Development of the Central Nervous System

Summary

Even before neurulation begins, the primordia of the three primary brain vesicles — prosencephalon , mesencephalon , and rhombencephalon —are visible as broadenings of the neural plate. During the fifth week, the prosencephalon subdivides into the telencephalon and diencephalon , and the rhombencephalon subdivides into the metencephalon and myelencephalon . Thus, along with the mesencephalon, there are five secondary brain vesicles . During this period, the rhombencephalon is divided into small repetitive segments called rhombomeres . The extension of the neural tube caudal to the rhombomeres constitutes the spinal cord .

The primordial brain portion of the neural tube undergoes flexion at three points. At two of these— mesencephalic (cranial) flexure and cervical flexure —the bends are ventrally directed. At the pontine flexure , the bend is dorsally directed.

Cytodifferentiation of the neural tube begins in the rhombencephalon at the end of the fourth week. During this process, the neural tube neuroepithelium proliferates to produce the neurons, glia, and ependymal cells of the central nervous system. The young neurons, born in the ventricular zone that surrounds the central lumen, migrate peripherally to establish the mantle zone , the precursor of the gray matter, wherein lie the majority of mature neurons. Axons extending from mantle layer neurons establish the marginal zone (the future white matter) peripheral to the mantle zone. In areas of the brain that develop a cortex, including the cerebellum and cerebral hemispheres, the pattern of generation and migration of neurons is more complex.

The mantle zone of the spinal cord and brain stem is organized into a pair of ventral (basal) plates and a pair of dorsal (alar) plates . Laterally, the two plates abut at a groove called the sulcus limitans ; dorsally and ventrally they are connected by non-neurogenic structures called the roof plate and the floor plate , respectively. Association neurons form in the dorsal plates as well as in the ventral plates, where they occupy one or two cell columns (depending on the level): the somatic motor column and the visceral motor column .

The nuclei of the 3rd to 12th cranial nerves are located in the brain stem (mesencephalon, metencephalon, and myelencephalon). Some of these cranial nerves are motor, some are sensory, and some are mixed, arising from more than one nucleus. The cranial nerve motor nuclei develop from the brain stem basal plates, and the associational sensory nuclei develop from the brain stem alar plates. The brain stem cranial nerve nuclei are organized into seven longitudinal columns, which correspond closely to the types of functions they subserve. From ventromedial to dorsolateral, the three basal columns contain somatic efferent , branchial (or special visceral) efferent , and (general) visceral efferent motoneurons , and the four alar columns contain general visceral afferent , special visceral afferent (subserving the special senses of taste and smell), general somatic afferent , and special somatic afferent (subserving the special senses of hearing and balance) associational neurons .

The myelencephalon gives rise to the medulla oblongata , the portion of the brain most similar in organization to the spinal cord. The metencephalon gives rise to the pons , a bulbous expansion that contains the massive white matter tracts serving the cerebellum, and to the cerebellum . A specialized process of neurogenesis in the cerebellum gives rise to the gray matter of the cerebellar cortex , as well as to the deep cerebellar nuclei . The cerebellum controls posture, balance, and the smooth execution of movements by coordinating sensory input with motor functions and, more generally, is thought to function as a comparator between higher (cortical) centers and the periphery.

The mesencephalon contains nuclei of three cranial nerves (III, IV, V) as well as various other structures. In particular, the alar plates give rise to the superior and inferior colliculi , which are visible as round protuberances on the dorsal surface of the midbrain. The superior colliculi control ocular reflexes; the inferior colliculi serve as relays in the auditory pathway.

The diencephalon consists of only alar plate, which is divided into a dorsal portion and a ventral portion by a deep groove called the hypothalamic sulcus . The hypothalamic swelling ventral to this groove differentiates into the nuclei collectively known as the hypothalamus , the most prominent function of which is to control visceral activities such as heart rate and pituitary secretion. Dorsal to the hypothalamic sulcus, the large thalamic swelling gives rise to the thalamus , by far the largest diencephalic structure, which serves as a relay center, processing information from subcortical structures and peripheral sensory input before passing it to the cerebral cortex. Finally, a dorsal swelling, the epithalamus , gives rise to a few smaller structures, including the pineal gland .

A ventral outpouching of the diencephalic midline, called the infundibulum , differentiates to form the posterior pituitary lobe . A matching diverticulum of the stomodeal roof, called Rathke’s pouch , grows to meet the infundibulum and becomes the anterior pituitary lobe . Cranial diencephalic outpouchings also form the retinae and optic stalks of the eyes, as covered in Chapter 19 .

The telencephalon is subdivided into a dorsal pallium and a ventral subpallium . The latter forms the large neuronal nuclei of the basal ganglia (corpus striatum , globus pallidus) —structures crucial for executing motor commands from the cerebral hemispheres . These cortical structures arise as lateral outpouchings of the pallium and grow rapidly to cover the diencephalon and mesencephalon. The hemispheres are joined by the cranial lamina terminalis (representing the zone of closure of the cranial neuropore) and by axon tracts called commissures , particularly the massive corpus callosum . The olfactory bulbs and the olfactory tracts arise from the cranial telencephalon and receive input from the primary olfactory neurosensory cells, which differentiate from the nasal placodes and line the roof of the nasal cavity.

The expanded primitive ventricles formed by the neural canal in the secondary brain vesicles give rise to the ventricular system of the brain. The cerebrospinal fluid that fills the ventricle system is produced mainly by secretory choroid plexuses in the lateral, third, and fourth ventricles, which are formed by the ependyma and overlying vascular pia. The third ventricle also contains specialized ependymal structures called circumventricular organs , some of which are secretory.

Structural Divisions of Nervous System

The nervous system of vertebrates consists of two major structural divisions: a central nervous system (CNS) and a peripheral nervous system (PNS) . The CNS consists of the brain and spinal cord. The development of the CNS is covered in this chapter. The PNS consists of all components of the nervous system outside of the CNS. Thus, the PNS consists of cranial nerves and ganglia, spinal nerves and ganglia, autonomic nerves and ganglia, and the enteric nervous system. The development of the PNS is covered in Chapter 10, Chapter 14 .

Functional Divisions of Nervous System

The nervous system of vertebrates consists of two major functional divisions: a somatic nervous system and a visceral nervous system . The somatic nervous system innervates the skin and most skeletal muscles (i.e., it provides both sensory and motor components). Similarly, the visceral nervous system innervates the viscera (organs of the body) and the smooth muscle and glands in the more peripheral part of the body. The visceral nervous system is also called the autonomic nervous system . It consists of two components: the sympathetic division and the parasympathetic division . The somatic and visceral nervous systems are covered both in this chapter (CNS components) and in Chapter 10 (PNS components).

Both divisions of the autonomic nervous system consist of two-neuron pathways. Because the peripheral autonomic neurons reside in ganglia, the axons of the central sympathetic neurons are called preganglionic fibers , and the axons of the peripheral sympathetic neurons are called postganglionic fibers . This terminology is used for both sympathetic pathways and parasympathetic pathways (discussed later in the chapter). Sometimes preganglionic fibers are also called presynaptic fibers , and postganglionic fibers, postsynaptic fibers . They are so called because the axons of the preganglionic fibers synapse on the cell bodies of postganglionic neurons in the autonomic ganglia.

Primary Brain Vesicles Subdivide to form Secondary Brain Vesicles

Animation 9.1: Neurulation.

Animations are available online at StudentConsult.

Chapter 3, Chapter 4 describe how, during neurulation, the rudiment of the central nervous system arises as the neural plate from the ectoderm of the embryonic disc and folds to form the neural tube. The presumptive brain is visible as the broad cranial portion of the neural plate (see Fig. 3.19 ). Even on day 19, before bending of the neural plate begins, the three major divisions of the brain— prosencephalon (forebrain) , mesencephalon (midbrain) , and rhombencephalon (hindbrain) —are demarcated by indentations in the neural plate. The future eyes appear as outpouchings from the forebrain neural folds by day 22 (covered in Chapter 19 ). Bending of the neural plate begins on day 22, and the cranial neuropore closes on day 24. The three brain divisions are then marked by expansions of the neural tube called primary brain vesicles ( Fig. 9.1A,B ).

An additional series of narrow swellings called neuromeres becomes apparent in the future brain (see Fig. 9.1A,B ). These swellings are prominent in the rhombencephalon, which is partitioned into segments called rhombomeres (seven or eight depending on the species). Rhombomeres are transient structures that become indistinguishable by early in the sixth week.

During the fifth week, the mesencephalon enlarges and the prosencephalon and the rhombencephalon each subdivide into two portions, thus converting the three primary brain vesicles into five secondary brain vesicles (see Fig. 9.1C,D ). The prosencephalon subdivides into a cranial telencephalon (“end-brain”) and a caudal diencephalon (“between-brain”). The rhombencephalon subdivides into a cranial metencephalon (“behind-brain,” consisting of rhombomeres one and two) and a caudal myelencephalon (“medulla-brain,” consisting of the remaining rhombomeres). Within each of the brain vesicles, the neural canal is expanded into a cavity called a primitive ventricle . These primitive ventricles will become the definitive ventricles of the mature brain (see Fig. 9.23 ). The cavity of the rhombencephalon becomes the fourth ventricle , the cavity of the mesencephalon becomes the cerebral aqueduct (of Sylvius) , the cavity of the diencephalon becomes the third ventricle , and the cavity of the telencephalon becomes the paired lateral ventricles of the cerebral hemispheres. After the closure of the caudal neuropore, the developing brain ventricles and the central canal of the more caudal spinal cord are filled with cerebrospinal fluid (CSF) , a specialized dialysate of blood plasma.

In the Research Lab

One of the major challenges facing the embryo is how to generate a very large number of different neuronal cell types while at the same time ensuring that each of them forms at its correct position in the neural tube. Distinguished and defined by the specificity of their connections with other neurons, the neuronal cell types of the CNS number in the many hundreds, or even thousands, and the embryo has to get the right cells in the right places for the system to wire up appropriately and function correctly. The highly elaborate patterning of cell specification and the subsequent formation of precise connections between remote cells during development set the CNS far apart from other organ systems; how these processes are controlled is thus an important question for researchers.

Positional Information Patterns Neural Plate and Tube

In addressing the issue of cell patterning , it is helpful to think in terms of a Cartesian system of positional information , in which undifferentiated precursor cells may sense their position on orthogonal gradients of morphogens acting along the cranial-caudal (CrCd) and medial-lateral (ML) axes of the neural plate. Cells would acquire a unique “grid reference” (coordinates) by measuring the ambient concentration of morphogen on each of the intersecting axes and would then interpret this, their positional value , by selecting an appropriate fate from the range made available in the genome. This concept is undoubtedly simplistic but not wholly unrealistic.

The events of pattern formation can be summarized as follows: first, polarization of the entire CrCd axis of the CNS primordium by a gradient of signaling activity; and next, the setting up of discrete morphogen sources at particular positions along the axis that act as local signaling centers , informing neighboring cells about their position and fate ( Fig. 9.2A,B ). Similar events occur on the ML axis of the neural plate (later the dorsal-ventral [DV] axis of the neural tube) except that, because it is considerably shorter than the CrCd axis, morphogen sources established at the dorsal and ventral poles are generally sufficient to pattern the entire axis (see Fig. 9.2C ).

During gastrulation, when a region of the dorsal ectoderm is set aside as the neural plate (see Chapter 3 ), the CrCd axis is polarized by a gradient of Wnt molecules diffusing from the caudal pole of the neural plate, and by counteracting Wnt inhibitors at the cranial pole. In the absence of Wnt signaling, the default neural fate of cranial is realized. Higher Wnt levels effectively confer successively more caudal neural fates. Gradients of retinoid and fibroblast growth factor (Fgf) signaling, also high at the caudal end of the embryo, operate in addition to Wnts to polarize the CrCd axis. The initially coarse regional subdivision of the CrCd axis is manifest by the expression of transcriptional control genes in distinct domains that dictate the direction of their subsequent development. For example, Otx2 is expressed only in the cranial neural plate (forebrain or prosencephalon and midbrain or mesencephalon), whereas Hox genes are expressed in nested subdomains of the caudal neural plate (hindbrain and spinal cord; see Chapter 8 , section entitled, “Specification of Vertebra Identity,” for further coverage of Hox genes). Another transcriptional control gene, Gbx2, is expressed between the Otx2 and Hox expression domains.

Gbx2 and Otx2 proteins mutually repress each other’s expression, so their domains abut at a sharp line—this will become the midbrain/hindbrain boundary (see Fig. 9.2A ). At this interface between gene expression domains (an area known as the isthmus ), a band of cells differentiates that secrete fibroblast growth factor 8 (Fgf8), which signals the formation of optic tectum in the Otx2 expression domain and cerebellum in the Gbx2 domain. Fgf8 is also released from a signaling center at the cranial pole of the axis (called the anterior neural ridge [ANR]), inducing the local expression of transcription factors such as FoxG1 that establish the telencephalon as a distinct region of the forebrain (see Fig. 9.2A ). Similarly, a further signaling center that develops in the middle of the diencephalon (at the zona limitans intrathalamica [ZLI]) releases another morphogen, sonic hedgehog (Shh), which signals the formation of prethalamus cranially and thalamus caudally (see Fig. 9.2B ).

As the initially flat neural plate neurulates to form the neural tube, distinct signaling centers form at both ventral and dorsal midlines, along almost the entire length of the CrCd axis (also covered in Chapter 4 ). The ventral pole cells, constituting the floor plate of the neural tube , secrete Shh (as does the underlying notochord and prechordal plate , more rostrally), whereas the dorsal cells, constituting the roof plate of the neural tube , secrete bone morphogenetic proteins (Bmps) and Wnts . In the context of midbrain, hindbrain, and spinal cord, Shh signaling from the floor plate induces the formation of a variety of neuronal cell types according to the concentration of Shh and length of exposure (as the neural tube develops, cells move further away from the source of Shh, reducing both the concentration of Shh a cell is exposed to and its time of exposure). At high levels and longer exposure, the cells closest to the floor plate form motoneurons, whereas a diversity of interneurons is induced at successively lower Shh levels (and shorter exposures to Shh signaling), impinging on precursor cells at successively more dorsal positions in the basal plate (see Fig. 9.2C ). The Bmp and Wnt signals from the roof plate counteract the Shh gradient in part by inducing the expression of Gli3, which antagonizes Shh signaling. A gradient of Bmps and Wnts is responsible for the elaboration of a range of alar plate cell types (see Fig. 9.2C ).

How CrCd and DV signals interact to confer position in two dimensions is not fully understood. However, it is clear that signals from the dorsal and ventral poles are essentially uniform along the length of the CrCd axis, yet they induce different cell types at different CrCd positions. For example, Shh from the midbrain floor plate induces the formation of oculomotor neurons at one CrCd position and dopaminergic neurons of the substantia nigra at another CrCd position. One explanation is that the uniform ventral signal in this case acts on a preexisting bias, or competence , of the receiving cells that is conferred during patterning of the CrCd axis.

In addition to patterning along the CrCd axis, in the early developing telencephalon, cells are patterned along the medial-lateral axis to separate the single eye field into two. This is achieved by Shh signaling from the prechordal plate (see Fig. 9.2A ). Defects in Shh signaling can result in cyclopia or holoprosencephaly (see Chapter 17, Chapter 19 for further coverage).

Having achieved a correct spatial pattern of differentiation, with individual brain domains and neuronal subtypes either in their correct positions or specified to migrate into new settling positions, the next major event in brain development is the outgrowth of axons to form connections with other neurons—the substrate of forming neural networks. A well-studied example is the visual system, where all sequential processes of cell patterning, axon outgrowth, and formation of appropriate connections are accessible. The development of the visual system will be considered later in this chapter.

Formation of Brain Flexures

Between the fourth and eighth weeks, the brain tube folds sharply at three locations (see Fig. 9.1C,E ). The first of these folds to develop is the mesencephalic flexure (cranial or cephalic flexure) , centered at the midbrain region. The second fold is the cervical flexure , located near the juncture between the myelencephalon and the spinal cord. Both of these flexures involve a dorsally convex folding of the brain tube. The third fold, a reverse, dorsally concave flexion called the pontine flexure , begins at the location of the developing pons. By the eighth week, deepening of the pontine flexure has folded the metencephalon (including the developing cerebellum) back onto the myelencephalon.

Cytodifferentiation of Neural Tube

Cytodifferentiation of the neural tube commences in the rhombencephalic region, just after the occipitocervical neural folds fuse, and proceeds cranially and caudally as the groove closes at these levels to form the neural tube. The precursors of most cell types of the future central nervous system—neurons, some types of glial cells, including the ependymal cells that line the central canal of the spinal cord and the ventricles of the brain—are produced by proliferation in the layer of neuroepithelial cells that immediately surrounds the neural canal ( Fig. 9.3 ). Early neuroepithelial cells share some glial characteristics and are often called radial glia cells when they span most of the wall of the early neural tube (e.g., the left-most cell in Fig. 9.3A ). These cells undergo proliferation to sequentially give rise to neuronal and glial cell progenitors (see Fig. 9.3A ). Proliferating neuroepithelial cells are contained within the ventricular layer of the differentiating neural tube, with mitosis occurring at the luminal surface. The first wave of cells produced in the ventricular layer consists of postmitotic young neurons , which migrate peripherally to establish a second layer containing cell bodies, the mantle layer , external to the ventricular layer. This layer containing neurons develops into the gray matter of the central nervous system. The neuronal processes (axons) that sprout from the mantle layer neurons grow peripherally to establish a third layer, the marginal layer , which contains no neuronal cell bodies and becomes the white matter of the central nervous system. The white matter is so called because of the whitish color imparted by the fatty myelin sheaths that wrap around many of the axons. In the CNS, these sheaths are formed by oligodendrocytes (discussed in the next section; in the PNS, myelin sheaths are formed by neural crest cell–derived Schwann cells; Schwann cells are covered in Chapter 10 ). The marginal layer contains axons entering and leaving the CNS, as well as axon tracts coursing to higher or lower levels in the CNS.

After production of neurons is waning in the ventricular layer, this layer begins to produce a new cell type, the glioblast (see Fig. 9.3A ). These cells differentiate into two classes of glia of the CNS— astrocytes and oligodendrocytes . Glia provide metabolic and structural support to the neurons of the central nervous system. The last cells produced by the ventricular layer are the ependymal cells ; these line the brain ventricles and the central canal of the spinal cord (see Fig. 9.3A,C ). Elaborations of the ependyma contribute to the choroid plexus responsible for producing CSF , which fills the brain ventricles, the central canal of the spinal cord, and the subarachnoid space that surrounds the CNS. The CSF is under pressure and thus provides a fluid jacket that protects and supports the brain.

Differentiation of Spinal Cord

The differentiation of the spinal cord is relatively simple compared with that of the brain, so we will begin our discussion with the spinal cord. Starting at the end of the fourth week, the neurons in the mantle layer of the spinal cord become organized into four plates that run along the length of the cord: a pair of dorsal or alar plates (columns) and a pair of ventral or basal plates (columns) ( Fig. 9.4 ). Laterally, the two plates abut at a groove called the sulcus limitans ; dorsally and ventrally, they are connected by non-neurogenic structures called, respectively, the roof plate and the floor plate . The cells of the ventral columns become the somatic motoneurons of the spinal cord and innervate somatic motor structures such as the voluntary (striated) muscles of the body wall and extremities. The cells of the dorsal columns develop into association neurons . These neurons receive synapses from afferent (incoming) fibers from the sensory neurons of the dorsal root ganglia (covered in Chapter 10 ). In addition, the axon of an association neuron may synapse with motoneurons on the same (ipsilateral) or opposite (contralateral) side of the cord, forming a reflex arc—or it may ascend to the brain. The outgoing ( efferent ) motor neuron fibers exit via the ventral roots.

In most regions of the cord—at all 12 thoracic levels, at lumbar levels L1 and L2, and at sacral levels S2 to S4—the neurons in more dorsal regions of the ventral columns segregate to form intermediolateral cell columns (see Fig. 9.4 ). The thoracic and lumbar intermediolateral cell columns contain the visceral motoneurons that constitute the central autonomic motoneurons of the sympathetic division , whereas the intermediolateral cell columns in the sacral region contain the visceral motoneurons that constitute the central autonomic motoneurons of the parasympathetic division . The structure and function of these systems are covered in Chapter 10 (where the peripheral components are described). In general, at any given level of the brain or spinal cord, the motoneurons form before the sensory elements.

Differentiation of Brain

For purposes of description, the brain can be divided into two parts: the brain stem , which represents the cranial continuation of the spinal cord and is similar to it in organization, and the higher centers , which are extremely specialized and retain little trace of a spinal cord–like organization. The brain stem consists of the myelencephalon , the metencephalon derivative called the pons , and the mesencephalon . The higher centers consist of the cerebellum (derived from the metencephalon) and the forebrain .