Sixteen

Question 1

Describe the events of neural tube formation including the day at which events occur and the correct names for the different parts. What does the central lumen become? What does the rostral 2/3 of the tube become? The caudal 1/3?

Answer 1

Formation of the neural plate begins in week 3 of development and is complete by week 4. This process is called neurulation. The underlying notochord induces the surface ectoderm to form the neural plate.

By day 18, the neural plate invaginates along its central axis to form a longitudinal median groove, the neural groove. The neural folds become particularly prominent at the cranial end and represent the first signs of brain development.

By the end of the third week and beginning of the fourth week, the neural folds of the cervical regions move together and fuse, converting the neural plate into a neural tube (day 22). At first the neural tube remains open at the anterior and posterior neuropores. The anterior neuropore closes at day 24, and the posterior neuropore closes at day 26. The rostral 2/3 of the neural tube becomes the brain, and the caudal 1/3 becomes the spinal cord. The central lumen of the neural tube becomes the central canal of the spinal cord and the ventricles of the brain.

Question 2

Describe what happens to neural crest cells. What do they become?

Answer 2

At the junction of the neural plate and ectoderm, some neuroectodermal cells, called neural crest cells, move ventrally as the neural folds approximate each other. These neural crest cells migrate laterally and give rise to the sensory and autonomic ganglia of the spinal and cranial nerves and the Schwann cells (which myelinate peripheral axons). They also form the most cranial portions of the arachnoid and pia. Adrenal Medulla.

Question 3

What is a neurocristopathy? Give two examples including signs and symptoms/pathophys.

Answer 3

Failure of neural crest cell migration, proliferation, and/or differentiation can result in a neurocristopathy. Because of the vast number of structures derived from neural crest
neurocristopathies are quite common.

One such neurocristopathy is Hirschsprung’s disease (congenital megacolon) in which there is absence of the parasympathetic ganglia in the colon and rectum (auerbachs/meissners plexus). Affected individuals suffer from chronic constipation and abdominal distention. Because of the lack of ganglion cells, the smooth muscle of the colon and rectum is not innervated and as a result, there is a lack of tonic activity so the muscle is constantly in a constricted state. The colon is dilated above the affected region and filled with stool.

Neurofibromatosis:
Genetic disease manifested by multiple tumors of neural crest origin. Cafe Au Lait, subcutaneous nodules, many tumors, bilateral facial palsy.

Question 4

What happens in neural tube defects? What are 3 types? What is a defects that occurs secondary to neural tube defects? What are they often caused by? How can they be diagnosed?

Answer 4

As the neural tube fuses and the neural crest is formed, the neural ectoderm becomes completely separate from the surface ectoderm that will form the epidermis. Failure of closure of the neural tube results in permanent continuity of the surface and neural ectoderm and a permanent opening between the lumen of the neural tube and the outer surface of the body.

Spina Bifida, Anencephaly, Encephalocele,

Arnold Chiari Malformation

• Folic acid deficiency
• ↑ α-fetoprotein in amniotic fluid & maternal serum

Question 5

What is the pathophys of spina bifida? What is the least severe form? What happens in it? What are the more severe forms termed? What are 3 examples of the more severe forms? What happens in them?

Answer 5

Failure of closure of the posterior neuropore and/or failure of the neural tube to appropriately induce the mesodermal formation of the posterior vertebral column results in spina bifida. This common congenital anomaly has varying manifestations.

In the least severe form, spina bifida occulta, the spinal cord and meninges are well formed and remain located entirely within the vertebral canal. The only anomaly is a failure of closure of vertebral arches, usually in the lower lumbar region. The only sign of this problem is often an
excessive growth of hair in the lower lumber region.

Progressively more severe manifestations of
spina bifida all of which are termed spina bifida cystica, involve (1) herniation of the meninges through a posterior opening in the vertebra, spina bifida meningocele (2) herniation of both the cord and meninges spina bifida meninomyelocele (3) failure of closure of the neural tube,
accompanied by failure of complete spinal cord formation and continuing attachment of epidermal and neural tissue with a permanent opening between the neural canal and the external body surface spina bifida rachischisis.

Question 6

What is anencephaly? What is the prognosis? Why?

Answer 6

Failure of closure of the anterior neuropore leads to anencephaly (no brain), more properly referred to as meranencephaly (partial brain, since the brain stem does form). This condition, which occurs in 1/2000 births, is not compatible with postnatal life and, like the most severe
form of spina bifida, results in open communication between the neural tube and the external body surface.

Question 7

What is an encephalocele? What are 3 types from least to most severe? What happens in each?

Answer 7

Failure of the brain to properly induce the formation of posterior regions of the skull leads to encephalocele (also referred to as cranium bifidum), characterized by posterior
openings in the skull. As in the case of vertebral openings, conditions range from mild, such as meningocele (only meninges herniate), to more severe, such as meningoencephalocele (meninges and brain matter), to most severe, such as meningohydroencephalocele (meninges, brain, and ventricle fluid), depending on whether the brain is well formed and only the meninges herniate or whether portions of the brain (usually
cerebellum or occipital lobe) are herniated, and/or poorly formed.

Question 8

What is Arnold-Chiar malformation? What are the signs and symptoms/pathophys?

Answer 8

Defects that occur secondarily to neural tube defects include Arnold-Chiari malformation in which the cerebellar vermis (tonsil) herniates through the foramen magnum. As a result, the outlet foramina of the 4th ventricle are obliterated which blocks the flow of cerebral spinal fluid resulting in an obstructive hydrocephalus, dilation of the ventricles due to excess CSF. Closely associated with this Arnold-Chiari malformation is syringomyelia which is the presence of a fluid filled cavity in the spinal cord.

Question 9

Explain the formation of the different segments of the brain. What flexures exist?

Answer 9

Fusion of the neural folds in the cranial region and closure of the rostral neuropore results in the formation of the three primary brain vesicles: prosencephalon, mesencephalon, and rhombencephalon. During the fifth week, the prosencephalon and rhombencephalon each
divide in two giving rise to five vesicles, the telencephalon, diencephalon, mesencephalon, metencephalon, and myelencephalon.

The telencephalon gives rise to the cerebral hemispheres. The diencephalon gives rise to the thalamus, hypothalamus, and epithalamus. The mesencephalon becomes the midbrain. The metencephalon becomes the pons and cerebellum, and the myelencephalon becomes the medulla oblongata.

As the neural tube enlarges, it develops several flexures. The cervical flexure occurs at the junction between the spinal cord and the hindbrain. It eventually disappears. The cranial flexure (or midbrain flexure) occurs at the junction of the midbrain and forebrain. The pontine flexure produces a thinning of the roof of the pons and medulla oblongata.

Question 10

What is holoprosencephaly? How does it manifest?

Answer 10

Holoprosencephaly is a condition in which the forebrain fails to divide into right and left portions of the telencephalon. The infant is, thus, born with a single prosencephalic-like forebrain. This condition is usually accompanied facial defects of varying degrees of severity including midline facial clefts, a single eye or a single nostril.

Question 11

After the closing of the neural tube, what kinds of cells does it consist of? What are the 3 layers of it? How are the layers formed? What do the layers consist of?

Answer 11

The cells of the neural tube differentiate into nerve cells and supporting cells from multipotential stem cells. Immediately after its closure, the neural tube consists of a pseudostratified neuroepithelium, from which many cell lines develop. Neuroblasts within the epithelium undergo a characteristic cell division in which the position of the nucleus corresponds to a particular stage of the cell cycle, resulting in daughter cells that migrate outward away from the lumen toward the surface. This process of cell division results in the formation of three fundamental layers: a ventricular zone adjacent to the lumen where cell division occurs, a mantle or intermediate layer which is occupied by the cell bodies of the differentiating postmitotic neurons and an outer marginal layer positioned farthest from the lumen and is formed predominantly by axonal and dendritic cell processes.

Question 12

What are the ventral and dorsal thickenings of the mantle layer called? What functions do their cells become involved with? Where do they each send their axons? What is the groove on the inner surface of the neural tube called? How do neurons migrate?

Answer 12

The continuous proliferation of neuroblasts produces ventral and dorsal thickenings in the mantle layer. The dorsal thickening, the alar plate, becomes sensory in nature and the ventral thickening, the basal plate, becomes motor. A groove on the inner surface of the neural tube between the alar and basal plates is the sulcus limitans. The neuroblasts in the alar plate send
their axons into the marginal layer for the most part. The neuroblasts in the basal plate give rise to axons that emerge from the neural tube and pass in to the periphery.

They migrate along radial glial cells.

Question 13

Why are many more neurons produced during histogenesis than are actually needed? What happens to excess ones? When?

Answer 13

During histogenesis many more neurons are produced than are present in the mature brain. Excess neurons are eliminated during development by a process of programmed cell death (apoptosis). This serves two purposes: 1) elimination of redundancy in the number of neurons and 2) regulation of neural connectivity.

Question 14

What are astrocytes and oligodendrocytes formed from? Where do they spread? What are microglial cells formed from?

Answer 14

A glial cell line forms astrocytes and oligodendrocytes which spread throughout the mantle and marginal layers of the neural tube. Microglial cells, which serve a phagocytic function after damage, are not derived from the neuroepithelium but are mesodermally derived and migrate into the CNS once it is penetrated by blood vessels.

Question 15

What is the order of the events of neurodevelopment?

Answer 15

neurogenesis, neuronal selection, migration from ventricular zone, differentiation and myelinaiton, synaptogenesis, competitive elimination

Question 16

Describe the steps of neuronal maturation. What is synaptic pruning?

Answer 16

Cellular maturation consists of 1) outgrowth and elongation of axons, 2) elaboration of dendritic processes, and 3) formation of synaptic contacts. Axonal outgrowth is guided by the movement of the axon tip called the growth cone. Extending actin containing filopodia, a growth cone moves and senses its environment. The growth cones are guided by chemoattractant and chemorepellent molecules that are bound to other cells or to the extracellular matrix. Dendrites grow after axons and unlike axons may form elaborate branches. Once the axon growth cone arrives at the target, they undergo morphological changes to establish synapses. Similarly, the target cells undergo changes as neurotransmitter receptors congregate under the synaptic area. More synapses are produced than are needed and many are subsequently eliminated.

Question 17

What are the meninges formed from?

Answer 17

For the most part, the meninges, for both the brain and spinal cord, derive from mesenchyme surrounding the neural tube. In the cranial regions, the pia and arachnoid form from neural crest cells rather than mesenchyme.

Question 18

When are peripheral nerves myelinated? When are CNS tracts myelinated? How does this explain the babinski response in children?

Answer 18

The myelin sheaths of the peripheral nerves begin to be formed at about 20 weeks, first in the motor roots and then in the sensory roots. By birth, most peripheral nerves are well myelinated. Schwann cells which derive from the neural crest, migrate peripherally and wrap themselves
around axons, thereby producing the myelin sheaths of the peripheral and cranial nerves.

Myelination in the central nervous system occurs later than that in the peripheral nervous system. By birth many brainstem fiber tracts are well-myelinated, but the cerebral hemispheres are only beginning to myelinate. Indeed, myelination of some parts of the cerebral hemispheres is not complete until the third decade of life. Functional paths remain “immature” until axons become fully myelinated. The observance of primitive reflexes which are exhibited by normal infants but not neurologically intact adults is due to the immaturity of the myelination in various paths.

For example, a positive Babinski response is normal in infants because the corticospinalpathway is not fully myelinated until the 2nd year. Within the spinal cord and the brain, the myelin of the nerve fibers is formed by a type of glia cell called oligodendrocytes. The plasmamembranes of the oligodendrocytes wrap around the axon, forming a number of layers.

Question 19

What do the alar plates and basal plates differentiate into in the spinal cord? What separates them in the lumen of the spinal cord?

Answer 19

The proliferation and differentiation of neuroepithelial cells produces an emerging spinal cord with thick walls and thin roof and floor plates. A shallow longitudinal groove appears on each side of the lumen of the spinal cord, the sulcus limitans. This sulcus marks the division of the
gray matter of the cord into dorsal and ventral parts: the alar and basal plates. The alar plate becomes the dorsal horn of the adult spinal cord, which contains sensory neurons, and thebasal plate becomes the ventral horn which contains motor neurons.

Question 20

What happens to the roof of the hindbrain due to the pontine flexure? What does the pia mater in this thinned roof become in the 4th ventricle? What does the pontine flexure do to the position of the alar and basal plates in the brainstem? What do the alar and basal plates give rise to in the pons, medulla, and midbrain? What are cerebellar neurons derived from? What do alar plates give rise to in the midbrain?

Answer 20

The pontine flexure results in a thinning of the roof of the hindbrain. The pia mater of this thinned roof proliferates and invaginates into the fourth ventricle where it becomes choroid plexus. (Similar processes of choroid plexus formation occur in the telencephalon and diencephalon).

The pontine flexure also results in a change in relative position of the alar and basal plates, such that the alar plate is dorsolateral to the basal plate instead of directly dorsal to it. In the pons, medulla, and midbrain, the alar plate cells become sensory neurons (afferent neurons) associated with the cranial nerves, and the basal plate cells become motor neurons (efferent neurons) associated with cranial nerves.

Cerebellar neurons also derive from the alar plate of the metencephalon. In the mesencephalon, the alar plates given rise to four large dorsal masses, the paired superior and inferior colliculi.

Question 21

How does the cerebellum first develop? What part of the cerebellum do they form first? How does the cerebellar cortex develop (in which direction)? In which order do the layers form? In which direction does the granule layer develop?

Answer 21

The cerebellum develops from the fusion of dorsolateral thickenings of the metencephalon that overgrow the roof of the fourth ventricle. These thickenings, referred to as rhombic lips, fuse in the midline to form the cerebellar vermis, which is flanked on either side by enlarging cerebellar hemispheres. The three-layered cerebellar cortex develops in an outside to inside direction.

The earliest generated neurons will form the cerebellar nuclei just above the fourth ventricle. Then Purkinje cells form and migrate radially along radial glial cells outward toward the surface.

Later, cortical interneurons are born and migrate past the Purkinje cells to form the outer molecular layer. This is followed by a second wave of neurogenesis located at the edge of the rhombic lip from which neuroblasts migrate onto the surface, where they divide and form the
external granule layer and then migrate inward to form the granule layer.

Question 22

What are the dandy-walker malformations caused by? What is the triad of defects? What are the symptoms?

Answer 22

Dandy-Walker malformations are a group of malformations resulting from disruptions in the development of the brainstem and cerebellum, probably related to the abnormal development of the rhombic lip. Clinically, there is usually a triad of defects: (1) partial or complete agenesis of the cerebellar vermis, (2) dilation of the 4th superior and (3) displacement of the tentorium. Affected individuals are developmentally delayed and ataxic.

Question 23

What does the diencephalon develop into (6)? What is it derived from? What develop occurs from there?

Answer 23

Develops into the hypothalamus, thalamus, subthalamus, and epithalamus

Posterior lobe of Pituitary Gland

Optic Vesicles

Unlike the medulla, pons, and midbrain which differentiate from the alar and basal plates, the diencephalon is derived solely from the alar plate. The alar plates in the developing diencephalon become divided into dorsal and ventral parts by a shallow groove, the hypothalamic sulcus. The ventral parts develop into the hypothalamus while the dorsal parts form the thalamus, subthalamus, and epithalamus.

Question 24

Describe telencephalic growth? In which directions does it occur? What is the oldest and most primitive component? The newest? What shape do the hemispheres take on? What happens after the smooth brain is grown? How many layers is in most of the cortex? What are the layers derived from? What direction do they grow?

Answer 24

Telencephalic growth is marked by tremendous growth of the cerebral hemispheres in the process referred to as cleavage in which the telencephalon sprouts bilateral symmetric outgrowths. These bilateral outgrowths expand rapidly in all directions to cover the diencephalon, the midbrain, and hindbrain. As they expand the roof and lateral walls of each hemisphere are relatively thin and represent the future cerebral cortex. The floor is thicker and contains neuronal aggregations which give rise to the basal ganglia. With further expansion, the cerebral hemispheres fuse with the diencephalon and the former border between the two regions becomes filled with axons of the internal capsule.

The oldest and most primitive component of the cerebral cortex is the rhinencephalon (archicortex and paleocortex) and is functionally involved in olfaction. The newest and most dominant cortex is called the neocortex. Early in development, the rhinencephalic areas occupy most of the telencephalon but with expansion of the cerebral hemispheres, the neocortex occupies most of the mass of the brain. As the neocortex expands both dorsally and ventrally, it takes on a C shape as it rotates around the future site of the insula. Simultaneous growth of the underlying corpus striatum and lateral ventricles causes these structures to also take on a C shape form. Growth of the cerebral hemispheres is continuous throughout embryonic and fetal development and continues after birth. Initially each cerebral hemisphere has a smooth surface but then begins to fold into an increasingly complex pattern of gyri and sulci.

Most cortex of the cerebral hemispheres has six layers (neocortex), labeled from outer to inner as layers 1-6, although some cortical areas have as few as three layers (allocortex). Early in development, the marginal zone develops into the acellular, most superficial layer 1 of the mature cerebral cortex. Layers 2 to 6 develop from the cortical plate, a group of cells that migrate from the ventricular zone to the outer part of the intermediate (mantle) zone. The development of layers 2 to 6 from the cortical plate is accomplished by an inside-out sequence
in which newly arrived cells migrate outward past their predecessors in the cortical plate. Thus, in the mature adult cerebral cortex, acelllular layer 1 is the oldest; cellular layer 6 is formed by the first wave of neuroblast migration, followed in chronologic sequence by cellular layers 5, 4, 3, and 2. As neurogenesis proceeds, even in adulthood, new neurons are formed in a germinative zone lying deep to the ventricular zone called the subventricular zone.

Question 25

What is microencephaly? What is an example of it? What causes it? What are the signs/symptoms?

Answer 25

Defective cell migration results in malformations of the cerebral cortex. A common malformation of individuals suffering from Fetal Alcohol Syndrome is microencephaly which is characterized by a small head and may be caused by a disturbance in neural proliferation. It is usually results in mental retardation. Children with Fetal Alcohol Syndrome have characteristic features that include an indistinct philtrum, thin upper lip, depressed nasal bridge, short nose and flat midface and a small head.

Question 26

What is schizencephaly? What causes it? What is it like histologically? Grossly? clinicallly?

Answer 26

Schizencephaly (no cortex) is a disorder of neuronal migration characterized by a cerebrospinal fluid–filled cleft, which is lined by gray matter. The cleft extends across the entire cerebral hemisphere, from the ventricular surface (ependyma) to the periphery (pial surface) of the brain. Histologically, the clefts consist of cortical neurons that are not arranged in the normal six layers. Clinically, it is manifested by seizures and developmental delay.

Question 27

What is Lissencephaly? What causes it? What is it like histologically? Grossly? clinicallly?

Answer 27

delay. Lissencephaly (smooth brain) is a defect of cell migration of cerebral neurons resulting in the failure of cortical gyri to develop. Grossly, the cerebral hemispheres are smooth, cortical sulci are absent, and cerebral fissures are shallow. Microscopically, the cortical cell layers are
aberrant typically consisting of four cortical layers. Affected children are severely mentally retarded, spastic and have seizures.

Question 28

What are heterotropias? What are they caused by? What are two different kinds? What are they like clinically?

Answer 28

Heterotopias comprise collections of ectopic “cortical” neurons that fail to reach the cortex as a result of defective radial neuronal migration. Islands of gray matter are commonly seen near the ependymal layers of the lateral ventricles (subependymal heterotopia) or within the cerebral white matter (subcortical and band heterotopia). Affected individuals present with delayed development and seizures.

Question 29

What are syndromes such as down syndrome, autism, and fragile x syndrome associated with histologically that might explain mental retardation?

Answer 29

It has been shown that many disorders such as autism, mental retardation (Down syndrome) and Fragile X syndrome are associated with abnormalities in dendritic spines, especially the number of spines and their maturity. These abnormalities lead to impaired synaptic signaling.

Question 30

Where does the commisural plate form? How does it develop? In what order do the commisures form? In what direction does the corpus collosm grow?

Answer 30

The commissural plate forms at the lamina terminalis. From here commissural fibers cross the midline with the help of glial cells, cell surface markers and chemotactic substances expressed in the extracellular environment. The first to form is the anterior commissure, followed by the hippocampal commissure and finally the corpus callosum. Growth of the corpus callosum occurs in an anterior to posterior direction.

Question 31

What causes agenesis of the corpus collusum? What happens with it? What occurs clinically?

Answer 31

Agenesis of the corpus callosum is usually associated with other anomalies. Both faulty neurulation and neural migration have been associated with agenesis of the corpus callosum. The axons destined to form the corpus callosum turn parallel and form longitudinal bundles (of Probst) which indent the lateral ventricles, giving them a “batman-like” appearance. Agenesis of the corpus callosum is accompanied by developmental delay and/or seizures.