2.7 Development of the Nervous System

Overview of Early Development

Fertilization of the egg is followed by a series of events that lead to the formation of a multicellular blastula, which has already begun to specialize. The blastula contains three main cell lines that, after a few days, form three layers: the ectoderm (outer layer) that will form the nervous system and the outer skin, lens of the eye, inner ear, and hair; the mesoderm (middle layer) that will form the skeletal system and voluntary muscle; and the endoderm (inner layer) that will form the gut and digestive organs. The early processes that go into forming the nervous system are called neurulation (Figure 2.45). During this stage, the ectodermal cells on the dorsal surface form the neural plate.

As the nervous system continues to develop, the cells at the lateral borders of the neural plate push upward. (Imagine joining the long sides of a rectangular piece of dough to form a tube.) This movement causes the more central cells of the neural plate to invaginate, or dip inward, to form the neural groove. As the groove deepens, the cells pushing up at the border of the neural fold region eventually meet and fuse, forming the neural tube that runs anteriorly and posteriorly along the embryo. The adjacent nonneural ectoderm then reunites to seal the neural tube within an ectodermal covering that surrounds the embryo.

At both ends of the neural tube are openings (the anterior and the posterior neuropores) that close on about the 23rd to 26th day of gestation. When the anterior neuropore is sealed, this cavity forms the primitive brain, consisting of three spaces, or ventricles. If the neuropores do not close correctly, neural tube defects such as anencephaly (absence of a major portion of the brain and skull) or spina bifida (incomplete formation of some of the vertebrae) may result. From this stage on, the brain’s gross features are formed by growth and flexion (bending) of the neural tube’s anterior portions (Figure 2.46). The result is a cerebral cortex that envelops the subcortical and brainstem structures. The final three-dimensional relations of the brain’s structures are the product of continued cortical enlargement and folding. The posterior portion of the neural tube differentiates into a series of repeated segments that form the spinal cord.

In primates, almost the full complement of neurons is generated prenatally during the middle third of gestation. The entire adult pattern of gross and cellular neural anatomical features is present at birth, and very few neurons are generated after birth (but see the end of this section, “Birth of New Neurons Throughout Life”). Although axonal myelination continues for some period postnatally (e.g., until adulthood in the human frontal lobe), the newborn has a well-developed cortex that includes the cortical layers and areas characterized in adults. For instance, BA17 (the primary visual cortex) can be distinguished from the motor cortex by cytoarchitectonic analysis of its neuronal makeup at the time of birth.

Neural Proliferation and Migration of Cortical Cells The neurons that form the brain arise from a layer of precursor cells in proliferative zones located adjacent to the ventricles of the developing brain. The cortical neurons arise from the subventricular zone, and those that form other parts of the brain arise from precursor cells in the ventricular zone. Figure 2.47 shows a cross section through the cortex and the precursor cell layers at various times during gestation. The cells that form the cortex will be the focus of this discussion. The precursorcells are undifferentiated cells from which all cortical cells (including neuronal subtypes and glial cells) arise through cell division and differentiation. For the first 5 to 6 weeks of gestation, the cells in the subventricular zone divide in a symmetrical fashion. The result is exponential growth in the number of precursor cells.

At the end of 6 weeks, when there is a stockpile of precursor cells, asymmetrical division begins. After every cell division, one of the two cells formed becomes a migratory cell destined to be part of another layer; the other cell remains in the subventricular zone, where it continues to divide asymmetrically. Later in gestation, the proportion of migratory cells increases until a laminar (i.e., layered) cortex made up of the migratory cells is formed. This cortex has a foundational epithelial layer that becomes the cell lining of the ventricles and is known as the ependymal cell layer.

The migratory cells travel outward from the subventricular zone by moving along peculiar cells known as radial glial cells, which stretch from the subventricular zone to the surface of the developing cortex. The work of radial glial cells does not end with development. These cells are transformed into astrocytes in the adult brain, helping to form part of the blood–brain barrier.

As the first migrating neurons approach the surface of the developing cortex—a point known as the cortical plate—they stop short of the surface. Neurons that migrate later pass beyond the termination point of the initial neurons and end up in more superficial positions—positions nearer the outer cortical surface. Thus, it is said that the cortex is built from the inside out, because the first neurons to migrate lie in the deepest cortical layers, whereas the last to migrate move farthest out toward the cortical surface.

The Baby Brain: Ready to Rock ’n’ Roll?

A host of behavioral changes takes place during the first months and years of life. What accompanying neurobiological changes enable these developments? Even if we assume that neuronal proliferation continues, we know that at birth, the human brain has a fairly full complement of neurons, and these are organized to form a human nervous system that is normal, even if not complete in all details. Which details are incomplete, and what is known about the time course of brain maturation?

Although the brain nearly quadruples in size from birth to adulthood, the change is not due to an increase in neuron number. A substantial amount of that growth comes from synaptogenesis (the formation of synapses) and the growth of dendritic trees. Synapses in the brain begin to form long before birth—before week 27 in humans (counting from conception)—but they do not reach peak density until after birth, during the first 15 months of life. Synaptogenesis is more pronounced early in the deeper cortical layers and occurs later in more superficial layers, following the pattern of neurogenesis described earlier.

At roughly the same time that synaptogenesis is occurring, neurons of the brain are increasing the size of their dendritic arborizations, extending their axons, and undergoing myelination. Synaptogenesis is followed by synapse elimination (sometimes called pruning), which continues for more than a decade. Synapse elimination is a means by which the nervous system fine-tunes neuronal connectivity, presumably eliminating the interconnections between neurons that are redundant, unused, or do not remain functional.

Use it or lose it! The person you become is shaped by the growth and elimination of synapses, which in turn are shaped by the world you’re exposed to and the experiences you have. A specific example of synaptic pruning comes from primary visual cortex (BA17): Initially, there is overlap between the projections of the two eyes onto neurons in BA17. After synapse elimination, the cortical inputs from the two eyes within BA17 are nearly completely segregated. The axon terminals relaying information from each eye form a series of equally spaced patches (called ocular dominance columns), and each patch receives inputs from predominantly one eye.

One of the central hypotheses about the process of human synaptogenesis and synapse elimination is that the time course of these events differs in different cortical regions. The data suggest that in humans, synaptogenesis and synapse elimination peak earlier in sensory (and motor) cortex than in association cortex. By contrast, in the brain development of other primates, synaptogenesis and pruning appear to occur at the same rates across different cortical regions. Differences in methodology, however, must be resolved before these interspecies variations will be wholly accepted. Nonetheless, compelling evidence suggests that different regions of the human brain reach maturity at different times.

The increase in brain volume that occurs postnatally is also a result of both myelination and the proliferation of glial cells. White matter volume increases linearly with age across cortical regions (Giedd et al., 1999). In contrast, gray matter volume increases nonlinearly, showing a preadolescent increase followed by a postadolescent decrease. In addition, the time courses of gray matter increase and decrease are not the same across different cortical regions. In general, these data support the idea that postnatal developmental changes in the human cerebral cortex may not occur with the same time course across all cortical regions (see also Shaw et al., 2006).

Birth of New Neurons Throughout Life

One principle about the human brain that once dominated in the neuroscience community was the idea that the adult brain produces no new neurons. This view was held despite a variety of claims of neurogenesis in the brain in histological studies dating as far back as the time of Ramón y Cajal. In the last couple of decades, however, studies using an array of modern neuroanatomical techniques have challenged this belief.

Neurogenesis in adult mammals has now been well established in two brain regions: the hippocampus and the olfactory bulb. Neurogenesis in the hippocampus is particularly noteworthy because it plays a key role in learning and memory. In rodents, studies have shown that stem cells in a region of the hippocampus known as the dentate gyrus produce new neurons in the adult, and these can migrate into regions of the hippocampus where similar neurons are already functioning. It is important to know that these new neurons can form dendrites and send out axons along pathways expected of neurons in this region of the hippocampus, and they can also show signs of normal synaptic activity. These findings are particularly interesting because the number of new neurons correlates positively with learning or enriched experience (more social contact or challenges in the physical environment) and negatively with stress (e.g., living in an overcrowded environment). Moreover, the number of newborn neurons is related to hippocampal-dependent memory (Shors, 2004).

Other investigators have found that these new neurons become integrated into functional networks of neurons and participate in behavioral and cognitive functions in the same way that those generated during development do (Ramirez-Amaya et al., 2006). Future work will be required to establish whether adult neurogenesis occurs more broadly in the mammalian brain or is restricted to the olfactory bulb and hippocampus.

What about the adult human brain? Does neurogenesis also occur in mature humans? In a fascinating line of research, a team of scientists from California and Sweden (Eriksson et al., 1998) explored this question in a group of terminally ill cancer patients. As part of a diagnostic procedure related to their treatment, the patients were given BrdU, a synthetic form of thymidine used as a label to identify neurogenesis. The purpose was to assess the extent to which the tumors in the cancer patients were proliferating; tumor cells that were dividing would also take up BrdU, and this label could be used to quantify the progress of the disease.

Neurons undergoing mitotic division during neurogenesis in these patients also took up BrdU, which could be observed in postmortem histological examinations of their brains. The postmortem tissue was immunostained to identify neuron-specific cell surface markers. The scientists found cells labeled with BrdU in the subventricular zone of the caudate nucleus and in the granular cell layer of the dentate gyrus of the hippocampus (Figure 2.48). By staining the tissue to identify neuronal markers, the researchers showed that the BrdU-labeled cells were neurons (Figure 2.49). These findings demonstrate that new neurons are produced in the adult human brain, and that our brains renew themselves throughout life to an extent not previously thought possible.

These exciting results hold great promise for the future of neuroscience. Research is under way to investigate the functionality of new neurons in the adult brain and to determine whether such neuronal growth can be facilitated to ameliorate brain damage or the effects of diseases such as Alzheimer’s.