mechanoreceptor]
kinocilium (real cilium)
plus about 30 stereoocilia
mechanoreception assisted by tip links - depolarization if move toward kinocilium
hyperpolarize if in opposite direction

***Audition

Audition


Fox, part of Chapter 10 and one figure in chapter 8

Physics of Sound

(not all of this is in the book)
Intensity dB = 20 log (pressure 1/pressure2)
standard is 0.0002 dynes/cm2
Threshold amplitude of vibration is 10 to the -11 m (10 pico meters)

waves of compressions and rarefactions of air (must have medium) described by sine wave
Frequency Hz cycles per sec
vibration - 20 - 20,000 Hz, above which is ultrasound .
Audibility curve - Intensity [dB] vs log (freq) [Hz] very sensitive

Ear

Fig. 10.18
Ear structure
pinna, eardrum=tympanic membrane, ossicles, cochlea, part of nerve VIII = cochlear nerve

Fig. 10.19
hammer, anvil, stirrup=malleus, incus, stapes - to match impedance of air -> fluid
Eustachian tube
oval window is "inner ear drum"
20:1 "amplification" tympanic to oval

Fig. 10.20
Since the cochlea is wound like a snail, a section through it shows repeated structures

Fig. 10.22
higher magnification, most importantly basilar and tectorial membrane
also inner hair cells and outer hair cells

Auditory transduction

hair cells on basilar and tectorial membranes
3,500 inner hair cells
many more outer hair cells
Bend as basilar membrane vibrates relative to tectorial membrane

(repeated from vestibular apparatus lecture)
kinocilium (real cilium, missing in post-natal human hair cells)
plus about 30 stereoocilia
mechanoreception assisted by tip links - depolarization if move toward kinocilium
hyperpolarize if in opposite direction
Threshold displacement is about 0.3 nm

go back to Fig. 10.20
perilymph is fluid of scala vestibuli and scala tympani is like CSF - bathes baso-lateral hair cell
High K+ in endolymph of scala media (bathing hairs)
stria vascularis (endothelium lining scala media) pumps ions to produce this unusual extracellular fluid
thus when channels open, K+ comes into cell
endocochlear potential endolymph 80 mV more + than perilymph

Frequency discrimination


At about 1000 Hz, you can tell the difference of a few Hz. This is explained by Helmholtz's place theory as modified by lateral inhibition as described in Bekesy's (1961) Nobel Prize winning work on "physical mechanism of stimulation within the coclea."

At low frequencies, frequency discrimination is better explained by Rutherford's telephone theory. Here, frequencies to both ears can cause neural impulses that stay true to the frequency so that beats can be from neural comparison from the two ears.

Fig. 10.21
Vibration of basilar membrane is mapped by tonotopy
fluid vibration at oval window through helicotrema
Low frequencies vibrate mostly near helicotrema
High frequencies vibrate mostly near oval window
But the localization is crude
Lateral nhibition refines localization on the way to brain so that cells in brain respond to only a few frequencies

Fig. 10.25
Frequency map on cortex

Frequency discrimination at low frequencies
there was another theory, Rutherford's "telephone" theory
phase-locking gives volley principle up to 4 kHz

Projection

Auditory nerve to dorsal and ventral cochlear nucleus - no crossing
Several synapses on the way to the Thalamus

Fig. 10.24
Thalamus to auditory cortex

Auditory localization

difference in time of arrival and intensity (in big headed animals) [human 700 micro sceond difference]
(speed of sound 1087 ft (331 m) / s in air)
Localization up and down does not rely on 2 ears,may relate to pinna
small-headed animals are extraordinary

***Vision

Eye and Vision


Fox, a substantial part of Chapter 10

Review

Vision is usually covered everywhere, and Freeman has the topic
TRANSPARENCY (intro book) eye and retina structure
TRANSPARENCY (intro book) spectrum and spectra for the 3 cones that mediate color vision

Eye structure


Fig. 10.27
the eye picture of an ophthalmologist's office
cornea, iris, pupil, conjunctiva, sclera, extraocular muscles
lens, aqueous (anterior chamber), vitreous (vitreous chamber), retina, fovea, optic n.
there is a blind spot where the optic nerve exits

Fig. 10.31
Here is a picture showing focus of an arrow up-side-down on the retina, trivial except that is shows that most of the bending is at the cornea where the change of index of refraction at the air-cornea interface is very large.

Refractive Disorders

Fig. 10.35
refractive errors
diopters - reciprocal of focal distance in m
cornea is 0.024 m, 42 diopters
Emmetropia-normal,
Hyperopia-far-sighted, need convex lens,
Myopia-near-sighted, need concave lens, involves abnormal elongation of the eye
visual angle, acuity - Snellen eye chart - 20/20 is seeing letter 5 min (1/60 degree)

Accomodation and presbyopia

Fig. 10.34
Accomodation
loss of accomodation with age explains Presbyopia
Benjamin Franklin developed bifocals
This is a difficult concept and the best figure I've seen to explain it:
If ciliary muscle is relaxed, ligaments are tight and lens is stretched flat
If ciliary muscle contracts, ligaments have slack and lens relaxes to greater bulge for near vision.

Here, in an albino rabbit eye dissection, you can see the suspensory ligaments of the ciliary muscle.

Other disorders:

Glaucoma - pressure is too high because aqueous humor does not drain well, ganglion cells die, treated with drops or surgery
Floaters in vitreous especially in myopia
Diabetic retinopathy blood vessels overgrow, leak, blast holes in retina with laser decreases angiogenesis
Cataract - lens becomes opaque, remove and often replace with intraocular lens, made of polymethyl methacrylate, known to be tolerated since pieces from airplane visors would nlodge in pilots under fire (and since about 1988, these have been doped with UV blockers)
Retinitis pigmentosa is tragic, people can see when young, lose rod vision (tunnel vision [ring scotoma] because rods are in mid-periphery).
Rods go first and eventually cones which is strange if rod molecules are mutant.
There are autosomal and X-linked types, dominant and recessive.
There are other genetic degenerations and stationary (not progressive) blindnesses are in molecules of transduction cascade (book only mentions missense mutations in opsin) as well as in other rod and cone molecules.
There is a web site where information relevant to the retina, especially genetic causes of blindness, accumulates (site)
Age related macular degeneration may have an genetic basis too

Pupil

Fig. 10.28
An interesting and related story has to do with dilation of the pupil.
Recall that atropine, a muscarinic antagonist, dilates the pupil.
That means that the parasympathetic nervous system constricts the pupil.
Recall that parasympathetic = cranio-sacral, and here the cranial nerve is the occulomotor nerve (#III)
By contrast, the sympathetic n.s. dilates (in dim light), and the nerve has to come up from the superior cervical ganglion (of the thoraco-lumbar system)
A bright light in one eye causes the other pupil to constrict too. (Try this in front of a mirror with a flashlight.)
Neurologists can make use of information based on defects in the pupillary reflex.

Eye structure

Fig. 10.30
"the eye is the window to the brain" -- physician can actually look at CNS
For instance, increased crainial pressure (like from tumor) shows up as papilledema
Optic disc is where optic nerve exits and blood supply enters and exits.
Fovea is high acuity cone vision.
Macula lutea is area where carotenoids (lutein and zeaxanthin) form blue-blocking (yellow) filter.

Here is a picture a friend (Lynette Feeney-Burns) gave me before she retired (in about 1990). It is labeled "normal macular pigment - chow diet," and it demonstrates the density of yellow pigment around the fovea in (presumably) monkeys fed a diet adequate in carotenoids. Currently, it is known that the carotenoids lutein and zeaxanthin are in nerve layers in the light path to the receptors of the fovea (cones). We get these yellow-appearing caroteinois in our diet (e.g. from spinach and corn). It is thought that they help to protect cones from damage that may be induced by blue light. It was found that the concentration is increased with dietary increases, and now lutein is included in multi-vitamins.

Here, in a sheep eye dissection, you can see the optic disc. Retina is white, pigment epithelium and choroid are black.

Rods and Cones

TRANSPARENCY (here is a pdf of this transparency)
Hecht, Schlaar and Pirenne (1942) published a study that a human subject can see a light so dim that 6-14 quanta were absorbed over a 500 rod area; that means one rod can "see" one quantum.
Here are some calculations showing how to determine the energy of a photon using Planck's constant (obviously very low).
I also roughly calculate to show that the threshold for audition is comparably low.

Fig. 10.44
Photoreceptors- 125 million receptors 20/1 rods to cones
(converge on 1 million ganglion cells)
Adds to sensitivity of rods and to acuity for cones.

Retinal circuitry

Fig. 10.36
Retina is mounted backwards relative to the path of light
expands on the above figure with retinal wiring diagram:
Straight through: Photoreceptor -> bipolar -> "ganglion" cells (whose axons form the optic nerve)
Horizontal interactions: Horizontal cells and amacrine cells
Pigment epithelium - melanin, vitamin A conversions, and phagocytosis of spent photoreceptor membrane

rods concentrated off-fovea, cones on-fovea
Rod, peripheral vision, dim black and white, sensitive - "scotopic"
Very sensitive - 1 photon
Cone, fovea, color, acuity - "photopic"
Shown in rats, rods are supported by retinal pigment epithelium
RPE: (1) melanin that blocks light reflection
(2) metabolism to provide 11-cis retinal (chromophore ofvisual pigment, rhodopsin)
(3) phagocytosis and recycling of shed rod tips
Cells are postmitotic and the indigestible residue of the phagolysosomal system is lipofuscin, a fluorescent aging pigment, a topic on which I've done research.

Color vision

Fig. 10.42
spectral sensitivity of rods and 3 cone types
confirms Young -Helmholtz trichromatic theory
3 kinds of cone 420 530 560
3 kinds of cone opsins which are evolutionarily related in humans and OW monkeys
green and yellow (middle and long wavelength) cone opsins are near each other on X
(blue cone opsin is on human chromosome 7, rod on chromosome 3)
evolutionary bottleneck hypothesis color vision re-evolves after nocturnal life (where adaptive pressure for cone vision is relaxed) early in mammalian evolution
Red or green color blindness - on X, thus preferentially in males.
Blindnesses were thought to be from altered genes, but numbr of copies in human population is variable, and cross-over accidents can even make chimeric genes.
Female "carriers" should actually be mosaics of color blind vs normal retina because of Mary Lyon X-inactivation hypothesis
superfamily of G-protein-coupled receptors (7 transmembrane domain receptors)

Phototransduction

Fig. 10.39
light causes 11-cis retinal (aldehyde of vitamin A, retinol) to turn to all-trans.
("retinene" - term used in book - is old fashioned)
George Wald 1967 Nobel prize

Fig. 10.40
The alpha subunit of transducin (the name for the G protein) activates cGMP PDE (phosphodiesterase)
Less cGMP (ligand) and channel closes so cell hyperpolarizes since sodium channel closes.

Fig. 10.41
This figure repeats the above point.
Because there are Na+ channels in the outer segment and a Na+-K+ ATPase in the inner segment (where there are lots of mitochondria manufacturing ATP), there is a dark current turned off in the light.
(Also shows how rod cell is a stack of disks with rhodopsin and other transduction molecules)
Transmitter is released in dark - but less when light is on

Wiring

(and processing - my coverage here will be minimal)

10.45
Temporal retina does not cross at optic chiasm but goes to ipsilateral lateral geniculate nucleus (part of the thalamus)
Nasal retina goes to contralateral LGN
At LGN, inputs from 2 eyes does not mix.
Projection to cortex where eye inputs mix for stereopsis, and processing for contrast, moving lines, angles, etc takes place.
Superior colliculus (important for eye movement control)

My interests center around vision, so a visit to the research interests of my home page will offer various topics about vitamin A, ultraviolet light, and Drosophila mutants. The Biology Department has a vertebrate vision specialist, Judith Ogilvie. Dr. Ariel in SLU's Pharmacology Physiology Department is one of my fellow wizards in visual science, also Dr. Kisselev in Ophthalmology