This describes “transsynaptic” communication with neurotransmitters. Except for one detail: what happens to the neurotransmitter molecules after they bind to the receptors? They don’t bind forever—remember that action potentials occur on the order of a millisecond. Instead they float off the receptors, at which point the neurotransmitters have to be cleaned up. This occurs in one of two ways. First, for the ecologically minded synapse, there are “reuptake pumps” in the membrane of the axon terminal. They take up the neurotransmitters and recycle them, putting them back into those secretory vesicles to be used again.* The second option is for the neurotransmitter to be degraded in the synapse by an enzyme, with the breakdown products flushed out to sea (i.e., the extracellular environment, and from there on to the cerebrospinal fluid, the bloodstream, and eventually the bladder).
These housekeeping steps are hugely important. Suppose you want to increase the amount of neurotransmitter signaling across a synapse. Let’s translate that into the excitation terms of the previous section—you want to increase excitability across the synapse, such that an action potential in the presynaptic neuron has more of an oomph in the postsynaptic neuron, which is to say it has an increased likelihood of causing an action potential in that second neuron. You could increase the amount of neurotransmitter released—the presynaptic neuron yells louder. Or you could increase the amount of receptor on the dendritic spine—the postsynaptic neuron is listening more acutely.
But as another possibility, you could decrease the activity of the reuptake pump. As a result, less of the neurotransmitter is removed from the synapse. Thus it sticks around longer and binds to the receptors repeatedly, amplifying the signal. Or, as the conceptual equivalent, you could decrease the activity of the degradative enzyme; less neurotransmitter is broken down, so more sticks around longer in the synapse, having an enhanced effect. As we saw, some of the most interesting findings that help explain individual differences in the behaviors that concern us in this book relate to amounts of neurotransmitter made and released, and the amounts and functioning of the receptors, reuptake pumps, and degradative enzymes.
Types of Neurotransmitters
So what is this mythic neurotransmitter molecule, released by action potentials from the axon terminals of all of the hundred billion neurons? Here’s where things get complicated, because there is more than one type of neurotransmitter.
Why more than one? The same thing happens in every synapse, which is that the neurotransmitter binds to its key-in-a-lock receptor and triggers the opening of various channels that allow the ions to flow and makes the inside of the spine a bit less negatively charged.
One reason is that different neurotransmitters depolarize to different extents—in other words, some have more excitatory effects than others—and for different durations. This allows for a lot more complexity in information being passed from one neuron to the next.
And now to double the size of our palette, there are some neurotransmitters that don’t depolarize, don’t increase the likelihood of the next neuron in line having an action potential. They do the opposite—they “hyperpolarize” the dendritic spine, opening different types of channels that make the resting potential even more negative (e.g., shifting from –70 mV to –80 mV). In other words, there are such things as inhibitory neurotransmitters. You can see how that has just made things more complicated—a neuron with its ten thousand dendritic spines is getting excitatory inputs of differing magnitudes from various neurons, getting inhibitory ones from other neurons, and integrating all of this at the axon hillock.
Thus there are lots of different classes of neurotransmitters, each binding to a unique receptor site that is complementary to its shape. Are there a bunch of different types of neurotransmitters in each axon terminal, so that an action potential triggers the release of a whole orchestration of signaling? Here is where we invoke Dale’s Principle, named for Henry Dale, one of the grand pooh-bahs of the field, who in the 1930s proposed a rule whose veracity forms the very core of each neuroscientist’s sense of well-being: an action potential releases the same type of neurotransmitter from all of the axon terminals of a neuron. Therefore there will be a distinctive neurochemical profile to a particular neuron—“Oh, that neuron is a neurotransmitter A–type neuron. And what that also means is that the neurons that it talks to have neurotransmitter A receptors on their dendritic spines.”*
There are dozens of neurotransmitters that have been identified. Some of the most renowned: serotonin, norepinephrine, dopamine, acetylcholine, glutamate (the most excitatory neurotransmitter in the brain), and GABA (the most inhibitory). It’s at this point that medical students are tortured with all the multisyllabic details of how each neurotransmitter is synthesized—its precursor, the intermediate forms the precursor is converted to until finally arriving at the real thing, the painfully long names of the various enzymes that catalyze the syntheses. Amid that there are some pretty simple rules built around three points:
You do not ever want to find yourself running for your life from a lion and, oopsies, the neurons that tell your muscles to run fast go off-line because they’ve run out of neurotransmitter. Neurotransmitters are therefore made from precursors that are plentiful; often they are simple dietary constituents. Serotonin and dopamine, for example, are made from the dietary amino acids tryptophan and tyrosine, respectively. Acetylcholine is made from dietary choline and lecithin.
A neuron can potentially have dozens of action potentials a second. Each involves restocking the vesicles with more neurotransmitter, releasing them, and mopping up afterward. Given that, you do not want your neurotransmitters to be huge, complex, ornate molecules, each of which requires generations of stonemasons to construct. Instead they are all made in a small number of steps from their precursors. They’re cheap and easy to make. For example, it takes only two simple synthetic steps to turn tyrosine into dopamine.
Finally, to complete this pattern of neurotransmitter synthesis as cheap and easy, multiple neurotransmitters can be generated from the same precursor. In neurons that use dopamine as the neurotransmitter, for example, there are two enzymes that do those two construction steps. Meanwhile, in norepinephrine-releasing neurons there’s an additional enzyme that converts dopamine to norepinephrine.
Cheap, cheap, cheap. Which makes sense. Nothing becomes obsolete faster than a neurotransmitter after it has done its postsynaptic thing. Yesterday’s newspaper is useful today only for house-training puppies.
Neuropharmacology
As these neurotransmitterology insights emerged, they allowed scientists to begin to understand how various “neuroactive” and “psychoactive” drugs and medicines work.
Broadly, such drugs fall into two categories: those that increase signaling across a particular type of synapse, and those that decrease it. We already saw some of the strategies for increasing signaling: (a) Stimulate more synthesis of the neurotransmitter (for example, by administering the precursor or using a drug that increases the activity of the enzymes that synthesize the neurotransmitter). As an example, Parkinson’s disease involves a loss of dopamine in one brain region, and a staple of treatment is to boost dopamine levels by administering the drug L-DOPA, which is the immediate precursor of dopamine. (b) Administer a synthetic version of the neurotransmitter, or a drug that is structurally close enough to the real thing to fool the receptors. Psilocybin, for example, is structurally similar to serotonin and activates a subtype of its receptors. (c) Stimulate the postsynaptic neuron to make more receptors. Fine in theory, but not easily done. (d) Inhibit degradative enzymes so that more of the neurotransmitter sticks around in the synapse. (e) Inhibit the reuptake of the neurotransmitter, prolonging its effects in the synapse. The modern antidepressant of choice, Prozac, does exactly that in serotonin synapses. Thus it is often referred to as an “SSRI”—a selective serotonin reuptake inhibitor.
Meanwhile, a pharmacopeia of drugs are available to decrease s
ignaling across synapses, and you can see what their underlying mechanisms are going to include—blocking the synthesis of a neurotransmitter, blocking its release, blocking its access to its receptor, and so on. Fun example: Acetylcholine stimulates your diaphragm to contract. Curare, the poison used in darts by Amazonian tribes, blocks acetylcholine receptors. You stop breathing.
A final, very relevant point—just as the threshold of the axon hillock can change over time in response to experience, nearly every facet of the nuts and bolts of neurotransmitterology can be changed by experience as well.
MORE THAN TWO NEURONS AT A TIME
We have now triumphantly reached the point of thinking about three neurons at a time. And within not too many pages, we will have gone wild and considered even more than three. The purpose of this section is to see how circuits of neurons work, the intermediate step before examining what entire regions of the brain have to do with the best and worst of our behaviors. Therefore, the examples here were chosen merely to give a flavor of how things work at this level.
Neuromodulation
Consider the following diagram:
The axon terminal of neuron B forms a synapse with the dendritic spine of the postsynaptic neuron (let’s call it neuron C) and releases an excitatory neurotransmitter. The usual. Meanwhile, neuron A sends an axon terminal projection on to neuron B. But not to a normal place, a dendritic spine. Instead its axon terminal synapses onto the axon terminal of neuron B.
What’s up with this? Neuron A releases the inhibitory neurotransmitter GABA, which floats across that “axoaxonic” synapse and binds to receptors on that side of neuron B’s axon terminal. And such an inhibitory effect (i.e., making that –70 mV resting potential even more negative) snuffs out any action potential hurtling down that branch of the axon, keeps it from getting to the very end and releasing neurotransmitter; in the jargon of the field, neuron A is having a neuromodulatory effect on neuron B.
Sharpening a Signal over Time and Space
Now for a new type of circuitry. To accommodate this, I’m using a simpler way of representing neurons. As diagrammed, neuron A sends all of its axonal projections to neuron B and releases an excitatory neurotransmitter, symbolized by the plus sign. The circle in neuron B represents the cell body plus all the dendritic branches.
Now consider the next circuit. Neuron A stimulates neuron B, as usual. In addition, it also stimulates neuron C. This is routine, with neuron A splitting its axonal projections between the two target cells, exciting both. And what does neuron C do? It sends an inhibitory projection back onto neuron A, forming a negative feedback loop. Back to the brain loving contrasts, energetically screaming its head off when it has something to say, and energetically being silent otherwise. This is a more macro level of the same. Neuron A fires off a series of action potentials. What better way to energetically communicate that it’s all over than to become majorly silent, thanks to the feedback loop? It’s a means of sharpening a signal over time.* And note that neuron A can “determine” how powerful that negative feedback signal will be by how many of the ten thousand axon terminals it shunts toward neuron C instead of B.
Such temporal sharpening of a signal can be accomplished in another way:
Neuron A stimulates B and C. Neuron C sends an inhibitory signal on to neuron B that will arrive sometime after B starts getting stimulated (since the A/C/B loop is two synaptic steps, versus one for A/B). Result? Sharpening a signal with “feed-forward inhibition.”
Now for another type of sharpening of a signal, of increasing the signal to noise ratio. Consider this six-neuron circuit, where neuron A stimulates B, C stimulates D, and E stimulates F:
So neuron C sends an excitatory projection on to neuron D. But in addition, neuron C’s axon sends collateral inhibitory projections on to neurons A and E.* Thus, if neuron C is stimulated, it both stimulates neuron D and silences neurons A and E. With such “lateral inhibition,” C screams its head off while A and E become especially silent. It’s a means of sharpening a spatial signal (and note that the diagram is simplified, in that I’ve omitted something obvious—neurons A and E also send inhibitory collateral projection on to neuron C, as well as to the neurons on the other sides of them in this imaginary network).
Lateral inhibition like this is ubiquitous in sensory systems. Shine a tiny dot of light onto an eye. Wait, was that photoreceptor neuron A, C, or E that just got stimulated? Thanks to lateral inhibition, it is clearer that it was C. Ditto in tactile systems, allowing you to tell that it was this smidgen of skin that was just touched, not a little this way or that. Or the ears telling you it was definitely an A, not an A-sharp or A-flat.*
Thus what we’ve seen is another example of contrast enhancement in the nervous system. What is the significance of the fact that the silent state of a neuron is negatively charged, rather than a neutral 0 mV? It’s a way of sharpening a signal within a neuron. Feedback, feed-forward, and lateral inhibition? A way of sharpening a signal within a circuit.
Two Different Types of Pain
This next circuit encompasses some of the elements just introduced and explains why there are, broadly, two different types of pain. I love this circuit because it is just so elegant:
Neuron A’s dendrites sit just below the surface of the skin, and the neuron has an action potential in response to a painful stimulus. Neuron A then stimulates neuron B, which projects up the spinal cord, letting you know that something painful just happened. But neuron A also stimulates neuron C, which inhibits B. This is one of our feed-forward inhibitory circuits. Result? Neuron B fires for a while and then is silenced, and you perceive this as a sharp pain—you’ve been poked with a needle.
Meanwhile, there’s neuron D, whose dendrites are in the same general area of the skin and respond to a different type of painful stimulus. As before, neuron D excites neuron B, and the message is sent up to the brain. But it also sends projections to neuron C, where it inhibits it. Result? When neuron D is activated by a pain signal, it inhibits the ability of neuron C to inhibit neuron B. And you perceive it as a throbbing, continuous pain, like a burn or abrasion. Importantly, this is reinforced further by the fact that action potentials travel down the axon of neuron D much slower than in neuron A (having to do with that myelin that I mentioned earlier—details aren’t important). So the pain in neuron A’s world is not only transient but also fast. Pain in the neuron D branch not only is long-lasting but also has a slower onset.
The two classes of fibers can interact, and we often intentionally force them to. Suppose that you have some sort of continuous, throbbing pain—say, an insect bite. How can you stop the throbbing? Briefly stimulate the fast fiber. This adds to the pain for an instant, but by stimulating neuron C, you shut the system down for a while. And that is precisely what we often do in such circumstances. An insect bite throbs unbearably, we scratch hard right around it to dull the pain, and the slow, chronic pain pathway is shut down for up to a few minutes.
The fact that pain works this way has important clinical implications. For one thing, it has allowed scientists to design treatments for people with severe chronic pain syndromes (for example, someone with a severe back injury). Implanting a little electrode into the fast pain pathway and attaching it to a stimulator on the person’s hip enables the patient to buzz that pathway now and then to turn off the chronic pain; it works wonders in many cases.
Thus we have a circuit that encompasses a temporal sharpening mechanism, introduces the double negative of inhibiting inhibitors, and is just all-around cool. And one of the biggest reasons why I love it is that it was first proposed in 1965 by the great neurobiologists Ronald Melzack and Patrick Wall. It was merely proposed as a theoretical model—“No one has ever seen this sort of wiring, but we propose that it’s got to look something like this, given how pain works.” And subsequent work showed that’s exactly how this part of the nervous system is wired.
Which Guy Is It?
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One final, completely hypothetical circuit.
Suppose we have a circuit made of two layers of neurons:
Neuron A projects to neurons 1, 2, and 3; neuron B projects to 2, 3, and 4, etc. Now let’s show how hypothetical this circuit is by giving neurons A, B, and C completely imaginary functions. Neuron A responds to the picture of the guy on the left, B to the guy in the middle, C to the one on the right:
What can neuron 1 learn? How to recognize that particular guy. Neuron 5 is equally specialized. But what can neuron 3 learn? How Victorian gentlemen dressed. It’s the neuron that will help you identify the Victorian in the quartet below:
Neuron 3’s knowledge is general and comes from the overlap of the first layer’s projections. Neurons 2 and 4 are also generalist neurons, but they’re less accurate because they have only two exemplars each.
So neuron 3 is at the convergent center of this network. And the fanciest parts of the brain are wired up in a way that resembles this fairy-tale circuit, writ large—at the same time, neuron 3 is a more peripheral element in some other circuit sending projections to it (say, a circuitry that would be drawn perpendicular to this page), neuron 1 is at the very center of some other network in the fourth dimension, and so on. All of these neurons are embedded within multiple networks.
What does this produce? The capacity for association, metaphor, analogy, parable, symbol. To link two disparate things, even from different sensory modalities. To Homerically associate the color of wine with the color of the sea, that both “tomato” and “potato” can be pronounced in two different ways in a song, that a bright red tongue sticking out can remind you of music by the Stones. It’s why I associate Stravinsky and Picasso, given that albums (remember those?) of Stravinsky’s music always seemed to have a Picasso painting on the cover. And it’s why a rectangular piece of cloth with a distinctive pattern of colors on it can stand for an entire nation or people or ideology.
Behave: The Biology of Humans at Our Best and Worst Page 70
