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Saturday, October 24, 2020



After initial brain morphogenesis is complete, and neural crest migration has established the peripheral nervous system (see Plate 1-4), several bendings, invaginations, and evaginations transform the geometry of the developing brain. The addition of neurons via neurogenesis, which begins in the first trimester, underlies these movements. Neurogenesis reaches a maximum during midgestation to late gestation and ceases (with few exceptions) shortly after birth. Accordingly, as brain morphology emerges, neurons that will form brain circuits differentiate for a lifetime of electrical signaling.


At 49 days of age (see top, Plate 1-9), the brain and spinal cord undergo further bending that situates both appropriately in the developing head and trunk. The cephalic flexure moves the diencephalon and telencephalon nearly parallel with the hindbrain. The pontine flexure anticipates the location of the cerebellum and pons, and the cervical flexure positions the spinal cord parallel to the body axis. At this stage, telencephalic and diencephalic landmarks are clearly visible: olfactory bulbs in the telencephalon; the optic cup, eventually located farther from the diencephalon as it generates the neural retina; the infundibulum (hypophysis), the rudimentary stalk of the pituitary gland; and the epiphysis, which forms the pineal gland.

Within 1.5 months, differential growth yields an even more mature embryonic brain and spinal cord. This reflects disproportionate growth of the cerebral hemi- spheres (or neopallium), from the posterior telencephalon, primarily due to addition of neural stem cells that generate neurons of the mature cerebral cortex. Dysregulation of this process has dramatic consequences. Mutations that result in microcephaly—dramatic reduction of cerebral hemisphere size—occur in genes that influence this expansion of cortical neural stem cells. Disproportionate cerebral hemisphere growth makes the diencephalon a “deep” structure, occluded from view. Diencephalic subdivisions, including the thalamus, epithalamus (habenular nuclei and pineal gland), hypothalamus, and posterior pituitary (neurohypophysis) are only seen by dissection, imaging, or histologic sectioning.

The hindbrain also undergoes dramatic changes. The posterior (tectum) and anterior (tegmentum) mesencephalon becomes distinct: a groove or sulcus divides two evaginating structures: the superior and inferior colliculi. The superior colliculus integrates visual information and motor commands for eye and head movements, and the inferior colliculus localizes sound in register with head movements. The posterior rhombencephalon expands dramatically as the rudimentary cerebellum becomes visible. The cerebellum is derived from stem cells in or near the roof of the fourth ventricle as well as progenitors that migrate from other rhombencephalic and mesencephalic locations. Local neurogenesis in the roof of the fourth ventricle, as well as migration of additional progenitors, results in dramatic cerebellar growth. The anterior rhombencephalon appears as the rudimentary pons, which expands dramatically as axons from the cerebral cortex innervate pontine relay neurons that project to the cerebellum.

The final dramatic change during this period is differentiation of spinal cord regions that innervate limbs or axial musculature. Posterior to the cervical flexure, the spinal cord appears broader, a region referred to as the cervical enlargement that includes larger numbers of motor and sensory relay neurons that innervate or receive inputs from muscles and sensory receptors in the shoulders, arms, and hands. The spinal cord then narrows, and this region, the thoracic cord, includes motor and sensory neurons that innervate or receive sensory inputs from axial musculature as well as preganglionic neurons that project to the autonomic ganglia of the sympathetic chain for central regulation of the sympathetic branch of the autonomic nervous system. The spinal cord expands again in the lumbar enlargement, reflecting larger numbers of motor and sensory relay neurons dedicated to the legs and feet. Finally, the narrow posterior region, the sacral cord, innervates and receives information from the pelvic and gluteal muscles. Thus differentiation in the spinal cord reflects distinct functional demands of arms and legs versus trunk and posterior midline structures.

As brain morphogenesis advances, the ventricles, defined initially by the space enclosed by the neural tube, become highly differentiated. The dramatic growth of the cerebral hemispheres is matched by growth of two bilaterally symmetric lateral ventricles.

Their c shape reflects development of “deep” telencephalic structures, including the hippocampus and basal ganglia. Continuity between the lateral and third ventricles (surrounded by the diencephalon) occurs at the intraventricular foramen of Monro. Occluding this opening leads to one type of noncommunicating hydrocephalus (see below). Cerebrospinal fluid trapped in the lateral ventricles causes secondary expansion of the cerebral hemispheres and overlying cranium (a second form, communicating hydrocephalus, reflects impaired reabsorption of CSF). The third ventricle also has a modest invagination, the infundibular recess, that reflects the position of the pituitary gland. The cerebral aqueduct, surrounded by the mesencephalon, and the fourth ventricle, defined by the rhombencephalon, become well defined. Occlusion of the cerebral aqueduct— aqueductal stenosis—is the most common noncommunicating hydrocephalus. In the fourth ventricle, a series of openings, the foramen of Luschka and Magendie establish continuity between the ventricles and subarachnoid space between the arachnoid and the pia, the innermost meningeal layer. These apertures permit CSF to flow into the subarachnoid space to mechanically cushion the brain as well as distribute signaling molecules to the developing meninges and the external surface of the developing brain. Occlusion of these foramina, which is rare, also leads to noncommunicating hydrocephalus. The fourth ventricle narrows dramatically in the medulla, defining the central canal that extends most of the length of the spinal cord.

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