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Chapter 8: The Nervous System by John F. NeasNeurulation The development of the nervous system begins at about seventeen days following fertilization. At that time, a thickening of the ectoderm, called the neural plate, forms along the entire dorsal midline of the embryo and becomes largest near the future head of the developing embryo. The neural plate will differentiate into all of the neurons and most of the supporting cells of the nervous system (neuroglial cells). The midline of the neural plate folds inward (invaginates) and forms a longitudinal neural groove. A concurrent proliferation of cells along the lateral margins of the neural plate produces thickened raised edges called neural folds. The neural groove continues to deepen as the neural folds become elevated. By the twentieth day, the neural folds meet and fuse at the dorsal midline, and the neural groove becomes a neural tube. The neural folds first contact each other midway along the axis of the neural plate. Openings, or neuropores, at the cranial and caudal ends of the neural tube close during the fourth week. Once formed, the neural tube separates from the surface ectoderm and eventually develops into the central nervous system (brain and spinal cord). The process of neural tube formation, called neurulation, is completed in less than a week. Lamination of Neural Tube The neural tube increases in thickness as its epithelial lining divides repeatedly by mitosis. The wall of the neural tube develops three distinct layers by the middle of the fifth developmental week. The inner ependymal layer lines the enclosed cavity, or neurocoel, and eventually forms the lining of the ventricles. The ependymal cells continue their mitotic activities, and daughter cells produce a middle mantle layer that develops into the gray matter. The first cells that develop in the mantle layer differentiate into neurons, while the last cells to arrive become astroyctes and oligodendrocytes. Axons from developing neurons form an outer marginal layer that develops into the white matter. Nervous tissue completes its mitotic activity during prenatal development. Thus, a person is born with all the neurons she or he will ever produce. Nervous tissue continues to grow and specialize after a person is born, however, especially during the fist several years of postnatal life. Neural Crest As the neural folds fuse longitudinally along the dorsal midline, cells at the tips of the neural folds develop into the neural crest that lies between the surface ectoderm and the dorsal surface of the neural tube. Most of the peripheral nervous system (PNS) develops from the neural crest, including the dorsal root ganglia of spinal nerves, ganglia of cranial nerves, and the somatic and visceral sensory neurons of spinal nerves and cranial nerves (V, VII, IX, and X). Some neural crest cells break away from the main tissue mass and migrate to other locations where they aggregate and differentiate into autonomic ganglia and postganglionic sympathetic and parasympathetic neurons near the vertebral column and in peripheral organs. Besides forming dorsal root ganglia and associated glial cells, neural crest cells migrate around the central nervous system and develop into the spinal and cranial meninges (pia and arachnoid mater). (The dura mater and sclera develop from epimere, or paraxial mesoderm.) Migrating neural crest cells contribute to the formation of teeth and produce laryngeal cartilages, melanocytes, portions of the skull, connective tissues around the eye, intrinsic muscles of the eye, amphicytes, adrenal medullae, and Schwann cells (a type of neuroglial cell important in the PNS). Histology of a Fetal Nerve This micrograph of a nerve from a human fetus illustrates the typical appearance of a medium–large sized peripheral nerve in transverse section stained with H & E. The section shown has numerous fascicles (F), each of which contains many nerve fibers. Each fascicle is invested by a condensed connective tissue layer, the perineurium (P), and the nerve as a whole is encased in a loose connective tissue sheath, the epineurium (E). Heavily myelinated fibers (M) and small non-myelinated fibers (N) can be easily identified can be identified. Schwann cells (S) are scattered among the nerve fibers, and several flattened fibroblast (Fb) nuclei are evident in the perineurium. The spinal cord, like the brain, develops as the neural tube differentiates. Throughout the developmental process, the hollow central canal (neurocoel) persists while the white and gray matter becomes specialized. The mantle layer in the spinal cord, which contains developing neurons and neuroglial cells, will produce the gray matter that surrounds the neurocoel. The axons of the developing neurons in the mantle layer grow toward central or peripheral destinations. The axons leave the mantle layer and grow toward synaptic targets within a peripheral marginal layer. Eventually, the growing axons produce bundles or tracts in the marginal layer. These tracts will crowd together in the columns that form the white matter of the spinal cord. Changes in the neural tube become apparent during the sixth week as the mantle enlarges. As the lateral walls (dorsolateral and ventrolateral plates) thicken, the central canal (neurocoel) becomes laterally compressed and relatively narrow. A groove called the sulcus limitans develops and separates dorsal pairs of alar plates from ventral pairs of basal plates. Relatively thin floor and roof plates interconnect the alar and basal plates. The alar plates specialize by the ninth week into the dorsal horns and ventral plates. The dorsal horns contain fibers of the afferent cell bodies that will receive and relay sensory information. The basal plates form the ventral and lateral horns that contain efferent cell bodies, the axons of which will develop into motor neurons. Afferent fibers of spinal nerves conduct impulses toward the spinal cord; efferent fibers conduct impulses away from the spinal cord. By this time, neural crest cells have migrated to both sides of the spinal cord and have formed the dorsal root ganglia. The neural crest cells become the sensory neurons and glial cells (Schwann cells and satellite cells). Processes from these sensory neurons grow to the periphery to contact receptors and into the central nervous system through the dorsal roots of the spinal nerves. The axons of the developing motor neurons in each segment form a pair of ventral roots that grow away from the spinal cord. Distal to each dorsal root ganglion, motor efferent neurons of the ventral root and sensory afferent neurons of the dorsal root are bound together into a single spinal nerve. Each developing limb receives its innervation from several spinal nerves. The nerves grow along with the embryonic muscle cells as the latter migrate from the myotome. If a large muscle in the adult develops from several myotomal blocks, connective tissue partitions will often mark the original boundaries, and the innervation will always involve more than one spinal nerve. Along much of the spinal cord, the sensory and motor nerves have a stereotypical pattern of peripheral branches that accounts for the distribution of dermatomes, or the areas of skin innervated by all the cutaneous neurons of a particular spinal or cranial nerve. Sensory fibers from the trigeminal nerve innervate most of the scalp and face. Except for the first cervical nerve (C1), all spinal nerves are associated with specific dermatomes. Dermatomes in the neck and torso regions are consecutive, but adjacent dermatome innervations overlap in the appendages. The apparently uneven dermatome arrangement in the appendages is attributable to the uneven rate of nerve growth into the limb buds. Dermatomes overlap only slightly in the limbs, which are segmented. Histology of the Spinal Cord in the Human Fetus The structure of the spinal cord is basically similar over its entire length, but functional differences at the four main levels are reflected in corresponding characteristic features. In transverse section, the central mass of gray matter has the shape of a butterfly, the ventral horns (V) are more prominent than the dorsal horns (D). This particular section appears to be at the lumbar level. There is a suggestion of a small lateral horn that would contain the cell bodies of preganglionic, sympathetic efferent neurons, as in the thoracic and upper lumbar regions, corresponding to the level of the sympathetic outflow from the spinal cord. The volume of gray matter is also much more extensive in the cervical and lumbar regions, corresponding to the great sensory and motor innervation of the limbs and this is reflected in the much greater diameter of the spinal cord in these areas. The neurocoel, or central canal (N), lying in the central commissure of gray matter (C), is lined with ependymal cells (E) and contains CSF. Externally, the spinal cord has a deep ventral median fissure (F) but dorsally there is only a shallow dorsal midline sulcus (S). On each side, a dorsolateral sulcus (DL) marks the line of entry of the dorsal nerve roots. The nearly triangular area of white matter between the dorsal horns represents the ascending dorsal columns (ADC). Ventrolateral sulci may be discernible, especially on the left side in this specimen, marking the sites of exit of the ventral nerve roots. The spinal cord, like the brain, is invested by meninges. The intervening epidural space is filled with loose adipose tissue and an extensive venous plexus. Primary Vesicles The brain begins its embryonic development as the cephalic portion of the neural tube begins to grow rapidly and differentiate. The initial expansion occurs as the neurocoel enlarges so that, by the middle of the fourth week, three distinct fluid-filled areas, or vesicles, are evident. These primary vesicles, so-called because they are the first to develop, include the (1) forebrain vesicle (prosencephalon), (2) midbrain vesicle (mesencephalon), and (3) hindbrain vesicle (rhombencephalon). Flexures As differential growth proceeds and the position and orientation of the embryo change during the fourth and fifth weeks, a series of bends, or flexures, appears along the axis of the developing brain. The midbrain flexure, the most prominent of these, develops along the ventral aspect of the mesencephalon. The cervical flexure develops at the junction of the myelencephalon and spinal cord. The less prominent pontine flexure develops between the midbrain and cervical flexure in the roof of the hindbrain. Secondary Vesicles Formation of the brain flexures during the fifth week results in subdivision of the three primary vesicles so that the embryonic brain consists of five secondary vesicles. The forebrain vesicle (prosencephalon) divides into an anterior telencephalon and a posterior diencephalon, and the hindbrain vesicle (rhombencephalon) divides into an anterior metencephalon and a posterior myelencephalon; the midbrain vesicle (mesencephalon) remains unchanged. Ventricles and Choroid Plexuses The cavities within the vesicles develop into the ventricles during the developmental transformation of the brain. The ventricles of the brain are continuous with one another and with the central canal of the spinal cord. The first and second ventricles (lateral ventricles) develop in the forebrain, a narrow third ventricle develops in the forebrain and midbrain, and the fourth ventricle develops from the cavity of the hindbrain. The roof of the diencephalon and myelencephalon fails to develop so that a thin layer of ependymal cells remains in contact with the developing meninges. Blood vessels invade these regions to produce a vascular capillary network called the choroid plexus in the roof of the third and fourth ventricles. Similar plexuses develop in the medial walls of the lateral ventricles. These plexuses secrete cerebrospinal fluid that circulates throughout the cavities of the central nervous system and within spaces outside the brain and spinal cord. Differentiation of the Telencephalon After the five principal regions of the brain develop, rapid differentiation occurs in each region, and soon all major structures of the brain are recognizable. The brain becomes increasingly more compact as growth continues and the pontine flexure develops. Greatest growth occurs within the telencephalon as its dorsal portions rapidly expand to form the two cerebral hemispheres. Migrating neuroblasts produce the cerebral cortex, and underlying masses of gray matter develop into the cerebral nuclei (basal ganglia). The expanding cerebral hemispheres overgrow the diencephalon, midbrain, and a portion of the hindbrain by about the eleventh week. The lobes of the cerebrum are developed, and the surface of the cerebrum is distinctly convoluted by the thirty-fifth week. The outer, convoluted portion of the cerebrum consists of gray matter; the inner portion consists of white matter. Differentiation of the Diencephalon Three swellings that develop in the walls of the third ventricle within the diencephalon become the epithalamus, thalamus, and hypothalamus. The pineal gland (epiphysis) develops in the diencephalon as a midline diverticulum from the roof of the third ventricle. The posterior portion of the pituitary gland develops from the ventral portion of the diencephalon. (The anterior pituitary develops from Rathke’s pouch, or surface ectoderm). The diencephalon also produces the anterior choroid plexus and infundibulum. Differentiation of the Mesencephalon The mesencephalon undergoes few developmental changes. The most obvious structures to develop here are the four aggregates of neurons that become the paired superior and inferior colliculi (corpora quadrigemina) concerned with visual and auditory functions, respectively. Fibers from the cerebrum extend through the midbrain to form the two tracts called cerebral peduncles. Other mesencephalic structures include the optic lobes, optic tectum, tegmentum, and the somatic motor neurons of cranial nerves III and IV. Differentiation of the Metencephalon Cortical formation and expansion of the walls of the metencephalon produce the cerebellum that overlies the nuclei and tracts of the pons. The cerebellum develops from a pair of dorsal swellings that join along the midline. The pons develops from many bands of nerve fibers. Differentiation of the Myelencephalon The caudal portion of the myelencephalon resembles the spinal cord with which it is continuous. The entire adult myelencephalon, called the medulla oblongata, develops from an aggregate of nerve fibers. The ventral pyramids of the myelencephalon develop from the nerve fibers that extend from the developing cerebral cortex. The myelencephalon produces the posterior choroid plexus, somatic motor neurons of cranial nerves VI and XII, and visceral motor neurons of cranial nerves V, VII, IX, X, and XI. The area of the neural tube posterior to the myelencephalon becomes the spinal cord. Major differences in brain and spinal cord development include (1) early breakdown of mantle (gray matter) and marginal (white matter) organization; (2) appearance of areas of neural cortex; (3) differential growth between and within particular regions; (4) appearance of characteristic bends and folds; and (5) loss of segmental organization. Cranial Nerves Cranial nerves develop as sensory ganglia join peripheral receptors with the brain, and motor fibers grow from developing cranial nuclei. Special sensory neurons of cranial nerves I, II, and VIII develop together with the developing receptors. The somatic motor nerves III, IV, and VI grow toward the eye muscles; the pharyngeal arches receive their innervation from mixed cranial nerves (IV, V, VII, IX, and X). Histology of the Fetal Cerebral Cortex This photomicrograph shows the fetal cerebral cortex. The neurons in the neocortex are arranged into six layers that differ in characteristic neuron morphology, size, and population density. There is no clear demarcation between the layers, and the layers vary somewhat from one region of the cortex to another depending on cortical thickness and function. The characteristics of each layer are as follows: I. Plexiform (molecular) layer; contains dendrites and axons of cortical neurons that synapse with each other; the sparse nuclei are those of neuroglia and occasional horizontal cells Cajal. II. Outer granular layer; a thin layer containing a dense population of small pyramidal (P) cells and stellate cells (S) and various axons and dendritic connections from deeper layers. III. Pyramidal cell layer; a broad layer of predominately pyramidal cells of moderate size that increase in size in the deeper layers. IV. Inner granular layer; a narrow layer consisting mainly of densely packed stellate cells. V. Ganglionic layer; consisting of large pyramidal cells and smaller numbers of stellate cells and cells of Martinotti. VI. Multiform cell layer; a layer with a wide variety of differing morphological forms, including numerous small pyramidal cells, cells of Martinotti, stellate cells, and fusiform cells. Histology of the Fetal Cerebellum The cerebellum consists of a cortex of gray matter with a central core of white matter. The cerebellar cortex forms a series of deeply convoluted folds or folia (F) supported by a branching central medulla of white matter (W). At higher magnification, the cortex is seen to consist of three layers, an outer "molecular layer" (M) containing relatively few cells, an extremely cellular inner "granule cell layer" (G) and a single intervening layer of huge neurons called Purkinje cells (P). Histology of the Fetal Pons In transverse section, the pons comprises a bulky ventral region (basal pons) and a smaller dorsal (tegmental) region. The basal pons, seen in this micrograph, consists of crisscrossed bundles of longitudinal and transverse fibers between which lie collections of neuron cell bodies called pontine nuclei (Nu). The myelin (M) investing the axons is stained blue. Ncb = neuron cell body. Primary Vesicles, Flextures, Secondary Vesicles, Ventricles, and Choroid Plexuses
Nervous tissue completes its mitotic activity during prenatal development. Thus, an individual begins life with all the neurons he or she will ever have. Nervous tissue, however, continues to grow and specialize after birth, particularly in the first several years of postnatal life. Recent studies indicate that learning increases the number of synapses between neurons within the cerebrum. Although the number of neurons becomes established during prenatal development, the number of synapses is variable and depends upon the learning process. The number of cytoplasmic extensions from the cell body of a neuron determines the extent of nerve impulse conduction and the associations made to cerebral areas that already contain stored information. The first indication of nervous system function in an embryo is reflex activity mediated by the spinal cord. The embryo can respond to tactile stimuli by late in the seventh or early in the eighth week. Spontaneous fetal movements are observable at nine or ten weeks. The mother in her first pregnancy can usually detect fetal movements by 18 to 20 weeks after the last menstrual period (LMP). The mother in her second or subsequent pregnancy generally experiences this sensation, known as quickening, between 15 and 17 weeks after the LMP. An experienced observer may palpate fetal movements with increasing reliability after 20 to 24 weeks. The first fetal movements felt in the lower abdomen are often described as a fluttering or gas bubbles. A newborn has many primitive reflexes that persist through the first few months of life. Palmar (grasp) and plantar (Babinski) reflexes are present at the end of the third intra-uterine month of life. These reflexes indicate neuromuscular maturity and increasing integration of sensory and motor nerves. Reflexes critical to survival include the following. (1) The suckling reflex causes a newborn to suck anything that touches its lips. (2) The rooting reflex helps a baby find a nipple by causing it to turn its head and start suckling whenever something brushes its cheek. (3) The crying reflex occurs when the baby’s stomach is empty or it is experiencing another discomfort. (4) The breathing reflex appears in a normal newborn even before losing its umbilical supply of oxygen. (5) The swallowing reflex occurs in response to taste facilitated by the location of taste buds at the brim of the pharynx, just before swallowing becomes involuntary. These reflexes are well established at full-term and are probably present much earlier, perhaps by the end of the embryonic period. The rooting, the grasp, and the tonic neck reflexes disappear within the first 6 to 12 months of life. The startle (Moro) reflex, in which the infant rapidly extends and then flexes the arms and legs in response to a sudden change in position or a loud noise, disappears by 3 to 6 months of life. The eyelids of the newborn are most often closed. When open, however, they may appear asymmetrical and seem to operate independent of each other. Newborns, and especially premature infants, typically have moderate intolerance to light, and they will promptly close the lids after exposure to bright light. Other stimuli that have some effect are loud noises and touching the eyelashes or cornea. The newborn lacks the protective blink reflex that occurs when an object moves suddenly toward the eyes. True blinking does not appear until six moths of age. The infant usually shows marked resistance to any attempt to force the eyelids open. Holding the infant upright and gradually rotating her or him may induce the eyes to open spontaneously. Newborn human beings see poorly. There may be several reasons for this, but one of the most striking is the immaturity of the retinal photoreceptors. A newborn responds to visual stimuli only when they are close to the baby’s face. The development of the human retinal photoreceptor provides an excellent example of differentiation that begins early in development but which does not become complete until years after birth.
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