Shortly after the closure of the neural tube, a series of three vesicle-like swellings appear at the rostral apex of the tube. These swellings will eventually form the three primary brain vesicles: the prosencephalic (forebrain), the mesencephalic (midbrain), and the rhombencephalic (hindbrain) areas. Through various folding patterns the three primary vesicles ultimately give rise to the mature brain structures. The development of the three primary vesicles into their representative mature structures results in the following progression: the prosencephalic region develops into the telencephalon and the diencephalon; the mesencephalon remains undifferentiated, giving rise to the mature mesencephalon; and the rhombencephalon develops into the myelencephalon and metencephalon. Each of these secondary brain vesicles further develops into the recognised mature divisions of the human brain (Figs 2.5 and 2.6).

Figure 2.5 This figure demonstrates the development of primary and secondary brain vesicles.

Figure 2.6 Development of the secondary vesicles from the precursor primary vesicles. The prosencephalon differentiates into the telencephalon and the diencephalon. The mesencephalon remains undifferentiated as the mesencephalon. The rhombencephalon differentiates into the myelencephalon and the metencephalon.

The wall of the neural tube is formed initially by pseudostratified columnar epithelium that rests on the external basement membrane. Each cell sends a peripheral process to both the external (basal) lamina and the neural tube internal (luminal) surface. At the luminal surface a complex of junctional connections allows communication with other cells. The nuclei are found at different levels within the neuroepithelium, except those in the later stages of mitosis which are constantly found at the luminal aspect (Cowan 1981). The young neurons constantly migrate from the internal or luminal lamina to the external or basal lamina in a process called interkinetic nuclear migration. Throughout this process the neurons must continually retract and reform their peripheral processes. At this stage of development the neural tube consists of two histological areas of tissues, the ependymal or germinal cell layer found on the luminal aspect of the tube and the ventricular zone or matrix layer which spans the remainder of the tube and is in contact with the basal membrane. Continued cell division leads to growth and expansion of the neural tube in three ways: general expansion of the neural tube surface epithelium, rapid growth of the brain and spinal cord, and differentiation of the different lineages of cell types including glial cells and neurons. This differentiation phase is marked by a migration of some of the cells from the ventricular zone to the newly emerging intermediate or mantle zone, away from the luminal surface. The neurons in the intermediate zone send processes outward towards the basal membrane which eventually develops into the marginal zone. To summarise, at this point (4 weeks or 28 days) the development of the neural tube consists of four histologically identifiable layers: the ependymal or germinal layer, from which all the cells of the central nervous system will develop; the ventricular or matrix layer, which consists of newly formed cells undergoing interkinetic nuclear migration and mitosis; the intermediate or mantle zone, which consists of cells migrating from the intermediate zone; and the marginal zone, which consists of the elongated cytoplasmic processes of the cells in the intermediate zone. Interposed throughout these layers are developing glial cells including the radial glial cells which seem to act as guide cells for the migrating neurons (Fig. 2.7).

Figure 2.7 This figure illustrates the migration of neurons from the ventricular surface toward the plial surface of the neural tube. This migration takes place along highly specialised cells called neural glial cells. Note that neural migration appears to occur in cohorts, with neural cells born at or near the same time migrating at the same time.

Each population of neurons is generated during a distinct period of embryonic or fetal life. This period is usually quite short, ranging from a few days to a week. Cells born of the same cohort can be classified as embryological homologues. The relationships that each cohort of neurons forms with other neurons of the same cohort become very important as the system matures. These relationships can be used clinically to gain insight into the function of other related homologous systems by stimulating one system of neurons and measuring the response of a homologous system through a variety of clinical testing procedures (see Embryological Homologous Relationships later in this chapter). The sequence at which the cells withdraw from the proliferative pool is well defined. For example, in the retina the ganglion cells farthest from the original luminal zone are generated first, followed by the inner nuclear layer, which are in turned followed by the photoreceptors. The actual sequence may vary somewhat from region to region; for example, the situation in the motor cortex is completely reversed with the deepest cells forming first (Fig. 2.8).

Figure 2.8 A magnified diagrammatic view of Fig. 2.7. The various cell proliferation zones, the intermediate zone, and the migration of the neurons via the radial glial cells are illustrated.

The process of neurogenesis seems to be highly programmed in both space and time. The process seems to progress largely in a ventral to dorsal, and cervical to sacral gradient (above, down, inside, out). In keeping with this strategy, the motor systems arising from the basal plate located ventrally are generally generated before the sensory systems arising from the alar plate, which is located dorsally (Figs 2.9A and 2.9B).

Figure 2.9 A transverse section through the developing spinal cord of a human embryo 4 weeks old. (A) A schematic drawing of the real slide (B). Note the roof or alar plate and the floor or basal plate in (B).

It is now apparent that neurons and glial cells are generated simultaneously, and not in isolation as was once thought. Glial cells, however, tend to develop and proliferate long after neurons have been generated. This is evident in the formation of myelinated axons by the proliferation of glial cells subsequent to axon formation.

In a vast majority of cases the larger neurons of a system are generated before the smaller neurons of the same general type in the system. A notable exception to this occurs in the motor cortex where the smaller stellate cells of the cortex develop prior to the large pyramidal cells. The extent to which genetic determination plays a role in the fate of individual cells is unknown in mammals but thought likely to play a role.