A Brief Introduction to the Neuron

This is one in the series of the ETFRC's "backward chaining" learning essays, intended to serve only as a rapid introduction to a particular subject, so that lack of familiarity with the subject doesn't block one from learning something else.  What is discussed here is only the briefest sketch of the structure and function of the neuron, but we hope the information is detailed enough that the topic, in this case cellular neurophysiology, doesn't become a stumbling block that stops the reader from learning what led him or her here.  Each of these essays provides a link to a far more in-depth book on the subject.  It is our hope that readers will want to continue their study at greater depth, for each of these topics is itself intrinsically interesting.

A neuron is a type of cell, out of which the nervous system is built.  Cells have many common features, such as lipid membranes, metabolic structures for producing energy, and so on.  But the cells in the body are also specialized for particular functions; for example, red blood cells are specialized for carrying oxygen, hepatocytes (liver cells) specialize in carrying out huge numbers of chemical reactions, and muscle cells are specialized for contracting in response to stimulation.  Neurons are probably the most highly specialized of all cells.   The brain and the spinal cord, which together make up the central nervous system (CNS), are composed of neurons (and several other types of cells), as are the nerves which carry signals between the CNS and the rest of the body (the peripheral nervous system).

The three principal things that neurons do are (1) maintain an electrical gradient between the inside of the cell and the external environment, that is, the inside of the neuron maintains a charge of -60 to -75 millivolts (mV) relative to the space outside of the cell, (2) summate, over space and time, the influence of other neurons in moving this electrical potential towards a more highly polarized state (hyperpolarization) or a less polarized state (depolarization), and (3) undergo an explosive event, called the action potential, when membrane depolarization reaches a certain critical threshold (around -50 mV), during which a reversal of charge propagates down the length of fibers called axons which originate in the neuronal cell body (the soma) and terminate extremely close to other neurons.  When the reversal of charge reaches the end of the neuron, chemicals called neurotransmitters are released into the synapse, an extremely small area between the axon and the next cell.  The neurotransmitters can be either excitatory or inhibitory, referring to the effect they have on the polarization state of the neurons they synapse on.  Excitatory transmitters push the next cell towards depolarization, and thus continuation of the action potential through another cell, while inhibitory transmitters push the cell towards hyperpolarization and thus tend to dampen the action potential and prevent its further propagation.  A neuron may have a very large number of inhibitory and excitatory influences impinging on it continuously; that is why we say that it functions to spatially (over a region of the nervous system) and temporally (over time) summate these influences and fire (i.e., produce an action potential) when the depolarization threshold is reached.   The production of action potentials through cellular depolarization is the way the nervous system transmits signals and thus ultimately exerts control over the whole organism.

The figure above is a schematic of a typical (if there is such a thing) neuron.  The cell body, or soma, is the locus of the nucleus, which carries the cell's DNA.  Projecting out of the soma is an axon.  The axon is wrapped in a myelin sheath, with periodic breaks in it called the nodes of Ranvier.  We will not detail this here, but this sheath/node system serves to improve electrical conduction along the axon.  At its end, the axon sprouts into many axon terminals, which may synapse upon many other neurons.  Each terminal contains the machinery to effect chemical neurotransmission to the cell upon which it synapses.

We said above that the neuron had three main functions; the first of these was the maintenance of a charge gradient relative to outside environment.  How does the neuron accomplish this?  Ordinarily, charge gradients, like chemical gradients, tend to dissipate until the charge, or the concentration of the chemical, is the same everywhere.  Some sort of active process is required to stop this natural "evening out" from happening.  To understand how this works, we need to get a good picture of the cellular membrane in our minds.  The cell membrane is composed of two layers of fatty acids.  A fatty acid is partially like a lipid, in that most of its body consists of a long, nonpolar portion, which, if removed from the rest, would be a fat.  However, in addition to their hydrophobic lipid portions, fatty acids have a "head" which is polar, and therefore water-soluble.  If placed in a jar of oil and water, then, the fatty acid would orient itself so that its head was in the water, while its lipid tail was in the oil.  This dual structure gives these molecules unique properties that are exploited all over the body, but are of special significance in cell membranes.  Cell membranes are composed of two layers of fatty acids, each with its hydrophilic "head" facing either the watery intracellular or extracellular space, while the hydrophobic "tails" both face inward forming a hydrophobic core.  This bilayer structure is the basis of the cell membrane, which defines a cell by separating it from the external environment and protecting the internal environment.

Now things get very interesting.  Floating around in this fatty structure are various things.  The ones that will concern us the most are various types of peptides, or proteins.  These polymers, or sequences, of amino acids, come in all different shapes and sizes, and serve many functions in the organism.  For example, all enzymes, which catalyze chemical reactions in the body, are peptides.  So are the receptors, ionophores (ion channels), neurotransmitter re-uptake pumps and various other active transport mechanisms, such as the sodium pump, that play a critical role maintaining the neuron's electrical gradient as well as in synaptic transmission.   The structure of the membrane is dynamic, and the proteins (or glycoproteins) are not anchored anywhere.  They float in the dual character hydrophilic/hydrophobic environment of the cell membrane.  My biochemistry teacher told us to think of the cell membrane as a raisin bread, in which the various floating structures were the raisins.  He was quick to add, "But it's a dynamic raisin bread, of course ..."

Schematic view of the neuronal cell membrane.

The Basis of the Resting Potential

We mentioned above that the basic thing that a neuron does is maintain an electrical charge gradient, or potential difference, between the inside of the cell and the extracellular environment.  This relative difference of electrical charge is called the resting potential.  How does the neuron maintain this charge difference against the tendency of entropy and diffusion to even things out everywhere?  To understand this, we must first understand the source of the electrical charges within and without the neuron.  The internal environment of the body is a kind of salt water, much like sea water.  Ordinary table salt is sodium chloride, and may be represented chemically as NaCl, where Na is the symbol for sodium and Cl is the symbol for chlorine.  NaCl is an ionically bound compound, which is to say, it is held together by the different electrical charges of the atoms that make it up.   Sodium is positively charged, and chlorine is negatively charged.  When sodium chloride is dissolved in water, the sodium and chlorine atoms separate into charged particles called ions.  The sodium ion, Na+, carries a positive charge, while the chloride ion, Cl-, carries a negative charge.  In the crystalline state, the charges exactly offset one another, but in solution, the atoms become free to move around in their ionized forms.  Many of the large proteins that project into the cell are also negatively charged (anionic).  The aqueous solution which makes up the intra- and extracellular environment of the neuron is not pure NaCl.  Several other ion species are present as well, including potassium (K+) and calcium (Ca++).   This mixture of several different salts closely mimics the chemical makeup of seawater, and is referred to as physiological saline.

Some of the proteins floating in the fatty acids of the cell membrane are ion channels, "tubes" which permit passive diffusion of certain ions into the cell.  The positively charged K+ (potassium) ions can freely move through ion channels in the cell, and they do this until they have offset the negative charge produced by the large anionic proteins inside the cell.   Negatively charged chlorine ions (Cl-) are greatly restricted in their ability to move into and out of the cell; they can only move through specialized chloride ionophores, channels which allow the chloride ions entry only under very particular circumstances.  But the engine that maintains the charge gradient is the active transport of sodium out of the neuron by the sodium pump.  The sodium pump is yet another of the proteins floating in the cell membrane.  By "active transport," we mean that the transport is against the natural direction of diffusion, and that metabolic energy, in the form of ATP, must be expended to actively push sodium ions out of the cell against their natural proclivity to move into the cell and eliminate the charge gradient.   Nature prefers everything -- chemical concentrations, electrical charges, and so on -- to even out.  For example, imagine that you have put a drop of blue ink into a pan of water.  What are the odds that the blue dot will remain small and dense as it was when you placed it there?  Very slim; it is much more likely that the ink will gradually spread out until all of the water is light blue and there is no "ink gradient" to be found.  It is only the ceaseless activity of the sodium pump, fueled by ATP whose energy ultimately comes from the digestion of food, that maintains the charge difference that we call the resting potential.  Every neuron in the nervous system is constantly using up ATP in order to continually pump sodium ions out of the neuron against their natural tendency to spread out evenly.

The Action Potential

When the neuron becomes depolarized to a certain threshold level, around -50 mV, an explosive event called the action potential takes place.  The basis of the the action potential and its explosive nature is that the conductance of sodium into the cell is increased by the depolarization of the cell.   The change in the sodium channel's electrical environment has become great enough to change the shape of the channel itself, such that sodium can now readily move through it.  Since the entry of the positively charged sodium ions further depolarizes the cell, sodium conductance is increased even more, in a positive feedback loop, and the charge gradient across the membrane actually reverses, so that the inside of the cell reaches about +30 mV relative to the outside.  This process begins at a particular area on the cell membrane, but, because depolarization increases local sodium conductance, it rapidly spreads and the charge reversal is propagated down the axon.  We will not go into the rather complicated electrochemical events underlying this process any further; the interested reader is referred to our Featured Reading on the subject, shown at the top of this essay.  The net result of this charge reversal, which is rapidly switched back to a resting potential, is that the axon's terminals release their neurotransmitter into the synaptic space between the axon and the dendrite of the next cell (in reality, the situation is more complex than this: axons don't necessarily synapse on dendrites; they can also synapse on other axons or on the cell body).  Just what the neurotransmitter released is varies enormously, with some cells using peptides, some monoamines like dopamine and serotonin, some GABA or glycine, and others as well.  All of these transmitters are either excitatory or inhibitory and tend to depolarize or hyperpolarize the cells they touch.  A fascinating question, seldom asked by neuroscientists, is: if all of these substances function simply to inhibit or to excite the next cell, then why are there more than two neurotransmitters?  Why are there dozens or perhaps hundreds?   Could there be something fundamentally wrong with our understanding of what is going on?  This last is a question seldom asked by any scientists, regarding any subject, at any point in the history of science.

Schematic illustration of a synapse.

Neurotransmission occurs when vesicles containing the transmitter substance fuse with the membrane and release the transmitter into the synaptic space, where it interacts with one or more receptors on the post-synaptic cell, and often on the pre-synaptic cell as well.  The presynaptic receptors often serve to inhibit, by feedback, further transmitter release.   After the transmitter has interacted with the various receptors, it is cleaned up, or removed from the synapse, by a few different methods.  Much of it is re-uptaken into the axon terminal by an ATP-driven re-uptake pump, conceptually similar to the sodium pump.  Reuptake spares the cell the task of synthesizing a new batch of transmitter every time there is an action potential.  This transmitter re-uptake is the operation on which the latest batch of psychopharmacological wonder drugs are supposed to exert their effects. The older "antidepressants," the prototypical imipramine and its tricyclic derivatives, were relatively nonselective in their action, blocking the re-uptake of serotonin and norepinepherine in a proportion controlled by a known feature of their chemical structure. 

Neuropharmacological-Sociological Digression

The first wave of the "new" antidepressants, which included fluoxetine (Prozac®), were drugs that were fairly selective at sticking to, and thereby blocking,  the serotonin re-uptake pump ("serotonin transporter").  What pharmacologists mean when they use the word "selective" this way is that the new drug didn't stick to every re-uptake pump -- the norepinepherine pump, the dopamine pump, and so on -- but rather, because of its chemistry, fluoxetine could block this one kind of re-uptake -- serotonin reuptake -- while disturbing other kinds of re-uptake only a little.  Drug companies immediately spun this "selectivity" into entirely groundless, even meaningless, and sometimes outright false and deceptive marketing babble, and people ended up believing that serotonin was "the chemical that controls your mood," and that you had a "level" of it that could be measured, much as you measure your car's oil level with a dipstick, and that, when this "level" got too low, you had a "chemical imbalance" and needed, you guessed it, a serotonin-reuptake inhibitor.  (For those who didn't realize it, all of these statements are false).  Much was made of the "selectivity" of these drugs for serotonin, which is unfortunate, since the target audience for this information consisted almost entirely of people who could not possibly have understood that there is no necessary relationship at all between "specificity" in this molecular sense, and "specificity" in terms of a drug's being a "specific" remedy for a disease, or acting "specifically" against that disease.  People came away with the belief that the new, "selective" drugs, were selective for depression -- and they had a lot of help getting that impression.  People thought that the drug companies had, at long last, found the magic bullet that fixed the bad biochemistry that depressed people suffered from.  All right!  I'm not unhappy because the existential givens of human life inexorably force impossible choices on me! It's got nothing to do with living in a period of history where friendships and families have lost all cohesion, and everyone is a lone atom spinning in the void!  Hey, quit the navel-gazin'!   I've just run a little low on my serotonin!  (Where'd I put that dang dipstick?)

The first irony was when less selective drugs (like Effexor® and Wellbutrin® and so on) started to prove more effective.  By the time the final irony happened, no one was really paying attention anymore: Our beloved "selective for depression" drugs turned out to be "good fer what ails ya," as they began to be handed out for PMS, overeating, anorexia, anxiety, obsessions and compulsions, post-traumatic stress "disorder" and, basically, everything else anyone complained about.  What happened to all that "selectivity?"

There is an inherent ambiguity in the way we speak of things in pharmacology, and the drug manufacturers were there, with full knowledge of what they were doing, exploiting the ambiguity between pharmacodynamic and intentional levels of description to create false beliefs which would turn out to be extremely profitable for them, and which would help make biopsychiatry, a behavioristic theory of mind which is inconsistent with almost every fundamental fact of human experience, not merely a respected position, but indeed the only respectable view with regard to psychology and what is called "mental illness."

Now that I've brought up the idea of pharmacology's various levels of description of drugs, I should explain it.  Why?  Because I believe that the use of semantic legerdemain to influence people's beliefs and actions is evil; and where drugs are concerned, conjuring tricks based on ignorance about science, language, and logic have a much bigger infulence on what is invented, marketed, prescribed, and taken than most people would be willing to concede.  I know that you're very intelligent, but remember -- we're talking about the people who are positive that TV advertising has no effect at all on them, notwithstanding the fact that really smart people spend enormous sums of money on it, and reap enormous profits for their trouble.  (Hey -- just as an aside, I've often wondered where on Earth all of the dummies who are affected by advertising are hiding?  I've yet to meet a single person who admits that advertising affects his or her beliefs or decisions.  Then again, 100% of people believe that their intelligence is above average, too). 

So, let's look at the ways we classify drugs.  We often refer to a drug as being a member of a certain class of drugs: penicillin, as everyone knows, is an "antibiotic."  When you catch a cold, you take an "antihistamine" or a "decongestant" (these are radically different kinds of drugs, and I've been quite stunned to discover that almost everyone believes they're the same thing).  Depressed people obviously need an "antidepressant," and hey, those "selective serotonin re-uptake inhibitors" sound pretty good, don't they?  I mean, if nothing else, they're really selective, and selectivity is a good thing, right?  

In fact, every drug belongs to three different kinds of categories -- you might say, three different classes of classes.   What are the three classes that we divide drugs into?

We'll skip the division of drugs into "good" drugs and "bad" drugs, even though that classification scheme has proven wildly popular among the simpleminded.  Instead, we'll stick to reality.  The most basic, and most objective, category is chemical class:  Valium® (diazepam) and Xanax® (alprazolam), when classed this way, are called benzodiazepines.  This is a very value-free term which describes nothing more than the molecular structure of this kind of drug.   Sometimes a chemical class gets famous, or infamous, as the barbiturates did, but generally, only chemists and pharmacologists are interested in this classification.

We can call the next level of description the pharmacodynamic class.  This describes the drug in terms of its molecular effects at its target sites.  For example, fluoxetine (Prozac®) is chemically is an aryloxyalkylamine (though, since there are no other marketed members of this family, one seldom sees the word).   This chemical class name describes, in a very general way, the shape of the fluoxetine molecule.  But it tells us nothing about what, if anything, the drug does once it is inside the body.  By contrast, the pharmacodynamic class tells us, at the molecular level, what kind of effect the drug exerts.  Fluoxetine belongs to the pharmacodynamic class serotonin reuptake inhibitors, and from this name, we can get a picture of what it actually does -- at the molecular level, not at the level of psychology.  It's vital to remember this difference.  The chemical class and the pharmacodynamic class of a drug are often confused, or thought to be the same thing, but it's important to remember that no particular pharmacological effect follows deductively from a particular chemical structure.  All such relationships are contingent and known only empirically -- that is, by seeing what the drug actually does when it gets inside an organism.  We cannot simply look at a drug's molecular structure and deduce its actions and effects from the phase of the moon, or the Krebs cycle, or the Cartesian cogito ergo sum, or Microsoft's Corporate Mission Statement, or something.  We only know what a drug does by watching it do that thing.  Of course, many times, drugs of similar chemical structure will have similar actions -- but not invariably, or even in a predictable way.  They are not logically guaranteed to have similar effects.  The pharmacodynamic class is a bit less objective than the chemical class.  Why?  Because the chemical class describes the molecular geometry, making no attempt to associate it with anything.   But a chemical set loose in the body will almost always have a large set of effects.  The pharmacodynamic class that the drug is placed in at least partially reflects that particular action of the compound that we are interested in.  As soon as our interests, beliefs, or intentions enter the picture, whatever we were doing is no longer "objective," if it ever was.

Finally, we have the least objective classification possible, which I call the drug's intentional class.  This is the level of description most people use and understand.  What they unfortunately don't generally understand is that intentional classes are entirely made up.  No molecular structures are intrinsically "stimulants" or "painkillers" or "hallucinogens."  These words describe us, the humans who interact with drugs, not the drugs.  The intentional class to which a drug belongs tells us nothing at all about the drug, except what human beings hope (or fear) the drug will do.  Drug companies take advantage of the fact that most people, even most doctors, do not understand what the intentional class really is, or even that it is a different thing from the pharmacodynamic class.  Prozac® (fluoxetine), chemically an aryloxyalkylamine, pharmacodynamically a serotonin reuptake inhibitor, belongs to the intentional class antidepressants.  Another example: let's look at Xanax® (alprazolam) again.  Chemical class: benzodiazepine.  Pharmacodynamic class: nonselective omega agonist.  Intentional class: tranquilizer, anti-anxiety agent, anxiolytic.  The intentional class reflects what we hope the drug will do, and the preferred name for that class changes over time as the fashionable nomenclature changes.  Someone who called Xanax® a "tranquilizer" today would either be old, or poorly informed.  "Anti-anxiety agent" became popular during the 1970s, when it became important to distinguish these drugs from the drugs we were feeding psychotics, which then went from being "neuroleptics" to being "anti-psychotic agent."  The latest step in the evolution of the intentional class name of the benzodiazepines is anxiolytic, a very scientific-sounding name (it just means "dissolving anxiety") that entirely obscures the fact that the drug is really just a sedative, and makes it sound like a targeted treatment for some disease entity -- a move that fits very nicely with the biopsychiatric trend to see all of psychology in terms of biochemistry, and thus entirely remove agency from the description of a person.  No, you're not anxious -- you have Generalized Anxiety Disorder.  You need an anxiolytic!

The single most important thing to know about these levels of description is this: in no way does the pharmacodynamic class entail any particular action in the whole organism.   Another way to put this is to say that, from the fact that a drug inhibits the re-uptake of serotonin, nothing at all logically follows about its effect on depressed mood, or anything else.  Platelets, the tiny components of blood that are active in clotting, are filled with serotonin re-uptake pumps (in fact, platelets, not neurons, are generally used to assay such activity).  Yet it is quite conceivable that a drug could be developed that inhibited serotonin re-uptake in platelets, but had no effect at all on mood or any other aspect of psychology.  How could this happen?  Well, there are a great many possible ways, but the simplest would be to design a serotonin reuptake inhibitor that didn't cross the blood-brain barrier and thus couldn't gain access to the nervous system, no matter what its pharmacodynamics were.  Drug companies are forever asking us (and doctors, who really should know better) to accept the idea that their new psychotropic drug has some advantage over older drugs, and to accept as evidence for this something about the molecular pharmacodynamics of the drug.  Every claim of this type must be rejected, since no logical relationship in fact exists between the two levels of description.

The transmitter molecules that are not re-uptaken are destroyed by various enzymes specific to the type of transmitter released.  Sometimes the clean-up enzyme is a very famous one, like monoamine oxidase (MAO), but sometimes it's something no one every heard of, like catechol-O-methyltrasferase, or, in the case of peptide neurotrasmitters, one of what may be thousands of still uncharacterized peptidases.   Once all transmitter molecules have been removed by re-uptake or by enzymatic destruction, and the neuron's resting potential has been restored, drug activity -- as pictured schematically -- is terminated.  Of course, in reality, there are an enormous number of drug molecules and an enormous number of neurons, each of which can be at different point in the drug action timeline, so what's really going on is vastly more complex than our models of what's going on are.  It's good to keep in mind that that's always the case.  Especially in the case of the nervous system, all imaginable models are laughably feeble in the face of the reality of the nervous system.  If someone does not agree with this, then that person has failed to understand the question.

So, we've reached the point where one neuron has sent a chemical packet with a message in it, so to speak, to another neuron.  What happens next?  Why does explaining this actually explain anything?  If you pick up a copy of the Physician's Desk Reference (PDR) and look up a narcotic analgesic, say, Percocet or Tylenol with Codeine, and read about its mechanism of action, you will read something like, "While the precise mechanism by which codeine relieves pain is not known, it is believed to relate to the existence of opiate receptors in the nervous system."  What kind of "explanation" is this?  It's as if aliens had landed on Earth, found some gloves, and were ordered by their superiors to determine what the gloves did, and, after a few weeks of study, they reported back, "We aren't exactly sure what gloves do or what they're for, but we believe it relates to the existence of hands in human beings."

Mechanisms of receptor-effector coupling.

There are a variety of ways that a neurotransmitter, drug, or other compound can produce an effect inside of a neuron by interacting with a structure, like a receptor, which lies outside of the neuron.  It is somewhat astounding, to me anyway, that this subject is now understood in such tremendous detail, when just 20 years ago, it was completely mysterious.  There are three main things that can be accomplished by a ligand's binding to a receptor.  First, remember that, like receptors, enzymes -- which catalyze biochemical reactions -- are also big peptide molecules: amino acids chained together, exactly like protein, but a bit smaller.  So it's not very far-fetched to imagine that certain enzymes are activated by the binding of a ligand, and, when activated, cause some chemical reaction to occur in the cell.  And this in fact does happen.  If you look at the illustration above, unless you have a background in biochemistry, you probably won't recognize any of the enzymes listed under "catalysis," which is fine.  The second way a receptor can work is as part of what is called a ligand-gated ion channel.  This is a big complex of related proteins whose central core forms a channel through which ions can flow -- but only if the proper receptors have been bound.  Then, as in the case of the benzodiazepines, there may be other receptors that regulate the sensitivity of the first receptors.  Many years of study could be spent on this subject alone; here, we're only trying to give you an idea of the sorts of things that happen.  Finally, there are "G protein-coupled receptors," in which the binding of a subunit of the receptor causes a related complex to expend energy by "burning" GTP to GDP, and uses that energy to power an effector, which might do any number of things from activate an enzyme to controling specific ionic currents into and out of the neuron.

The variety of neurotransmitters and neurotransmitter types, the astounding array of receptor mechanisms and the exquisitely subtle systems for fine-tuning their responses, the complex cascades of events that are always just waiting to happen in response to something -- all of this barely scratches the surface of neurophysiology, yet it entirely outruns the human ability to imagine it (I don't mean the ability to imagine the diagrams; I mean the ability to imagine the reality -- it seems that there will always be a set of otherwise intelligent people who can't be made to comprehend this difference).  Yet here is what I find truly astounding: as far as we understand things, all of this complex biochemistry serves to do only one thing: add up excitatory and inhibitory influence on neurons, which will then fire or not fire.  On the modern understanding of the brain, this is all that is ultimately going on: the emission of action potentials in a delicately balanced environment of excitation and inhibition.  This is sufficient to explain consciousness.  I can only speak for myself, but what I take away from this information is simple: despite all that has been learned, no one has even the slightest idea what the brain is actually doing.

You are free to draw your own conclusions, of course.

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