Neurobiological studies of the developing brain provide much information on how the brain initially forms in the fetus. At first glance, we might conclude that early brain development depends strictly on nature—intrinsic genetic directives—and Chapter 1 appears to support this view. But it is important to recognize that environment and nurture can also play a role in early brain development. I use the term “environment” here and in the rest of this discussion on brain development very broadly. Essentially, I mean nongenetic factors, of which environment is only one, although perhaps the major one. As I discussed in Chapter 5, random developmental variations due simply to chance could and probably do occur during development, and affect brain development to some extent. In most instances, this might make little or no difference, but in others it could well make a substantial one. We simply don’t yet know. However, certain environmental factors that perturb early brain development are easy to document, and some can have devastating effects.

An obvious and dramatic example of the substantial role that environment can play in early brain development is that of fetal alcohol syndrome (FAS). Children born to alcoholic mothers show a wide range of developmental brain disorders, from misaligned cortical cells and abnormal clusters of cells in parts of the brain to an absence of many of the cortical infoldings and a significantly undersized brain. Severely affected children are dramatically retarded mentally, and less affected children demonstrate learning disabilities, lower IQ scores, and behavioral problems, including hyperactivity.

How much alcohol consumption is required to cause such problems? No one knows for sure, but binge drinking, especially early in pregnancy, seems to result in the most severe cases of FAS. And it is easy to show that just a few drops of vodka added to their surrounding water cause zebrafish embryos to develop significant brain malformations.

Coupled with alcohol consumption in causing severe FAS is the nutritional state of the mother and the use of other drugs, including tobacco. Thus, early brain development can be influenced by a variety of environmental factors, including the mother’s health, her diet, and perhaps even her level of anxiety and or stress. In support of this notion is the evidence that socio-economic status is the best predictor of health, longevity, and absence of mental illness in all societies. This is not a very well studied area, but it needs to be kept in mind when thinking about the relative roles of nature and nurture in early brain development.

Environmental influences on a fetus might be subtler than the examples given above. One accepted notion put forward to explain the differences between identical twins is that the in utero environment can be different for different fetuses. Some fetuses might receive slightly more or less nutrition because of a somewhat different blood supply to the fetus or perhaps where a fetus resides in utero at a particular time could make a difference. The observation that infants at birth prefer the language spoken by their mothers (discussed in Chapter 3) suggests that even sensory

input in utero might influence brain development to some extent. The question is how much do these subtle factors matter? We simply don’t know the answer. And of course, every pregnant woman wants to know what she should do to optimize her baby’s health and future happiness, but again we can’t say what. We can describe things not to do, but this is as far as neurobiological facts can take us.

We must grant, though, that in healthy mothers, nature—intrinsic genetic directives—is of primary importance in establishing the framework of the developing brain, though framework is probably not the best word or correct concept to describe early brain development. Indeed, the evidence is that the brain substantially develops—even overdevelops—by these intrinsic genetic directives. Sophisticated neuronal circuits are formed by intrinsic mechanisms, and remarkably adult-like responses can be elicited from neurons in newborn, environmentally inexperienced, brains. The visual system results described in Chapter 2 make this point well.

This does not mean that intrinsic directives wire everything up precisely. Refinement of circuits clearly involves experience, and early in its development the brain is particularly amenable to modification, modulation, refinement, or whatever you might wish to call it. These early times of exceptional plasticity are the critical and sensitive periods.

What we know about maturation of the brain (Chapter 2) might surprise some and is perhaps an area where educators and others might be influenced by the neurobiological evidence. The sculpting of the brain during its maturation phase consists to a considerable extent of a pruning and refinement process. The young brain has more neurons, more expansive branching patterns, and more synapses than the adult brain, and environment—nature—plays a critical role in the refinement and pruning. In birds, for example, at the end of the critical period for either vocal learning or imprinting the density of synaptic spines on the key neurons in the appropriate nuclei drops to about half of what it was during the critical period. (Chapter 3 discusses these changes.)

Thus, the amount of potential synaptic input into these neurons is significantly reduced after the critical period is over.

The unexpected conclusion is that the brain initially has great intrinsic capability and potential, and during brain maturation some capability is lost—the adage “Use it or lose it” fits here. The game, then, is to work toward losing as little brain capability as possible. Language acquisition is the model here (discussed in Chapter 3). Young infants can distinguish and make the sounds of any language, but they lose this ability within the first few years. Children readily learn languages early on, but by puberty it becomes more difficult for virtually everyone to learn a new language. Should we be exposing our youngsters to the sounds of many different languages early on, and should we begin language instruction much earlier than we presently do? We don’t know the answers, but they seem worth considering.

This general principle for language acquisition holds for other capabilities as well, from learning to throw a ball to playing a musical instrument or manipulating a computer. Encouraging youngsters to develop skills early would appear to make sense from what we now know. The example here, of course, is the observation that string players who learned to play their instrument before the age of 12 have a greater cortical representation of the left fingering hand than do musicians who began to play later in life. The point is that the young brain is more plastic, more modifiable than the adult brain, and perhaps we should take advantage of this property.

But a critically important question is how far can we push the envelope? How far can experience go in taking advantage of early brain capability or, to go further, can the brain’s capability be expanded beyond what is there initially? The experiments with rats and enriched environments indicated that it is possible to induce the sprouting of new processes and the formation of new synapses in the young animal, but this occurs, fortunately, over one’s entire lifetime and is not limited to the young brain, as discussed in Chapter 2. By raising animals in enriched environments, new

brain circuitry can be induced to form, but it is superimposed on a massive pruning and refinement of neural circuitry that is naturally occurring. The owl experiments described in Chapter 3 suggest that new synapses and circuits formed early in an animal’s life—during the critical or sensitive period—might remain into adulthood even if they are not used for a considerable time and even if they have become entirely silent.

What the neurobiology is telling us—the bottom line—is that genetic directives are clearly most critical in brain building, although the environment can also play some role, whereas environmental factors play the fundamental role during brain maturation, although there is genetic restraint. This does not mean that environmental factors during brain maturation can greatly override the brain’s intrinsic capability. We all differ significantly because we are different genetically. The view of behaviorist John Watson in the 1920s that he could turn any healthy infant into a “doctor, lawyer, artist, merchant-chief and yes, even beggar-man and thief” by environmental influences is not accepted by any serious scientist today. Each of us has different capabilities and talents and this certainly reflects to a great extent our genetic makeup. But within that genetic makeup, there is room for modification, even perhaps for some elaboration, and this is where experience and environment come in. Of course, these are extraordinarily contentious issues, not because most people today do not agree that what we are is a mix of nature and nurture, but because we are not sure how much each contributes to the final product. This is where the great sticking points lie, although attempts to put numbers on the extent that behavior or capability is genetically or environmentally based are continually being made. (See Chapter 5 for a discussion of this.)

Neurobiology contributes little to this debate, except to say that both nature and nurture are clearly involved. But to reiterate, what we have learned neurobiologically about brain development should guide us as we raise and educate our children.

Unequivocal examples of individual genes causing specific neurological diseases that significantly alter behaviors are now known, Huntington’s disease being one (discussed in Chapter 5). A dominantly inherited disorder, it occurs in everyone who inherits a sufficiently defective copy of the gene. The nature of the gene defect in Huntington’s disease is now understood, and the previously unexplained variation in onset and progression of the disease observed in those suffering from it appears to relate mainly to the extent of the defect in the gene. That is, the defective gene has an excessive number of CAG repeats, and the more repeats, the earlier the onset and the faster the progression of the disease.

That individual genes can exert different phenotypic effects on individual organisms has long been appreciated and is usually termed gene penetrance. It is often ascribed to environmental or epigenetic effects on gene expression, and this might be true in many cases. However, in the case of Huntington’s disease, gene penetrance is explained to a considerable extent by variations in the defective gene itself. It might also be explained by variations in normal genes in an individual—so-called polymorphisms. These are alterations in genes that produce proteins that function quite normally but that alter the response of a tissue or organism to a particular environmental condition. Let me illustrate with a dramatic example. Rodents, especially albino ones, are quite susceptible to light damage of their photoreceptor cells. If continuously exposed to ordinary room lights for just a few days, the animal’s photoreceptor cells degenerate. A surprise observation made a few years ago was that one strain of albino mice is highly resistant to light damage. Much more continuous light exposure is required to cause photoreceptor damage in these animals compared to most strains of mice. Comparing the photoreceptor responses of this strain to others reveals no very significant differences; they all seem to function within normal limits. The variation shows up only under the stress of continuous light.

A genetic difference between this and other strains has now

been uncovered. It is the result of a single amino acid change in a protein needed to make the correct form of the vitamin A derivative bound in rhodopsin (discussed in Chapter 6). In the resistant strain, the correct form of the vitamin A derivative needed to make rhodopsin is not made quite as fast; thus, after being broken down by light, a normal event, rhodopsin is not reformed as quickly in the light-resistant strain as in light-sensitive strains.

This change probably has little effect on the visual performance of the animals. Indeed, the resistant animals make as much rhodopsin as do the light-sensitive ones and their photoreceptors can detect dim light stimuli as efficiently as those in other mouse strains; it just takes the light-damage-resistant mice somewhat longer to reach this level of performance. It is only under conditions of continuous light that the retinas of the light-resistant and light-sensitive strains respond very differently—and because of a tiny—one amino acid—difference in one protein.

The point here is that very different phenotypes under specific environmental conditions can result from what might be considered insignificant genetic differences. The relationships, then, between genes, their products, and the environment are complex and not easy to sort out.

That a number of neurological diseases such as Alzheimer’s disease and cognitive diseases such as schizophrenia have links to genetics is not at all surprising. Indeed, it might be inevitable, but the nature of the genetic link is the critical question. We talk of predisposing genes for such diseases, but exactly what that means in many cases is difficult to define. In the case of Alzheimer’s disease, the predisposing genes all appear to be related to the synthesis or breakdown of β-amblyoid, the protein that accumulates in the brains of sufferers and is its precipitating cause (discussed in Chapter 6). This makes sense, and if we propose that there might be genes that predispose someone not to be susceptible to a disease, we might then be able to explain the Aunt Marians who live to be 102 and remain perfectly normal cognitively. The example described earlier, of a polymorphism in a protein that makes photoreceptors resistant to breakdown in continuous light,

could be viewed as the product of a predisposing gene that acts like that—to counter an environmental stressor and prevent neuronal degeneration.

At least an order of magnitude more difficult to answer is the question of genes and cognitive behaviors. As noted in Chapter 5, whereas claims have been made for individual genes controlling, or even strongly predisposing people to a specific complex behavior, none of these claims have held up in a convincing way. It is almost certainly true that there are predisposing genes for cognitive behaviors, but this has not yet been pinned down, and for any such behavior there are, in virtually all cases, multiple genes involved—pulling and pushing in opposing directions. It is no wonder, then, that the field of behavioral genetics is in a muddle as far as complex cognitive behaviors are concerned. Some believe that we will never be able to relate complex behaviors to genetics in any meaningful way because of the complexity and obviously large role that environment must play.

A recent article in Science magazine entitled “Rethinking Behavior Genetics” by Dean Hamer, a behavioral geneticist at the National Institutes of Health, reflects the frustration of those in the field. He ends his article with the following:

But it is perhaps useful to point out some of the remarkable similarities in identical twins raised apart and studied by Thomas Bouchard before completely dismissing the idea that the study of human behavioral genetics is irrelevant. One of the first pairs of identical twins studied by Bouchard were boys separated five weeks after birth and raised in different families about 80 miles apart in Ohio. When they were reunited after 39 years, the similarities between them were remarkable. They both were 6 feet

tall and both weighed 180 pounds, but more surprising was the striking similarity of many of their behavioral characteristics. They had the same walk and many identical mannerisms—from the way each picked up a knife to nail-biting. They had similar likes and dislikes—from stock-car racing (like) to baseball (dis-like). Their houses were similar in design and size and each had an elaborate workshop where he made wooden objects similar to those made by his twin. As far as these two were concerned, it was harder to find differences than similarities in their behavior and personalities.

Because these twins were raised in the same state, less than 100 miles apart, it might be supposed that proximity could account for at least some of the remarkable similarity between them. But another set of male twins, split apart only a few months after birth, were brought up in very different environments—one in Trinidad and the other in Germany. They first met at age 21, but then had very little communication until they were reunited in Minneapolis in the early 1980s when they were about 50 years old and were studied by Bouchard and his colleagues. Again, some of the similarities between these two were astonishing. Their gaits were similar; they had unusual habits in common such as storing rubber bands on their wrists and reading magazines from back to front. There were certainly differences between them, but the similarities in mannerisms and temperament were striking. Sets of identical female twins raised apart showed similar mannerism identities, from excessive giggling to one set of twins arriving in Minneapolis with each having seven rings on her fingers.

What are we to make of these curious similarities? No one is sure, and other investigators have described identical twin pairs raised in homes differing in social class as having quite different behavioral traits, but I don’t think the above examples can be easily dismissed as chance. They would seem to be genetically based, but how? One would imagine that such trivial personality traits would reflect environment much more than genetics and, if genetics, an exceptionally complex genetics that would not likely result in such obvious similarities.

A major realization of the past two decades is that the adult brain is more modifiable than previously believed (discussed in Chapter 4). That we can learn and remember things our entire lives has long been recognized, of course, but this was viewed as the exception, not the rule, as far as modifiability of the adult brain is concerned. Today the view has softened—not that we believe the adult brain is as plastic as the young developing brain, but we do think it is possible for the adult brain to acquire abilities previously thought unavailable to it.

This new realization has encouraged researchers to seek ways to allow the adult brain to achieve skills ordinarily managed only by the developing brain. One undertaken by Jay McClelland and his colleagues at Carnegie-Mellon University is to teach Japanese adults to distinguish “r” from “l” sounds which they have difficulty doing (see Chapter 3). McClelland and colleagues have reported some success, albeit with only a few subjects. They did this by first presenting to the subjects exaggerated and even distorted speech sounds that never occur normally. As the subjects began to discriminate these sounds, they were gradually presented with more normal, harder to discriminate sounds. Whereas initially the subjects could discriminate the sounds at levels only just above chance (that is, 50-60 percent), after 480 training trials, the subjects improved to 80-100 percent correct discriminations. Obviously this preliminary study needs to be expanded and repeated, but it is promising, and other, more effective, ways might be found to achieve such results.

Another approach being undertaken is to study that small cohort, less than 5 percent of the population, that learns second languages very effectively as adults. What is different about these people’s brains, and how do they go about learning a new language? Can any light be shed on the issue by studying them? As yet no definitive answers are available.

A third approach is to carry out such studies in animals, and a recent report by Knudsen and his colleagues at Stanford suggests

that it is possible to achieve some compensation in adult owls when prisms that shift their visual field are placed on the animals, something thought not possible after the critical period for this plasticity had passed. (Knudsen’s work with owls is discussed in Chapter 3.) The key here was to shift the visual field by only a small amount at a time. Using such a training paradigm, the adult owls showed some compensation. The extent of compensation was limited compared to young owls, but that some plasticity could be induced was unequivocal and interesting.

Some ocular dominance plasticity has now been observed in the visual cortex of adult mice also. Mice, unlike cats, monkeys, and ourselves, have only a small area of visual field overlap in the two eyes because their eyes are on the sides of their head and do not point forward. In the area of visual field overlap, inputs from the opposite-side (contralateral) eye to the cortical neurons predominate, although weak input from the same-side (ipsilateral) eye can be detected. By occluding the dominant eye by lid suture and extending the period of deprivation, strengthening of the ipsilateral input to the cortical neurons was found. Interestingly, this cortical plasticity depended on the presence of NMDA receptors; the ocular dominance plasticity was not observed in mice that had the NMDA receptors knocked out genetically. As discussed in Chapter 4, these glutamate receptors are critical for the generation of long-term potentiation not only in memory and learning but in other forms of cortical plasticity as well.

How far we can go in training the adult brain is, of course, not at all clear, but the new data are certainly encouraging and recommend that we rethink the issue. Approaches might involve not only training normal adult brains but also retraining damaged brains. Are we too quick to decide that nothing can be done following a stroke or other serious neurological conditions? I noted in Chapter 5 the devastating injury to the actor Christopher Reeve, whose spinal cord was crushed in a riding accident. Whereas it was generally believed that his injury was permanent and nothing could be done to help him, some novel treatment approaches applied to him appear to have resulted in surprising

progress. The reports so far have appeared mainly in the media but, if confirmed, suggest that we might be able to do much more than previously thought for such serious neurological injuries.

At the same time we are beginning to achieve some understanding of the neurobiological factors involved in promoting neuronal cell survival or inhibiting neuronal cell death as well as promoting axonal regeneration. As this work progresses, it is likely that new therapies will become available to deal with neurological injuries and disease.

In Chapter 6, I argued that a biological limit to maximum human life expectancy is likely and that within a few years average life expectancy will reach a plateau, at least in the developed countries. The reason, according to biodemographers, that average life expectancy will plateau is that many of the causes of early death—especially infectious diseases—have been dealt with. Furthermore, there has been substantial progress in reducing early death from the other major killers, including cardiovascular disease, diabetes, and cancer.

My own view is that our life span is determined mainly by our brain. That neurons are not replaced in the brain for the most part and that brain structure and function gradually deteriorate with age seem unequivocal and the ultimate determinant of a finite life span. As noted in Chapter 6, it is possible to transplant hearts, livers, and kidneys as well as other organs from humans and even animals, and artificial organs are being developed. But I don’t think anyone seriously believes that we can transplant a whole brain or make an artificial brain. Indeed, even if one could do this, the uniqueness of that individual would be destroyed. Furthermore, as noted earlier, if whole brain transplantation were possible, it would be better to be the donor than the recipient!

It is conceivable that we will find ways to replace neurons with stem cells, either those that exist in certain brain regions or others that are transplanted into the brain, but I think these possibilities are still remote and, even if they do become feasible, would they ever be able to maintain or replace an entire brain? And, of course, is this something we would even want to do—to prolong human life to 150-200 years or longer? (Chapter 6 discusses this.)

I am not suggesting that we should stop trying to cure neurodegenerative diseases or to find ways to replace dead or dying neurons with stem cells. But our goal in these studies should be to improve the quality of life for those in their later years, not to increase maximal life span. One might relate to the other, but not necessarily so, and it is the former goal—to optimize the years we have to spend on this planet—we should strive for.

To end this book on a more positive note, let me emphasize again that neuroscience as a field has progressed spectacularly over the past half century. Much of this progress has been at the cell and molecular levels. We now have quite a good grasp of how individual neurons function—how they receive, integrate, and carry signals and how they pass on information to other cells. The field is now turning to a systems-level analysis—how aggregates of neurons interact to underlie behaviors. These studies provide the links with psychology and promise to give us an understanding of the brain, behavior, and a number of the issues described in this book.

In this quest, it is still early days, and it might still be asking too much of neuroscience to provide definitive answers to such contentious issues as the nature-nurture debate in brain development or the relative roles of genetics and environment in human behavior. I have emphasized the point over and over that neuroscience at the moment can take us only so far. However, I think that neuroscience has given us some glimpse of how many of these questions might be answered and even, perhaps, models to ponder.

Further, the future for much more progress is bright. Several noninvasive techniques for studying the human brain—PET scanning, fMRI, and magnetoencephalography and their variants—are available. And we can already analyze what is going on in animal brains down to the single synapse. Combining the two approaches is powerful and is key to providing a compelling picture of how the brain works, how best to encourage its development, and how best to maintain it.

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