The Mind and the Brain (15 page)

The molecular basis of memory and learning, the discovery of which earned Kandel a share of the 2000 Nobel Prize in physiology or medicine, stands as one of the best understood of the changes the brain undergoes. It is one of the mechanisms that underlie the plasticity of the developing brain. Changes in how an organism interacts with its environment result in changes in connectivity.

We’ve spent some time on synaptic efficiency, and the “cells that fire together, wire together” mantra, because similar phenomena seem to underlie the plasticity of the developing brain, the diminution of plasticity in the mature brain, and the possibility of directed or induced neuroplasticity in every brain. At the beginning of the 1990s, neuroscientists had only a general idea of how a few embryonic cells transform themselves into a brain, a spinal cord, and a skein of peripheral nerves, all hooked up in such a way as to form a sensing, thinking, feeling human being. Wiring up the circuits of neurons that support those tricks is, to put it mildly, a daunting task. Neurons must appear in the right place at the right time and in the right quantity, to be sure. But contrary to Woody Allen’s conclusion that 90 percent of life is just showing up, for a neuron, showing up is just the start. The axons that shoot out of the neurons must also find their way to the correct target cells and make functional connections, and in the last few years researchers started to glimpse how the brain does it. The key finding is that the brain wires itself in response to signals it receives from its environment, a process very similar to that underlying neuroplasticity in the adult brain, too.

It has become a cliché to note that the human brain is, as far as
we’re aware, the most sophisticated and complex structure in the known universe. A newborn brain contains something on the order of 100,000,000,000—that’s 100 billion—nerve cells. That is most of the neurons a brain will ever have. Although 100 billion is an impressive number, it alone cannot explain the complexity, or the power, of the brain that lets us see and hear, learn and remember, feel and think; after all, a human liver probably contains 100 million liver cells, but if you collect 1,000 livers, you fall quite a few synapses short of a brain. The complexity of a brain, as distinct from a liver, derives chiefly from the connections that its neurons make. Neurons consist of that cell body we described, of course, but it is the neuron’s accessories—axons and dendrites—that truly set a neuron apart from a liver cell.

Axons and dendrites enable neurons to wire up with a connectivity that computer designers can only fantasize about. Each of the 100 billion neurons connects to, typically, anywhere from about a few thousand to 100,000 other neurons. The best guess is that, at birth, each neuron makes an average of 2,500 of these specialized junctions, or synapses; reaches a connectivity peak of 15,000 synapses at age two or three; and then starts losing synapses in a process called pruning. If we take a conservative mean for the number of connections (1,000), then the adult brain boasts an estimated 100,000,000,000,000—100 trillion—synapses. Other estimates of the number of synapses in the adult brain go as high as 1,000 trillion.

Although it would be perfectly reasonable to posit that genes determine the brain’s connections, just as a wiring diagram determines the connections on a silicon computer chip, that is a mathematical impossibility. As the Human Genome Project drew to a close in the early years of the new millennium, it became clear that humans have something like 35,000 different genes. About half of them seem to be active in the brain, where they are responsible for such tasks as synthesizing a neurotransmitter or a receptor. The
brain, remember, has billions of nerve cells that make, altogether, trillions of connections. If each gene carried an instruction for a particular connection, we’d run out of instructions long before our brain reached the sophistication of, oh, a banana slug’s. Call it the genetic shortfall: too many synapses, too few genes. Our DNA is simply too paltry to spell out the wiring diagram for the human brain.

Before we explore what makes up the shortfall, it’s only fair to give genes their due by describing some aspects of brain development that they do deserve credit for. Since fetal brains follow almost identical developmental sequences and reach the same developmental milestones at about the same time, it’s safe to say that the overall pattern of brain development is surely under genetic control (which is not to say that developmental neuroscientists have figured out how the genes do it). The brain starts down the developmental highway soon after a sperm fertilizes an egg. By the fourteenth day, what is now a ball of hundreds of cells folds in on itself, resembling a cleft in a plump chin: cells on the outer surface infold, until they arrive in the interior of the ball. As the ball of cells continues folding in, it simultaneously lengthens, forming a tube. One end will become the spinal cord; the other will develop into the brain. At about three weeks the embryo begins to produce neurons, reaching a peak of production in the seventh week and largely finishing by the eighteenth. Running the numbers shows what a prodigious feat neurogenesis is: since a newborn enters the world with 100 billion or so neurons in its brain, and since the lion’s share of neurogenesis is completed just short of halfway through gestation, the fetal brain is producing something on the order of 500,000 neurons every minute during the high-production phase, or 250,000 per minute averaged over the entire nine months in utero. More than 90 percent have formed midway through gestation. After nine months, the newborn’s brain is a jungle of that estimated 100 billion nerve cells.

From stem cells on the walls of the brain-to-be’s ventricles,
immature neurons are born. Starting in the second trimester of pregnancy, these protoneurons immediately begin to migrate outward in a journey so challenging that it has been likened to a baby’s crawling from New York to Seattle and winding up in the precise neighborhood, on the right street, at the correct house that he was destined for from the moment he left Manhattan. These baby neurons follow a sort of cerebral interstate, a structure of highways laid down by cells called
radial glia
. These cells form an intracranial road network complete with rest stops (for the glial cells also nourish the traveling neurons). Protoneurons destined for the cortex observe a first-to-go, first-to-stop rule: those that first leave the ventricular walls stop in the closest cortical layer. The second wave of émigrés continues on to the second-closest layer, and the subsequent waves migrate past each formative layer before stopping at an ever-more-distant layer, until all six cortical layers are populated. Once the immature neurons are in place, the radial glia vanish. How neurons realize that they have reached their final destination remains a mystery, too. But we do know that it is only when the immature neurons are in place that they become full-fledged neurons and put down roots, blossoming with dendrites and sprouting an axon by which they will communicate with, and form a circuit with, other neurons near and far.

Timing also seems to be under clear genetic control. For instance, the
sulci
—invaginations, or fissures—that divide one lobe of the brain from another emerge at what seem to be genetically programmed times: the central sulcus, dividing the frontal lobe from the parietal, appears around the twentieth week of gestation and is almost fully formed in the seventh month. At about the fifteenth week after conception a body map appears in the brainstem and then in the thalamus (a sort of relay station for incoming sensory input), whose neurons begin forming synapses in what will be the brain’s somatosensory cortex. Only several weeks into the final trimester do thalamic axons begin to form synapses on cortical neurons that will be their (normally) permanent partners. In fact, it is
the arrival of these thalamic axons that turns this strip of cortex into the somatosensory region. By the third trimester, if all is going as it should, most of the neurons have found their place, and, although the circuits are only rough approximations of what they will ultimately become, at least the brain’s major structures have taken shape.

At birth, the spinal cord and brainstem are just about fully formed and functional. That works out well, since it is these structures that carry out such vital tasks as thermoregulation, heartbeat, and reflexes such as grasping, sucking, and startling. Soon after birth the cerebellum and midbrain become
myelinated
(encased in the fatty coating of myelin that enables them to carry electrical impulses efficiently); the thalamus, basal ganglia, and parts of the limbic system follow suit in the first and second years after birth. Finally, the cerebral cortex, led by sensory areas, comes fully on line. At birth the somatosensory cortex, which processes the sense of touch, is a mess, with neurons from different points on the body converging in cortical regions that overlap so much that a newborn cannot tell where she is being touched. But through the experience of touch the somatosensory cortex develops into a precise “map,” which means that one spot receives tactile stimuli from the lips and only the lips, and another receives tactile stimuli from the right knee and only the right knee, until every speck of skin is represented. This maturation proceeds from head to toe, with the mouth the first part of the body to become touch-sensitive. The rest of the cortex follows on the somatosensory toward maturity: motor regions first, followed by the parietal, temporal, and frontal association cortices (the seats of judgment, reason, attention, planning, and language, among other higher-order function), which are still forming in the late teens.

It is not merely gross anatomic structures of the brain that form during gestation and early childhood. Moving a few billion neurons to a particular site doesn’t give you a working brain any more than
throwing a few million integrated circuits into a plastic box gives you an iMac. All of those nerve cells need not only to find their way to the right location in the nascent brain but, crucially, to make the right connections once there, so that a taste detected on the tongue can make its way to the brainstem and from there to cortical regions that will identify it as, say, vanilla, or a tickle on the right cheek will be transformed into electrochemical signals that reach the part of the somatosensory cortex responsible for processing tactile sensations on that cheek.

Forming the right connections is no simple matter; that baby crawling from New York to a particular address in Seattle has it easy compared to what neurons face. Consider the challenge faced by neurons of the nascent visual system. Their goal is to form a functional pathway that goes like this: neural signals from the rods and cones of the eye’s retina travel to retinal interneurons, which hand them off to retinal ganglion cells (which constitute the optic nerve) and then to a relay station called the
lateral geniculate
nucleus, where axons from the left eye alternate with axons from the right eye to form eye-specific layers. From there, the signal travels to cells in the primary visual cortex all the way in the back of the brain, where clusters of neurons receiving signals from the left eye form separate, alternating layers with clusters of neurons receiving input from the right eye. In order to effect this signal transfer properly, then, axons from the eye must grow to the correct spot in the lateral geniculate nucleus (LGN). Axons growing from the LGN must resist the urge to terminate in synapses in the auditory or sensory cortex (where they arrive first) and instead continue growing until they reach the appropriate target all the way back in the primary visual cortex. More than that, cells lying beside each other in the retina must extend their axons to neighboring neurons in the lateral geniculate, which must in turn extend their axons to neighboring cells in the visual cortex: for the ultimate goal is for each clump of a few hundred neighboring neurons in
the visual cortex to form synapses only with neurons responding to the same little region of the baby’s visual field. How in the world do they do it?

The first part of the axon’s journey—the extension of its tip in the right direction—is the easy part. That’s because target neurons emit come-hither signals called
trophic factors
. These provide general directions that tell each growing axon from the retina to form a synapse with a particular target neuron in the visual cortex; which neurons emit trophic factors and which traveling axons respond to them seems to be under genetic control. Using a specialized tip called a
growth cone
, the axon is programmed to sniff out and grow toward molecules of specific trophic factors scattered along the predestined route, like Hansel and Gretel following the trail of crumbs through the forest path back to their cottage. Growth cones have what seem to be genetically encoded receptor molecules that make the axon elongate and migrate in the direction of attractant molecules. In this sense, target selection is preprogrammed, with genes directing axons and dendrites to grow to their approximate final destinations. At the same time neurons with which the axon is not destined to form a synapse release chemical signals that repel the axons. Between the attractants and repellents—which have been given names like
netrin
(from the Sanskrit
netra
, meaning “leader” or “guide”) and
semaphorin (semaphor
is Greek for “signal”)—the axon stays on track to its destination.

Once the axon has arrived in Seattle, to continue the analogy, it still has to find the right neighborhood and the right house that will be its ultimate cellular address. And this is anything but preprogrammed, for as we’ve seen humans simply don’t have enough genes to specify every connection that the neurons in the brain must forge. To make up the genetic shortfall, it slowly dawned on neuroscientists in the 1980s, the brain must assemble itself into functional circuits through experience. Once the genes have run out, experience directs the axons to complete their journey.

The factor that provides the developing brain with the right
connections is, ironically, an early profusion of wrong connections. The fetal brain is profligate in its overproduction of both neurons and synapses. Not all the axons trying to reach out and touch another will manage it; the failures die. About half the neurons that form in the fetal brain die before the baby is born: 200 billion neurons, give or take, are reduced to the 100 billion of a newborn as neurons that fail to form functional synapses vanish.