Determined, page 38
But be honest—would your life be so different if those endocrine changes had instead occurred twenty-four hours later?
Second scenario: Emerging from a store, you are unexpectedly chased by a lion. As part of the stress response, your brain increases your heart rate and blood pressure, dilates blood vessels in your leg muscles, which are now frantically working, sharpens sensory processing to produce a tunnel vision of concentration.
And how would things have turned out if your brain took twenty-four hours to send those commands? Dead meat.
That’s what makes the brain special. Hit puberty tomorrow instead of today? So what? Make some antibodies in an hour instead of now? Rarely fatal. Same for delaying depositing calcium in your bones. But much of what the nervous system is about is encapsulated in the frequent question in this book: What happened one second before? Incredible speed.
The nervous system is about contrasts, unambiguous extremes, having something or having nothing to say, maximizing signal-to-noise ratios. And this is demanding and expensive.[*]
One Neuron at a Time
The basic cell type of the nervous system, what we typically call a “brain cell,” is the neuron. The hundred billion or so in our brains communicate with each other, forming complex circuits. In addition, there are “glia” cells, which do a lot of gofering—providing structural support and insulation for neurons, storing energy for them, helping to mop up neuronal damage.
Naturally, this neuron/glia comparison is all wrong. There are about ten glial cells for every neuron, coming in various subtypes. They greatly influence how neurons speak to each other, and also form glial networks that communicate completely differently from neurons. So glia are important. Nonetheless, to make this primer more manageable, I’m going to be very neuron-centric.
Part of what makes the nervous system so distinctive is how distinctive neurons are as cells. Cells are usually small, self-contained entities—consider red blood cells, which are round little discs.
Neurons, in contrast, are highly asymmetrical, elongated beasts, typically with processes sticking out all over the place. Consider this drawing of a single neuron seen under a microscope in the early twentieth century by one of the patriarchs of the field, Santiago Ramón y Cajal:
It’s like the branches of a manic tree, explaining the jargon that this is a highly “arborized” neuron (a point explored at length in chapter 7, concerning how those arbors form in the first place).
Many neurons are also outlandishly large. A zillion red blood cells fit on the proverbial period at the end of this sentence. In contrast, there are single neurons in the spinal cord that send out projection cables that are many feet long. There are spinal cord neurons in blue whales that are half the length of a basketball court.
Now for the subparts of a neuron, the key to understanding its function.
What neurons do is talk to each other, cause each other to get excited. At one end of a neuron are its metaphorical ears, specialized processes that receive information from another neuron. At the other end are the processes that are the mouth, that communicate with the next neuron in line.
The ears, the inputs, are called dendrites. The output begins with a single long cable called an axon, which then ramifies into axonal endings—these axon terminals are the mouths (ignore the myelin sheath for the moment). The axon terminals connect to the spines on the branches of dendrites of the next neuron in line. Thus, a neuron’s dendritic ears are informed that the neuron behind it is excited. The flow of information then sweeps from the dendrites to the cell body to the axon to the axon terminals, and is then passed to the next neuron.
Let’s translate “flow of information” into quasi chemistry. What actually goes from the dendrites to the axon terminals? A wave of electrical excitation. Inside the neuron are various positively and negatively charged ions. Just outside the neuron’s membrane are other positively and negatively charged ions. When a neuron has gotten an exciting signal from the previous neuron at a spine on a dendritic branch, channels in the membrane in that spine open, allowing various ions to flow in, others to flow out, and the net result is that the inside of the end of that dendrite becomes more positively charged. The charge spreads toward the axon terminal, where it is passed to the next neuron. That’s it for the chemistry.
Two gigantically important details:
The Resting Potential
So when a neuron has gotten a hugely excitatory message from the previous neuron in line, its insides can become positively charged, relative to the extracellular space around it. When a neuron has something to say, it screams its head off. What might things look like then when the neuron has nothing to say, has not been stimulated? Maybe a state of equilibrium, where the inside and outside have equal, neutral charges.[*] No, never, impossible. That’s good enough for some cell in your spleen or your big toe. But back to that critical issue, that neurons are all about contrasts. When a neuron has nothing to say, it isn’t some passive state of things just trickling down to zero. Instead, it’s an active process. An active, intentional, forceful, muscular, sweaty process. Instead of the “I have nothing to say” state being one of default charge neutrality, the inside of the neuron is negatively charged.
You couldn’t ask for a more dramatic contrast: I have nothing to say = inside of the neuron is negatively charged. I have something to say = inside is positive. No neuron ever confuses the two. The internally negative state is called the resting potential. The excited state is called the action potential. And why is generating this dramatic resting potential such an active process? Because neurons have to work like crazy, using various pumps in their membranes, to push some positively charged ions out, to keep some negatively charged ones in, all in order to generate that negative internal resting state. Along comes an excitatory signal; channels open, and oceans of ions rush this way and that to generate the excitatory positive internal charge. And when that wave of excitation has passed, the channels close and the pumps have to get everything back to where they started, regenerating that negative resting potential. Remarkably, neurons spend nearly half their energy on the pumps that generate the resting potential. It doesn’t come cheap to generate dramatic contrasts between having nothing to say and having some exciting news.
Now that we understand resting potentials and action potentials, on to the other gigantically important detail.
That’s Not What Action Potentials Really Are
What I’ve just outlined is that a single dendritic spine receives an excitatory signal from the previous neuron (i.e., the previous neuron has had an action potential); this generates an action potential in that spine, which spreads the axonal branch that it is on, on toward the cell body, over it, and on to the axon and the axon terminals, and passes the signal to the next neuron in line. Not true.
Instead: The neuron is sitting there with nothing to say, which is to say that it’s displaying a resting potential; all of its insides are negatively charged. Along comes an excitatory signal at one dendritic spine on one dendritic branch, emanating from the axon terminal of the previous neuron in line. As a result, channels open and ions flow in and out in that one spine. But not enough to make the entire insides of the neuron positively charged. Simply a little less negative just inside that spine. Just to attach some numbers here that don’t matter in the slightest, things shift from the resting potential charge being around −70 millivolts (mV) to around −60 mV. Then the channels close. That little hiccup of becoming less negative[*] spreads farther to nearby spines on that branch of dendrite. The pumps have started working, pumping ions back to where they were in the first place. So at that dendritic spine, the charge went from −70 mV to −60 mV. But a little bit down the branch, things then go from −70 to −65 mV. Farther down, −70 to −69. In other words, that excitatory signal dissipates. You’ve taken a nice smooth, calm lake, in its resting state, and tossed a little pebble in. It causes a bit of a ripple right there, which spreads outward, getting smaller in its magnitude, until it dissipates not far from where the pebble hit. And miles away, at the lake’s axonal end, that ripple of excitation has had no effect whatsoever.
In other words, if a single dendritic spine is excited, that’s not enough to pass the excitation down to the axonal end and on to the next neuron. How does a message ever get passed on? Back to that wonderful drawing of a neuron by Cajal.
All those bifurcating dendritic branches are dotted with spines. And in order to get sufficient excitation to sweep from the dendritic end of the neuron to the axonal end, you have to have summation—the same spine must be stimulated repeatedly and rapidly and/or, more commonly, a bunch of the spines must be stimulated at once. You can’t get a wave, rather than just a ripple, unless you’ve thrown in a lot of pebbles.
At the base of the axon, where it emerges from the cell body, is a specialized part (called the axon hillock). If all those summated dendritic inputs produce enough of a ripple to move the resting potential around the hillock from −70 mV to about −40 mV, a threshold is passed. And once that happens, all hell breaks loose. A different class of channels opens in the membrane of the hillock, which allows a massive migration of ions, producing, finally, a positive charge (about +30 mV). In other words, an action potential. Which then opens up those same types of channels in the next smidgen of axonal membrane, regenerating the action potential there, and then the next, and the next, all the way down to the axon terminals.
From an informational standpoint, a neuron has two different types of signaling systems. From the dendritic spines to the axon hillock, it’s an analog signal, with gradations of signals that dissipate over space and time. And from the axon hillock on to the axon terminals, it’s a digital system with all-or-none signaling that regenerates down the length of the axon.
Let’s throw in some imaginary numbers, in order to appreciate the significance of this. Let’s suppose an average neuron has about one hundred dendritic spines and about one hundred axon terminals. What are the implications of this in the context of that analog/digital feature of neurons?
Sometimes nothing interesting. Consider neuron A, which, as just introduced, has one hundred axon terminals. Each one of those connects to one of the one hundred dendritic spines of the next neuron in line, neuron B. Neuron A has an action potential, which propagates down to all of its hundred axon terminals, which excites all one hundred dendritic spines in neuron B. The threshold at the axon hillock of neuron B requires fifty of the spines to get excited around the same time in order to generate an action potential; thus, with all one hundred of the spines firing, neuron B is guaranteed to get an action potential and is going to pass on neuron A’s message.
Now instead, neuron A projects half of its axon terminals to neuron B and half to neuron C. It has an action potential; does that guarantee one in neurons B and C? Each of those neurons’ axon hillocks has that threshold of needing a signal from fifty pebbles at once, in which case they have action potentials—neuron A has caused action potentials in two downstream neurons, has dramatically influenced the function of two neurons.
Now instead, neuron A evenly distributes its axon terminals among ten different target neurons, neurons B through K. Is its action potential going to produce action potentials in the target neurons? No way—continuing our example, the ten dendritic spines’ worth of pebbles in each target neuron is way below the threshold of fifty pebbles.
So what will ever cause an action potential in, say, neuron K, which only has ten of its dendritic spines getting excitatory signals from neuron A? Well, what’s going on with its other ninety dendritic spines? In this scenario, they’re getting inputs from other neurons—nine of them, with ten inputs from each. In other words, any given neuron integrates the inputs from all the neurons projecting to it. And out of this comes a rule: the more neurons that neuron A projects to, by definition, the more neurons it can influence; however, the more neurons it projects to, the smaller its average influence will be upon each of those target neurons. There’s a trade-off.
This doesn’t matter in the spinal cord, where one neuron typically sends all its projections to the next one in line. But in the brain, one neuron will disperse its projections to scads of other ones and receive inputs from scads of other ones, with each neuron’s axon hillock determining whether its threshold is reached and an action potential generated. The brain is wired in these networks of divergent and convergent signaling.
Now to put in a flabbergasting real number: your average neuron has about ten thousand to fifty thousand dendritic spines and about the same number of axon terminals. Factor in a hundred billion neurons, and you see why brains, rather than kidneys, write good poetry.
Just for completeness, here are a couple of final facts that should be ignored if this has already been more than you wanted. Neurons have some additional tricks, at the end of an action potential, to enhance the contrast between nothing-to-say and something-to-say even more, a means of ending the action potential really fast and dramatically—something called delayed rectification and another thing called the hyperpolarized refractory period. Another minor detail from that diagram above: a type of glial cell wraps around an axon, forming a layer of insulation called a myelin sheath; this “myelination” causes the action potential to shoot down the axon faster.
And one final detail of great future importance: the threshold of the axon hillock can change over time, thus changing the neuron’s excitability. What things change thresholds? Hormones, nutritional state, experience, and other factors that fill this book.
We’ve now made it from one end of a neuron to the other. How exactly does a neuron with an action potential communicate its excitation to the next neuron in line?
Two Neurons at a Time: Synaptic Communication
Suppose an action potential triggered in neuron A has swept down to all those tens of thousands of axon terminals. How is this excitation passed on to the next neuron(s)?
The Defeat of the Synctitium-ites
If you were your average nineteenth-century neuroscientist, the answer was easy. Their explanation would be that a fetal brain is made up of huge numbers of separate neurons that slowly grow their dendritic and axonal processes. And eventually, the axon terminals of one neuron reach and touch the dendritic spines of the next neuron(s), and they merge, forming a continuous membrane between the two cells. From all those separate fetal neurons, the mature brain forms this continuous, vastly complex net of one single superneuron, called a “synctitium.” Thus, excitation readily flows from one neuron to the next because they aren’t really separate neurons.
Late in the nineteenth century, an alternative view emerged, namely that each neuron remained an independent unit, and that the axon terminals of one neuron didn’t actually touch the dendritic spines of the next. Instead, there’s a tiny gap between the two. This notion was called the neuron doctrine.
The adherents to the synctitium school were arrogant as hell and even knew how to spell “synctitium,” so they weren’t shy in saying that they thought that the neuron doctrine was asinine. Show me the gaps between axon terminals and dendritic spines, they demanded of these heretics, and tell me how excitation jumps from one neuron to the next.
And then in 1873, it all got solved by the Italian neuroscientist Camillo Golgi, who invented a technique for staining brain tissue in a novel fashion. And the aforementioned Cajal used this “Golgi stain” to stain all the processes, all the branches and branchlets and twigs of the dendrites and axon terminals of single neurons. Crucially, the stain didn’t spread from one neuron to the next. There wasn’t a continuous merged net of a single superneuron. Individual neurons are discrete entities. The neuron doctrine–ers vanquished the synctitium-ites.[*]
Hooray, case closed; there are indeed micro-microscopic gaps between axon terminals and dendritic spines; these gaps are called synapses (which weren’t directly visualized until the invention of electron microscopy in the 1950s, putting the last nail in the synctitial coffin). But there’s still that problem of how excitation propagates from one neuron to the next, leaping across the synapse.
The answer, whose pursuit dominated neuroscience in the middle half of the twentieth century, is that the electrical excitation doesn’t leap across the synapse. Instead, it gets translated into a different type of signal.
Neurotransmitters
Sitting inside each axon terminal, tethered to the membrane, are little balloons, called vesicles, filled with many copies of a chemical messenger. Along comes the action potential that initiated at the very start of the axon, at that neuron’s axon hillock. It sweeps over the terminal and triggers the release of those chemical messengers into the synapse. Which they float across, reaching the dendritic spine on the other side, where they excite the neuron. These chemical messengers are called neurotransmitters.
How do neurotransmitters, released from the “presynaptic” side of the synapse, cause excitation in the “postsynaptic” dendritic spine? Sitting on the membrane of the spine are receptors for the neurotransmitter. Time to introduce one of the great clichés of biology. The neurotransmitter molecule has a distinctive shape (with each copy of the molecule having the same). The receptor has a binding pocket of a distinctive shape that is perfectly complementary to the shape of the neurotransmitter. And thus the neurotransmitter—cliché time—fits into the receptor like a key into a lock. No other molecule fits snugly into that receptor; the neurotransmitter molecule won’t fit snugly into any other type of receptor. Neurotransmitter binds to receptor, which triggers those channels to open, and the currents of ionic excitation begin in the dendritic spine.
