Central Nervous System Development Notes

Central Nervous System (CNS) Development

Formation of the Neural Tube

The CNS originates from the neural plate, a thickened region of ectoderm, during the third week of development.
The lateral edges of the neural plate elevate to form neural folds.
These neural folds fuse to create the neural tube. This fusion begins in the cervical region and extends in cephalic (cranial) and caudal directions (Fig. 18.3A).
The open ends of the neural tube are called cranial and caudal neuropores, which connect with the amniotic cavity (Fig. 18.3B).
The cranial neuropore closes around the 25th day (18- to 20-somite stage), while the caudal neuropore closes approximately 3 days later.

Brain Vesicle Formation and Differentiation

The cephalic end of the neural tube dilates to form three primary brain vesicles:
- Prosencephalon (forebrain)
- Mesencephalon (midbrain)
- Rhombencephalon (hindbrain)
Simultaneously, two flexures appear:
- Cervical flexure (between hindbrain and spinal cord)
- Cephalic flexure (in the midbrain region)
By the fifth week, these primary vesicles differentiate into five secondary vesicles:
- Prosencephalon divides into telencephalon and diencephalon.
- Mesencephalon remains as the midbrain.
- Rhombencephalon divides into metencephalon and myelencephalon.
The rhombencephalic isthmus separates the mesencephalon and metencephalon. The pontine flexure marks the boundary between the metencephalon and myelencephalon (Fig. 18.5).
Each secondary vesicle contributes to different parts of the brain; their main derivatives are:
- Telencephalon: Cerebral hemispheres
- Diencephalon: Optic vesicle, thalamus, hypothalamus, pituitary gland
- Mesencephalon: Anterior (visual) and posterior (auditory) colliculi
- Metencephalon: Cerebellum, pons
- Myelencephalon: Medulla oblongata
The central canal of the spinal cord is continuous with the lumen of the brain vesicles.
The cavities of the brain vesicles become:
- Rhombencephalon: Fourth ventricle
- Diencephalon: Third ventricle
- Cerebral hemispheres: Lateral ventricles
The lumen of the mesencephalon connects the third and fourth ventricles and becomes the narrow aqueduct of Sylvius.
Each lateral ventricle communicates with the third ventricle through the interventricular foramina of Monro (Fig. 18.5).

Spinal Cord Development

Layers of the Neural Tube

The wall of the neural tube consists of neuroepithelial cells that form a pseudostratified epithelium (Fig. 18.6).
These cells divide rapidly to form the neuroepithelial layer or neuroepithelium.
Neuroepithelial cells then give rise to neuroblasts (primitive nerve cells).
Neuroblasts form the mantle layer around the neuroepithelial layer (Fig. 18.8). This layer becomes the gray matter of the spinal cord.
The outermost layer, the marginal layer, contains nerve fibers from neuroblasts in the mantle layer. Myelination gives this layer a white appearance, forming the white matter of the spinal cord (Fig. 18.8).

Plates of the Neural Tube

The neural tube develops ventral (basal) and dorsal (alar) thickenings due to neuroblast addition.
- Basal plates: Contain ventral motor horn cells and form the motor areas of the spinal cord.
- Alar plates: Form the sensory areas (Fig. 18.8A).
A longitudinal groove, the sulcus limitans, separates the basal and alar plates.
The roof and floor plates serve as pathways for nerve fibers crossing from one side to the other, without containing neuroblasts.
An intermediate horn, containing sympathetic nervous system neurons, forms between the ventral and dorsal horns at thoracic (T1-T12) and upper lumbar levels (L2 or L3) (Fig. 18.8B).

Differentiation of Nerve and Glial Cells

Nerve Cells (Neurons)

Neuroblasts arise from the division of neuroepithelial cells.
Initially, neuroblasts have a central process (transient dendrite).
They become round and apolar as they migrate into the mantle layer (Fig. 18.9A).
Two cytoplasmic processes then appear, forming a bipolar neuroblast (Fig. 18.9B).
One process elongates into the primitive axon, and the other develops cytoplasmic arborizations (primitive dendrites) (Fig. 18.9C).
This forms a multipolar neuroblast, which further differentiates into an adult nerve cell or neuron.
Once formed, neuroblasts lose their ability to divide.
Axons of neurons in the basal plate form the ventral motor root of the spinal nerve, conducting motor impulses to muscles (Fig. 18.10).
Axons of neurons in the alar plate penetrate the marginal layer and ascend to higher or lower levels as association neurons.

Glial Cells

Glioblasts, the primitive supporting cells, are formed by neuroepithelial cells after neuroblast production ceases.
Glioblasts migrate to the mantle and marginal layers.
In the mantle layer, they differentiate into protoplasmic and fibrillar astrocytes (Fig. 18.11), providing support and metabolic functions between blood vessels and neurons.
Oligodendroglial cells, found primarily in the marginal layer, form myelin sheaths around axons.
Microglial cells, highly phagocytic cells derived from vascular mesenchyme, appear in the CNS during the second half of development (Fig. 18.11).
Neuroepithelial cells differentiate into ependymal cells lining the central canal of the spinal cord.

Neural Crest Cells

Neural crest cells, ectodermal in origin, appear along the edges of the neural folds (Fig. 18.2).
They migrate laterally and give rise to sensory ganglia (dorsal root ganglia) of the spinal nerves and other cell types (Fig. 18.2).
Neuroblasts of the sensory ganglia form two processes (Fig. 18.10A):
- Centrally growing processes penetrate the dorsal portion of the neural tube and form the dorsal sensory root of the spinal nerve.
- Peripherally growing processes join fibers of the ventral motor roots, forming the trunk of the spinal nerve.
Neural crest cells differentiate into autonomic neuroblasts, Schwann cells, pigment cells, odontoblasts, meninges, and mesenchyme of the pharyngeal arches.

Spinal Nerves

Motor nerve fibers appear in the fourth week, arising from nerve cell bodies in the basal plates (ventral horns) of the spinal cord.
These fibers collect into ventral nerve roots (Fig. 18.10).
Dorsal nerve roots, carrying sensory fibers, originate from nerve cell bodies in dorsal root ganglia derived from neural crest cells.
Processes from these ganglia form bundles that grow into the dorsal horns of the spinal cord.
Distal processes join the ventral nerve roots to form a spinal nerve (Fig. 18.10).
Spinal nerves divide into dorsal and ventral primary rami, containing both motor and sensory fibers.
Dorsal primary rami innervate dorsal axial musculature, vertebral joints, and the skin of the back.
Ventral primary rami innervate the limbs and ventral body wall and form major nerve plexuses.

Myelination

Schwann cells myelinate peripheral nerves, with each cell myelinating a single axon (Fig. 18.12).
These cells originate from the neural crest, migrate peripherally, and form the neurilemma sheath.
Myelin deposition begins at the fourth month of fetal life.
Oligodendroglial cells myelinate nerve fibers in the spinal cord. A single oligodendrocyte can myelinate up to 50 axons (Fig. 18.12).
Myelination in the spinal cord begins around the fourth month of intrauterine life, but some motor fibers are not myelinated until the first year of postnatal life.
Tracts become myelinated when they begin to function.

Positional Changes of the Spinal Cord

In the third month, the spinal cord extends the entire length of the embryo.
The vertebral column lengthens more rapidly than the neural tube, causing the terminal end of the spinal cord to shift to a higher level.
At birth, this end is at the level of the third lumbar vertebra (Fig. 18.13C).
As a result, spinal nerve roots run obliquely from their origin in the spinal cord to the corresponding level of the vertebral column.
In adults, the spinal cord terminates at L2-L3, while the dural sac extends to S2.
The filum terminale is a threadlike extension of pia mater that passes caudally, providing support for the cord.
Dorsal and ventral roots of spinal nerves below the end of the cord form the cauda equina.
Lumbar punctures are performed at the L4-L5 level to avoid the spinal cord.

Molecular Regulation of Nerve Differentiation

Dorsal (sensory) and ventral (motor) regions of the developing spinal cord are influenced by concentration gradients of growth factors (Fig. 18.14A).
Transforming growth factor B (TGF-B) family members are secreted in the dorsal neural tube.
Sonic hedgehog (SHH) is secreted by the notochord and floor plate.
Bone morphogenetic proteins (BMPs) 4 and 7 are secreted by ectoderm overlying the neural tube, establishing a signaling center in the roof plate.
These gradients activate transcription factors that regulate neuronal differentiation (Fig. 18.14B).

Clinical Correlates: Neural Tube Defects (NTDs)

General Information

NTDs result from abnormal closure of the neural folds during the third and fourth weeks of development.
NTDs may involve the meninges, vertebrae, muscles, and skin.
The birth prevalence of NTDs varies among different populations. Folate supplementation has decreased the rate of NTDs in the US by 25% since 1998.
Spina bifida is a general term for NTDs affecting the spinal region.

Types of Spina Bifida

Spina bifida occulta: Defect in the vertebral arches covered by skin, usually not involving underlying neural tissue (Fig. 18.15A). Affects about 10% of people. Often in the sacral region and marked by a patch of hair.
Meningocele: Neural tissue and/or meninges protrude through a defect in the vertebral arches and skin to form a cyst-like sac (Fig. 18.15B). Only fluid-filled meninges protrude through the defect. Lies in the lumbosacral region.
Myelomeningocele: Neural tissue is included in the sac (Fig. 18.15C). Lies in the lumbosacral region.
Rachischisis: The neural folds do not elevate but remain as a flattened mass of neural tissue (Fig. 18.15D,E).

Associated Conditions

Hydrocephaly develops in 80-90% of children with severe NTDs, often related to the Arnold-Chiari malformation (herniation of the cerebellum into the foramen magnum).
Spina bifida can be diagnosed prenatally by ultrasound and by determination of $a$ -fetoprotein levels in maternal serum and amniotic fluid.
Experimental treatment includes surgery in utero as early as 22 weeks of gestation.

Prevention

Hyperthermia, valproic acid, and hypervitaminosis A and other teratogens can cause NTDs.
Taking folic acid (400 ${\mu}g$ /day) starting at least 1 month before conception and throughout pregnancy can prevent many NTDs.

Brain Development

Brain Structure

The brain is sometimes divided into the brainstem (myelencephalon, pons, mesencephalon) and the higher centers (cerebellum and cerebral hemispheres).
The brainstem is a direct continuation of the spinal cord and has a similar organization.
The higher centers show accentuation of the alar plates and regression of the basal plates.

Rhombencephalon (Hindbrain)

The rhombencephalon consists of the myelencephalon and the metencephalon (Figs. 18.5 and 18.17).

Myelencephalon

The myelencephalon gives rise to the medulla oblongata.
Its lateral walls are everted compared to the spinal cord (Fig. 18.18).
Alar and basal plates are clearly distinguished.
The basal plate contains three groups of motor nuclei:
- Medial somatic efferent group
- Intermediate special visceral efferent group
- Lateral general visceral efferent group (Fig. 18.18C; Table 18.1).
The somatic efferent group contains motor neurons forming the cephalic continuation of the anterior horn cells.
- In the myelencephalon, it includes neurons of the hypoglossal (XII) nerve.
- In the metencephalon and mesencephalon, the column contains neurons of the abducens (VI), trochlear (IV), and oculomotor (III) nerves.
The special visceral efferent group extends into the metencephalon, forming the special visceral efferent motor column. Its motor neurons supply striated muscles of the pharyngeal arches.
The general visceral efferent group contains motor neurons that supply involuntary musculature of the respiratory tract, intestinal tract, and heart.
The alar plate contains three groups of sensory relay nuclei (Fig. 18.18C; Table 18.1):
- Somatic afferent (general sensory) group
- Special afferent group
- General visceral afferent group
The roof plate of the myelencephalon consists of a single layer of ependymal cells covered by the pia mater, forming the tela choroidea.
This forms the choroid plexus, which produces cerebrospinal fluid (Fig. 18.18C).

Metencephalon

The metencephalon is characterized by basal and alar plates (Fig. 18.19). This forms the cerebellum and the pons.
Each basal plate contains three groups of motor neurons and the alar plate contains three groups of sensory nuclei (Table 18.1).
The marginal layer of the basal plates expands to form the pons.
The pons contains the pontine nuclei, which originate in the alar plates of the metencephalon and myelencephalon (Fig. 18.19, arrows).

Cerebellum

The dorsolateral parts of the alar plates bend medially and form the rhombic lips which fuse to form the cerebellar plate (Fig. 18.18).
The cerebellar plate shows a small midline portion, the vermis, and two lateral portions, the hemispheres.
During development the cerebellar plate consists of neuroepithelial, mantle, and marginal layers (Fig. 18.21A).
Some cells formed by the neuroepithelial layer migrate to the surface of the cerebellum to form the external granular layer.
In the sixth month of development, the external granular layer gives rise to the granule cell layer in the fully differentiated cerebellum (Fig. 18.22A).

Mesencephalon (Midbrain)

Each basal plate contains two groups of motor nuclei:
- Medial somatic efferent group (oculomotor and trochlear nerves)
- Small general visceral efferent group (nucleus of Edinger-Westphal).
The marginal layer of each basal plate enlarges to form the crus cerebri.
The allar plates form the anterior and posterior Colliculi.

Prosencephalon (Forebrain)

The prosencephalon consists of the telencephalon (cerebral hemispheres) and the diencephalon.

Diencephalon

Roof Plate and Epiphysis

The diencephalon consists of a roof plate and two alar plates but is thought to lack floor and basal plates.
The roof plate consists of a single layer of ependymal cells covered by vascular mesenchyme, giving rise to the choroid plexus of the third ventricle (Fig. 18.30).
The caudal part of the roof plate develops into the pineal body, or epiphysis. It serves as a channel through which light and darkness affect endocrine and behavioral rhythms.

Alar Plate, Thalamus, and Hypothalamus

The alar plates form the lateral walls of the diencephalon.
A groove, the hypothalamic sulcus, divides the plate into the thalamus and hypothalamus (Figs. 18.24 and 18.25).
The hypothalamus differentiates into nuclear areas that regulate visceral functions.
The mamillary body forms a distinct protuberance on the ventral surface of the hypothalamus.

Hypophysis (Pituitary Gland)

The hypophysis develops from two parts:
- Rathke pouch: An ectodermal outpocketing of the stomodeum (primitive oral cavity).
- Infundibulum: A downward extension of the diencephalon (Fig. 18.26).
Rathke pouch forms the anterior lobe, an extension of the lobe forms the pars tuberalis, and the posterior lobe.
The infundibulum gives rise to the stalk and the pars nervosa, or posterior lobe of the hypophysis (neurohypophysis).

Telencephalon

The telencephalon consists of two lateral outpocketings, the cerebral hemispheres, and a median portion, the lamina terminales (Figs. 18.5, 18.24, and 18.25).
The cavities of the hemispheres, the lateral ventricles, communicate with the lumen of the diencephalon through the interventricular foramina of Monro (Fig. 18.24).

Cerebral Hemispheres

The cerebral hemispheres arise at the beginning of the fifth week as bilateral evaginations of the lateral wall of the prosencephalon (Fig. 18.24).
The basal part of the hemispheres begins to grow and bulges into the lumen of the lateral ventricle and into the floor of the foramen of Monro (Figs. 18.24B and 18.25A,B).
The rapidly growing region is therefore known as the corpus striatum.

Cortex Development

Continuous growth of the cerebral hemispheres in anterior, dorsal, and inferior directions results in the formation of frontal, temporal, and occipital lobes, respectively.
During the final part of fetal life, the surface of the cerebral hemispheres grows so rapidly that many convolutions (gyri), separated by fissures and sulci, appear on its surface (Fig. 18.28B).
The cerebral cortex develops from the pallium (Fig. 18.24B).
In the neopallium, waves of neuroblasts migrate to a subpial position and then differentiate into fully mature neurons.

Commissures

By the end of the third month, collections of nerve fibers grow across, connecting one hemisphere to the other.
The first of the crossing bundles to appear in the lamina terminalis is the anterior commissure. The second commissure to appear is the hippocampal commissure (fornix).
Another important commissure is the corpus callosum which appears by the 10th week of development and connects the nonolfactory areas of the right and the left cerebral cortices.
In addition to the commissures developing in the lamina terminalis, the posterior and habenular commisures also appear outside of this region.
Optic chiasma appears in the rostral wall of the diencephalon, containing fibers from the medial halves of the retinae.

Meninges

The meninges are the three membranous layers that cover the brain and spinal cord.
These membranes are derived from a combination of mesoderm and neural crest cells and begin to form in the fourth to fifth weeks.
During the early fetal period, the external layer thickens to form the dura mater, whereas the inner layer forms the pia-arachnoid mater.
One of the septa is the falx cerebri which seperates the two cerebral hemispheres.

Cerebrospinal Fluid

Cerebrospinal fluid (CSF) is secreted by the choroid plexuses in the brain ventricles.

Molecular Regulation of Brain Development

Anteroposterior (craniocaudal) patterning of the CNS begins early in development, during gastrulation and neural induction (see Chapters 5 and 6).
Hindbrain has eight segments, the rhombomeres, that have variable expression patterns of the Antennapedia class of homeobox genes, the HOX genes.
LIM1, expressed in the prechordal plate, and OTX2, expressed in the neural plate, are important for designating the forebrain and midbrain areas, with LIMI supporting OTX2 expression.
ANR lies in the most anterior region of the neural plate and secretes fibroblast growth factor 8 [FGF8], which induces expression of FOXGi in adjacent neurectoderm. Sonic hedgehog [SHH], secreted by the prechordal plate and notochord

Cranial Nerves

By the fourth week of development, nuclei for all 12 CNs are present.
All except the olfactory (I) and optic (II) nerves arise from the brainstem, and of these, only the oculomotor (III) arises outside the region of the hindbrain.
Cranial nerve sensory ganglia originate from a series of ectodermal placodes and neural crest cells.
Parasympathetic (visceral efferent) ganglia are derived from neural crest cells, and their fibers are carried by CNs III, VII, IX, and X.

Autonomic Nervous System (ANS)

General

The ANS is composed of motor (efferent) fibers that innervate smooth and cardiac muscle and secretory glands, and it is divided into two parts: a sympathetic portion and a parasympathetic portion.
Both parts rely on two neurons to provide innervation, a preganglionic and a postganglionic neuron.

Sympathetic Nervous System

Cell bodies of preganglionic neurons are located in the intermediolateral cell columns (horns) of the spinal cord at the levels of T1-L2.
Cell bodies for postganglionic neurons are located in paravertebral ganglia on each side of the vertebral column and in prevertebral (preaortic) ganglia located around major vessels branching from the aorta.
Migration and positioning of crest cells in regulated by BMPs secreted by the dorsal aorta that act as chemoattractants for the migrating cells.
Postganglionic fibers from the sympathetic trunk ganglia to blood vessels, arrector pili muscles (goose bumps), and sweat glands in the head and neck, body wall, and limbs travel from the sympathetic trunk through gray rami communicantes to ventral rami of all 31 spinal nerves and travel on blood vessels to reach their destinations.

Parasympathetic Nervous System

Preganglionic parasympathetic neuron cell bodies are located in the brainstem and the sacral region (S2-S4) of the spinal cord and consequently are sometimes called the craniosacral portion of the ANS.
Preganglionic parasympathetic fibers from nuclei in the the brainstem travel via the oculomotor (CN 111), facial (CN VII), glossopharyngeal (CN IX), and vagus (CN X) nerves to structures in the head and neck. From the sacral portion, pelvic splanchnic nerves innervate the rectum (Figure 18.43).
Postganglionic parasympathetic neuron cell bodies in the cranial region reside in four ganglia: the ciliary (CN 111), pterygopalatine and submandibular (CN VII), and otic (CN IX; Figure 18.43).

Suprarenal (Adrenal) Gland

The gland develops from two components: a mesodermal portion, which forms the cortex, and an ectodermal portion, which forms the medulla (Fig. 18.41).
Cortex forms in two waves from mesothelial cells, the first forming the fetal cortex and the second forming the definitive cortex.
Neural crest cells invade the medial aspect and are arranged to form the medulla.(Figs. 18.41 and 18.44A)
Upon differentiation chromaffin cells are present and produce epinephrine (adrenaline) and norepinephrine (noradrenaline) that are released directly into the bloodstream (Fig. 18.44B).