Background on nerves and hormones

A nerve can be divided into two functional parts:

1) the cell body and dendrites, which receive electrical inputs from other nerves or from sensory cells, and
2) the axon, which transmits impulses to other cells.

Dendrites are short, thin, highly branched, and are passive conductors of electrical impulses; axons may be very long (e.g., the spinal chord), generally have few branches (collateral axons), and actively transmit nerve impulses. This diagram is a highly simplified picture of a simple nerve; in reality there would be many dendrites and thousands of synaptic inputs into them.

Mechanism: Nerves generate electricity chemically. Ions (electrically charged atoms or molecules) are actively transported across the cell membrane -- from inside the cell (cytoplasm) to outside (interstitial fluid), and vice versa. By selectively "pumping" different ions, the cell membrane acts to make the inside of the cell negatively charged relative to the outside. The major ions are sodium, potassium, chlorine, and calcium (Na, K, Cl, & Ca); at rest, the difference generated is usually about -60 to -90 millivolts. The membrane is polarized.

Now the entering impulse. Molecules of neurotransmitter are released from the synaptic vessicles in which they are stored, and diffuse into the synaptic cleft. This being very narrow, many/most contact the other side where they bind with specific receptor molecules on the postsynaptic cell membrane.

This is analogous to a lock and key mechanism, apparently even to the critical factor being the match between the physical shapes of the transmitter and receptor molecules. When the transmitter "clicks into place," it causes the receptor molecule to change shape, and this sets in motion a set of physical/chemical interactions in the membrane of the postsynaptic cell that result in a sudden increase in the permeability of the membrane near the receptor to specific ions. When this happens, positive ions (mainly Na⁺) are pulled into the cell by the negatively charged cytoplasm (osmotic pressures and other ions are involved and complicate this simplistic picture).

The flow of ions across the membrane is an electrical event, and if enough transmitter has been received this depolarization creates an electrical impulse that is carried along the dendrite to the cell body. The trick here is that the ion flow itself causes neighboring "gates" in the membrane to "open" to Na⁺ and so the process is self-reinforcing. The nerve impulse itself is simply a self-propagating electrical event that moves the length of the axon; the current crossing the membrane causes the membrane just ahead to let in Na⁺ (current) which of course affects the next bit of membrane.

This is the basic idea behind the impulse. I haven't distinguished between passive (dendritic) and active (axonal) transmission; the observed difference is that dendritic impulses lose strength over distances, whereas active impulses -- action potentials -- do not.

Because it is self-maintaining, the axonal impulse is all-or-none: varying the stimulus intensity (i.e., dumping few or many vessicles, or applying a mild or strong electrical current) can have one of only two outcomes -- the impulse is triggered or it's not. Think about what this lack of individually graded response means for information processing.

When the impulse reaches the end of the axon, the changes it elicits in the cell membrane cause vessicles to be released, dumping neurotransmitter molecules, and we're back to the beginning.

Going from how a neuron sends signals to how information is acquired, stored, and retrieved is a bit of a jump even for this course. If you want to tackle it, look into a major in cogsci or physiological psych. Presumably at least part of the story lies in wiring changes; nerves grow dendrites and make connections as a function of experience/stimulation.

Loose ends:

1. It's logical to assume that the membrane simply pulls in negative ions and expels positive ones to arrive at the -90mv resting potential. However, reality is more complex. Like, really complex; take neurophys if you're interested.

2. Neurotransmitter molecules that don't hit a receptor are either reabsorbed presynaptically or broken down in the synaptic cleft. When they "click into place," one of two things can happen, depending on the particular system involved:

   i) the binding is temporary, and the released molecules (having acted on the receptor) are reabsorbed or broken down; or

   ii) the action of the transmitter may take place inside the postsynaptic cell, instead of on the surface; in this case the receptor either "carries" or "passes" the molecules through. After acting, the transmitter is broken down postsynaptically.

3. Interference with neurotransmitters can result in various disorders, of which some are diseases (Parkinson's disease, some chronic depression, mania etc.) and some can be sought-after states (various hallucinogens and other psychoactive drugs). Interference can be: blocking or over-facilitating release from vessicles, increasing or decreasing rates of breakdown in the synaptic cleft, or blocking or over-facilitating binding to receptors.

4. As the impulse passes, the membrane potential is biologically restored to its original state (i.e., work is done by the cell; your brain is responsible for about 20% of your basal metabolic rate).

5. All of the synaptic events described take place in much less than 1/100th of a second, over an area so small it can only be seen with a very powerful microscope. It sounds -- and is -- complex, but it is also fast and small!

6. There are junctions between nerve cells that don't involve neurotransmitters -- the gap is so small that the electrical event just continues right over it. These are rare, at best, in vertebrates.

7. This example dealt with one synapse and one impulse. In reality it takes several to many synapses "firing" at once to cause a big enough electrical event in the nerve cell body to initiate an action potential. Picture a cell with inputs from hundreds of thousands of other nerve cells; no one synapse can trigger the postsynaptic cell, but if many neighboring synapses fire at the same time (i.e., within, say, 1/100th of a second of each other), together they can depolarize enough of the cell membrane to trigger an impulse. To add to the complexity -- some of the inputs, instead of depolarizing the cell membrane, hyperpolarize or stabilize it. In other words, if they are fired, they transiently make it harder for an impulse to be triggered at that site on the cell (logically enough, these are called "inhibitory synapses"). The result is a cell that fires only if the right combinations among thousands of inputs all fire at once; this cell itself may send the resulting impulse (via its axon) to thousands more cells.
   This is, we think, how we think. (No wonder it hurts!)

8. FINALLY: Although our attention tends to get focussed on the relatively straightforward nerve cells (at least we know what they do!), there are also cells called glial (or Schwann) cells which are also highly important. These fatty cells wrap around axons, making a sort of sheath (called a myelin sheath), that functions to speed conduction of nerve impulses and reduce the time needed to re-polarize the neuron. Besides myelinating nerves and so improving their conductance (they act like insulation on an electrical wire), there is evidence that glial cells mechanically direct the growth of axons and dendrites. It may be that by pulling together several axons to one spot on a dendrite, the glial cell creates a functional unit; the simultaneous firing of the cluster may be more likely to trigger the postsynaptic cell than would the same number of synapses spread over a wider area. And glial cells may do much more that we only suspect....

A hormone as presently conceived is:

secreted by living cells in
trace amounts from
within the organism and is
transported usually by the blood to a
specific site of action where it is
not used as a source of energy but acts to
regulate and not initiate reactions in order to
bring about an appropriate response by the organism.

Thus, vitamins, major energy sources, enzymes and the like are not hormones.

The definition may turn out to be unduly restrictive, however, since some humoral substances may be formed from precursors in the blood stream or at the site of action and so are not themselves secreted. Others may act locally by diffusion without ever getting into the blood stream at all. Nevertheless, it is a useful working definition.

Since there is no direct cellular connection between the cells of secretion and the effector site, the endocrine system differs from the other great regulatory system, the nervous system. Nevertheless, the ties with the nervous system are extensive and are now recognized as being of great importance, so important that neuroendocrinology is a separate field of study.

A major point, and one that is easy to loose site of in the forest of facts to follow, is that most hormones are present in the circulation at all times, albeit in greater or lesser amounts. While it is neccessary to discuss them one at a time, this is an arbitrary and artificial separation from the body's point of view. One must try to see what the combined effects of the hormone "soup" are and imagine the final response of the body to the mixture of the moment.

There are three major classes of hormone that you're likely to run into in readings etc. Steroid hormones (estrogen, testosterone etc.) are small and can diffuse through cell membranes. They bind to receptor molecules in the cytoplasm of target cells. They are synthesized by enzymatic reactions from molecules (such as cholesterol) that we eat.

Next are the protein hormones. These are generally much larger, and can't simply float into the cell. They bind to receptor molecules on the cell membrane, where they initiate responses much as described above for neurotransmitters. Proteins being simple chains of amino acids, they can be "read" directly off of the sequences of bases on DNA. While I'm not sure is all of them are made this way, insulin is, as those following recombinant DNA work know. Other protein hormones include oxytocin, adrenocorticotropic hormone (ACTH), growth hormone, etc.

The third group is the amines -- epinepherine (= adrenalin), melatonin, thyroxine, & a few more. These are mainly synthesized from the amino acid tyrosine; some are bound (probably) to membrane receptors, and some enter the cell first (like steroids, but they don't necessarily then enter the nucleus and act on the DNA as steroids do).

Hormones, once secreted, last for varying lengths of time in the blood. All of them are broken down eventually, though; the enzymes responsible are present continually (more or less), so the level of a hormone in the blood is set by the rate at which it's secreted relative to the (fairly constant) amount of specific enzymes.

A good example of a system that uses nerves and hormones is the stress response. A stressful event (a gun going off unexpectedly, say, or an announcement of a pop quizz...) is perceived, and the appropriate nerves in the hypothalamus are stimulated. Some of these have direct axonal connections to the adrenal medulla (the adrenal glands are next to your kidneys; the inside is the medula and the outer layer is the cortex). When these fire, medullary cells release adrenalin, which causes the rush you feel as you mobilize your body -- it acts as a stimulant to get you out of harm's way. Other nerves in the hypothalamus release corticotropin releasing factor (CRF) which is carried to the anterior pituitary where it stimulates the release of ACTH. The ACTH is carried in the blood to the adrenal cortex, where it stimulates the release of cortisol -- a more low-keyed, but longer-lasting, mobilizer of the body's energy. As you can imagine, the hormone system takes longer to start up; but once going, it keeps working longer. A rule of thumb -- nerves are better for fast, acute responses; hormones for slower, chronic ones (but note that slow is only relative; it takes only a few seconds for ACTH to start releasing cortisol). Note the pinkish gland in the center (figuratively as well as literally) is the pituitary; the anterior pituitary (lighter color) is not innervated from hypothalamus; posterior pituitary receives direct nervous inputs and secretes e.g. oxytocin. "+" and red arrows and "-" and blue arrows signs indicate positive & negative feedback. (After Clegg & Clegg [1969] Hormones, Cells and Organisms. Stanford University Press.)

Feedback control: Although feedback "loops" are involved in the function of both endocrine and nervous systems, hormonal loops are both simpler and probably more important to the total system than are nerve loops (imagine a "loop" involving a hundred thousand cells and several million synapses -- the principle is similar, but the actual description is way beyond us). This discussion therefore focuses only on hormonal systems.

The principle is simple: hormone secreted by a cell may act, directly or indirectly, to increase (positive feedback) or to decrease (negative feedback, the more common type) the output of that hormone. For example -- cell A receives a nervous or chemical message to secrete hormone X, which it begins to do. Cell A has receptors in its membrane that, when bound with X, alter the enzyme reaction such that the secretion of X is halted. Clearly, as the blood level of X rises it will "turn itself off" -- direct negative feedback. Complexity is introduced into the system by the potential for indirect feedback (e.g., X causes cell B to release Y which, among other things, causes neuron C to fire, causing D to release Z which turns off cell A...) and by systems or inputs controlling the loops and that sort of thing.

E.g., the stress system mentioned above. Adrenalin released from the adrenal medulla stimulates hypothalamic cells that secrete CRF, which are already active due to nerve inputs. This results in a high CRF (--> ACTH --> cortisol) output. But cortisol has a negative effect on the production of CRF and ACTH; as cortisol builds up and nerves slow their repsonse to the stressor (you got away, or the lion wasn't hungry, etc.) a crossover is reached where the negative feedback outweighs the stimulation and the stress response turns itself off.

Vocabulary: There are almost as many terms as chemicals floating around. Some guidlines: "H," as in LH, means hormone. "F" in a similar context means "factor," which is what it's called when everybody knows it's there but nobody knows exactly what it is yet. Thus, you may see both LHRF and LHRH; LHRF is just the older term. "Epinepherine" is just British for adrenalin.

Many hormones can be kept straight by knowing what the names mean. FSH is follicle stimulating hormone; egg cells are contained in follicles (look it up) within the ovary that must develop before ovulation. So -- what does FSH do? Similarly, pro- is a prefix meaning "for" or "in favor of;" you know what lactation and gestation mean, so what do prolactin and progesterone do? And again, it's no surprise that LH (luteinizing hormone) causes ovulation and stimulates the resulting corpus luteum (itself an endocrine organ). Adrenalin (adrenal), cortisol (adrenal cortex), and thyroxine (thyroid) all tell you where they're produced.

Releasing hormones (RF or RH) are produced by neurosecretory cells -- essentially nerves that "synapse" into the circulatory system instead of other cells -- and cause the release of other hormones. So far, all RHs are hypothalamic. Tropic (or trophic) hormones are released by one endocrine gland and affect a different one. Now -- since the chorion is a membrane around the embryo, it's hopefully no surprise that human chorionic gonadotropin (HCG) is released by the chorion and affects hormone secretion by the gonads of a pregnant woman. And what about ACTH -- adreno cortico tropic hormone?

Origins of sex (and hormones):

People sometimes view "male" and "female" as opposites. This is very much an exageration. One might think in terms of a broad gradation from extremely "masculine" to very "feminine;" people near the "masculine" end tending to be males and people near the "feminine" end more often being female. In the middle it can get hard to differentiate the sexes in terms of behaviors that aren't actually related to sex and parenting. Research on sex and gender is a fascinating subfield in anthropology, one that can be approached from either the cultural or the biological side. For now: on the next page are schematics of the chemical structures for the two major "sex hormones" and their precursor, cholesterol. Don't sweat the details -- you don't need to be a rocket scientist to see the similarities. In fact, one of the steps in going from cholesterol to estradiol 17 b (the primary estrogen in humans) is testosterone.

Physiological sex is usually unambiguous (though hermaphrodites do happen). But when people start talking about behavioral traits like math ability, aggressiveness, etc., it is good to keep in mind that even at the most fundamental level there is no reason to expect a clear distinction between males and females.

Dietary cholesterol (above) provides the basic structure for the synthesis of testosterone (left) and estradiol 17 b (right). Both are found in the blood of both men and women, though generally in very different amounts.

The problem of the mechanism of hormone action is difficult. ... The hormone, very often after binding to a specific tissue or tissue component, might then:

1. Affect membrane transport of various substances.
2. Affect the activity of the gene in running the cell by changing DNA-directed mRNA synthesis, perhaps by decreasing intrastrand bonds of DNA or by regulating which area of DNA is to be active.
3. Affect protein synthesis at some point beyond mRNA synthesis, probably at the ribosome-polysome level.
4. Change the amount or activity of enzyme(s) or other specific proteins.
5. Change the amount or availability of a cofactor. [ACTH] and thyroid-stimulating hormone (TSH) are thought by some to do this.
6. Act itself as a coenzyme.
7. Exert an allosteric effect on a membrane, nucleic acid, polysome, or enzyme. Here the hormone binds to one part of a molecule or membrane, causing a molecular rearangement whereby actions are changed at a distant part of the molecule or membrane.
8. Affect the entire cytoskeleton of some of the structural elements of the cell in a subtle way, thus causeing some or all of the above.
9. Stimulate or inhibit the formation of a hormonal mediator, for example, cyclic 3',5'-adenosine monophosphate (cyclic AMP or cAMP) or perhaps a prostaglandin, which then brings about the observed effect.

Last update: 5 Jan 1999