Motor axons travel in parallel through a cranial nerve in a mouse. The Brainbow neuroimaging technique used to create this image permits labeling of individual neurons with distinct colors. The method has advanced dramatically our ability to map and visualize neurons in the living brain. (Reproduced, with permission, from Joshua Sanes. Image appeared in Livet J, Weissman TA, Kang H, Draft RW, Lu J, Bennis RA, Sanes JR, Lichtman JW. Nature 2007; 540:56-61)
All of the innumerable behaviors controlled by the mature nervous system—from the perception of sensory input and the control of motor output to cognitive functions such as learning and memory—depend on precise interconnections formed by many millions of neurons during embryonic and postnatal development.
More than a century ago, Santiago Ramón y Cajal undertook a comprehensive series of anatomical studies on the structure and organization of the nervous system, and then set out to probe its development. Modern developmental neuroscientists follow in Ramón y Cajal's footsteps, trying to uncover the processes underlying the formation of neural circuits. In the intervening years technical advances have made it possible to extend this inquiry to the molecular and genetic levels. During the past few decades there have been many striking advances in understanding the molecular basis of neural development. These advances include the identification of proteins that determine how nerve cells acquire their identities, how they extend axons to target cells, form synaptic connections, and have also provided insight into how synaptic connections are modified by experience.
Development of the nervous system depends on the expression of particular genes at particular times and places. This spatial and temporal pattern of gene expression is regulated by both hardwired molecular programs and epigenetic processes. The factors that control neuronal differentiation originate both from cellular sources within the embryo and from the external environment. Internal influences include cell surface and secreted molecules that control the fate of neighboring cells, as well as transcription factors that act at the level of DNA to control gene expression. External factors include nutrients, sensory stimuli, and social experience, the effects of which are mediated through patterned changes in the activity of nerve cells. The interaction of these intrinsic and environmental factors is critical for the proper differentiation of each nerve cell.
The recent progress in defining the mechanisms that control the development of the nervous system is due largely to molecular biological studies of neural function. To take but one example, the molecular cloning of genes encoding extrinsic factors (eg, secreted proteins) and intrinsic determinants (eg, transcription factors) has provided unanticipated insight into the differentiation of the nervous system. Moreover, the function of specific genes can now be tested directly in transgenic animals or in animals in which individual genes have been inactivated by mutation.
Other important advances have emerged from the analysis of simple and genetically accessible organisms such as the fruit fly Drosophila and the nematode worm Caenorhabditis elegans. Most of the key molecules that control the formation of the nervous system are found to be conserved in organisms separated by millions of years of evolution. Thus, despite the great diversity of animal forms, the developmental programs that govern body plan and neural connectivity are conserved throughout phylogeny. It is now clear that mutations in these genes are responsible for some degenerative and even behavioral disorders. Thus, studies of neural development are beginning to provide practical insight into neurological diseases and to suggest rational strategies for restoring neural connections and function after disease or traumatic injury.
There is, however, one major way in which humans—and to a lesser extent other mammals—differ from invertebrates and lower vertebrates. Although humans are quite helpless at birth, their capacities to learn, reason, decide and abstract are prodigious. A newly-hatched bird or fly is not remarkably different in its behavioral repertoire from its adult self, but no one could say that about a person. This is largely because the nervous system of a newborn human is something of a rough draft. The hard-wired circuits that lay out its basic plan are then modified over a prolonged postnatal period by experience, acting via neural activity. In this way, the experience of each individual can leave indelible imprints on his or her nervous system and the cognitive abilities of the brain can be enhanced by learning. These processes act in all mammals, and neuroscientists now use mice to probe the mechanisms that underlie them—but they are especially prominent and prolonged in humans. It may be that the prolonged period during which experience can sculpt the human nervous system is the most important single factor in making its capabilities unique among all species.
In human infants the experience-dependent acquisition of cognitive abilities is a social feature illustrated by the fact that infants learn better from other people than from television programs. The social interactions help language development, and as language development progresses, it helps social interactions. Until recently, analysis of this late, experience-dependent remodeling of the nervous system was primarily the province of psychology. Over the past several decades, however, neuroanatomists and neurophysiologists have made strides in understanding cellular changes that underlie it. Perhaps most exciting, continued progress in genetic and molecular technologies are now being applied to the topic. The issues have been more complex and harder to define than those encountered at the early stages in neural development mentioned above, so the molecular revolution has been slower in coming to them—but the pace is now increasing rapidly. The implications of this new knowledge are great. For example, understanding how cognitive abilities are acquired during the preschool years helps us enhance the ability to educate all children. Moreover, there is increasing reason to believe that some behavioral disorders, such as autism or schizophrenia, may result in part from defects in the experience-dependent tuning of neural circuits during early postnatal life.
In Part VIII, we examine vertebrate neural development in a sequential manner. Beginning with the early stages of neural development, we concentrate on the factors that control the diversity and survival of nerve cells, guide axons, and regulate the formation of synapses. We then explain how interaction with the environment, both social and physical, modifies or consolidates the neural connections formed during early development. Depriving individuals of their normal environment during the early critical period of development can have profound consequences for the later maturation of the brain and thus for behavior. Finally, we examine factors, such as steroid hormones, that continue to influence the structure of the brain during early postnatal development and the biochemical changes that occur as the brain ages.