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Central Nervous System
EARLY DEVELOPMENT
Induction of the central nervous system results in the formation of a thickened ectodermal
neural plate overlying the notochord. After folding of the neural plate, the neural tube is
formed. Until fusion of the neural folds is complete, the neural tube is open at the cephalic
and caudal ends and communicates with the amniotic fluid through the cranial and caudal
neuropores, respectively. Even before closure of the neuropores (24 days cranial and 26
days caudal) some subdivisions of the early nervous system become evident: the future spinal
cord and parts of the brain. Within the brain are forebrain (prosencephalon), midbrain
(mesencephalon), and hindbrain (rhombencephalon).
At the end of the third week, C – shaped bend appears at the mesencephalic level of the
neural tube, the cephalic or midbrain flexure. At the beginning of the fifth week a cervical
flexure appears at the boundary between the hindbrain and spinal cord. A rhombencephalic
isthmus separates the mesencephalon from the rhombencephalon.
By the end of the fifth week, the original three-part brain becomes subdivided into five
parts. The prosencephalon gives rise to the telencephalon (endbrain), with prominent lateral
outpockets that ultimately form the cerebral hemispheres, and a more caudal diencephalon.
The diencephalon will produce optic vesicles, which will later help form the visual organs.
The mesencephalon remains undivided and tubular in structure. The roof of the
rhombencephalon becomes thin and subdivides into a metencephalon (pons and cerebellum)
and a more caudal myelencephalon (medulla). The pontine flexure separates the
metencephalon from the myelencephalon.
The central canal of the spinal cord is continuous with 4th ventricle. The 4th ventricle
communicates with the 3rd ventricle through the aquaduct of Sylvius. Interventricular
foramina of Monro connect the 3rd ventricle with the paired lateral ventricles in the
cerebral hemispheres.
Proliferation within the Neural Tube
Shortly after induction, the thickening neural plate and early neural tube organize into a
pseudostratified epithelium (all cells are attached to a basement membrane: not stratified).
The neuroepithelial cells have a high mitotic activity. Neuroepithelial cells give rise to
bipotential progenitor cells: cells that become neuronal progenitor or glial progenitor cells.
When the formation of neuroblasts ceases, the bipotential cells will form gliablasts and
ependymal cells.
DNA synthesis occurs in nuclei located near the external limiting membrane (the basal
lamina surrounding the neural tube). As these nuclei prepare to undergo mitosis, they
migrate toward the lumen of the neural tube and complete their mitotic division. The
orientation of the mitotic spindle during metaphase determines the fate of the daughter cells.
If the metaphase plate is perpendicular to the apical (inner) surface of the neural tube, the two
daughter cells migrate toward the outer side of the neural tube, where they prepare for
another round of DNA synthesis. Alternatively, if the metaphase plate is parallel to the inner
surface of the neural tube, the daughter cell that is closer to the external limiting membrane
moves away from the inner, apical surface to become a neuroblast. The other daughter cell
closer to the apical surface remains a cell that is capable of mitosis. Neuroblasts become
neurons and produce axons and dendrites.
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The neuronal progenitor cells (one of the two lines of cells made by the bipotential
progenitor cells) give rise to neuroblasts give rise to bipolar, unipolar, and multipolar
neuroblasts. Glial progenitor cells (the other cell line) have several lineages of cell lines.
One is for precursors to oligodendrocytes and type-2 astrocytes. A second gives rise to
type-1 astrocytes. Astrocytes in gray matter are protoplasmic, while those in white matter
are fibrous astrocytes. A third glial lineage gives rise to radial glial cells, which act as
guide wires in the brain for migrating young neurons.
Microglial cells are phagocytic and are derived from mesoderm.
Organization of the Developing Neural Tube
With proliferation of neuroepithelium and differentiation of cells in the neural tube, the
architecture of the neural tube becomes layered. The layer closest to the lumen (central
canal) remains epithelial and is called the ventricular zone. Ultimately, this zone becomes
the ependyma lining the central canal and ventricular system. Farther from the ventricular
zone is the intermediate (mantle) zone, which contains cell bodies of differentiated
postmitotic neuroblasts. Outside of the intermediate zone is the marginal zone, which
contains neuronal processes, but no neuronal cell bodies.
As the spinal cord matures, the intermediate zone becomes the gray matter, which
contains cell bodies of neurons. The marginal zone is called the white matter because of the
tracts of myelinated axons.
A sulcus limitans within the central canal divides the cord into a dorsal alar plate and a
ventral basal plate. A roof plate connects the right and left alar plates and the basal plates
are connected by a floor plate.
The basal plate represents the motor portion of the spinal cord. Axons arising from
neurons located in the ventral horn of gray matter exit the spinal cord as ventral motor
roots of spinal nerves. In the alar plate, the gray matter of the dorsal horn contains sensory
neurons. Sensory axons from the spinal ganglia (derivatives of neural crest) enter the spinal
cord as dorsal roots and synapse on the neurons of the dorsal horn. From cord levels T1
through L2 there is a small lateral projection of gray matter that projects from the junction of
the ventral and dorsal horns. This projection is the lateral horn or intermediolateral gray
column, which contains primary sympathetic neurons.
Through its action on the floor plate, the notochord effects the organization of the dorsal
and ventral roots that enter and leave the spinal cord. If the notochord is absent, the neural
tube closes, but recognizable dorsal and ventral roots are absent.
In the lateral regions of the neural plate (future dorsal region of the neural tube), signaling
proteins are expressed by the overlying ectoderm. These have an inductive effect on
neuroectodermal cells, causing them to form a roof plate and the alar plate. Within the basal
plate is an array of five types of neurons: motor neurons and four types of interneurons,
arranged in a well-defined dorsoventral pattern. A number of neuronal processes cross from
one side of the central nervous system to the other through the floor plate as commissural
axons.
Spinal Nerves
Neural crest cells are ectodermal in origin and are present throughout the length of the neural
tube. They give rise to several types of tissue and one of them is the sensory ganglia that
provide for the dorsal roots of the spinal cord. Centrally growing process (axons) of
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neuroblasts in the sensory ganglia may synapse with neurons in dorsal horn of the spinal
cord, or continue to more cranial levels before synapsing. Their peripheral processes
(dendrites) terminate in receptor organs.
Motor nerve fibers arise from neurons in the basal plates (ventral horns) and collect into
bundles know as ventral nerve roots. Axons of motor nerves exit the spinal cord, while
their dendrites stay in the gray matter. When dorsal and ventral roots combine they form a
spinal nerve. Spinal nerves divide into dorsal and ventral primary rami. Dorsal primary
rami innervate dorsal axial musculature, vertebral joints, and skin of the back. Ventral
primary rami innervate the limbs and ventral body wall, and form major nerve plexuses.
Within the gray matter, short interneurons connect the terminations of sensory axons to
motor neurons, constituting the reflex arc.
Another cell type arising from neural crest cells are Schwann cells. Schwann cells coat
the peripheral nerves. Both myelinated and unmyelinated axons have Schwann cells.
Myelinated axons have a neurolemma sheath made by the Schwann cells and there is a
phospholipid material produced around one axon with nodes of Ranvier between adjacent
cells. Unmyelinated axons do not have the phospholipid material, but one Schwann cell can
ensheathe several axons.
Oligodendrocytes produce the myelin in the central nervous system, however, one
oligodendrocyte can ensheathe several axons. These cells are derived from neuroblasts.
Some motor fibers descending from higher brain centers do not become myelinated until the
first year of postnatal life. Hence, a positive Babinski sign is present: fanning out of toes on
sharply rubbing the lateral part of the foot and seen in upper motor neuron damage.
Neurite Outgrowth
During development, neurons become assembled into functional networks by growing out
axons and dendrites, collectively called neurites. They connect synaptically to other neurons
and muscle fibers.
A growth cone caps the actively elongating neurite. The expanded region of cytoplasm
characterizing the growth cones has numerous spikelike projections called filopodia.
Growth cones contain numerous cytoplasmic organelles, but much of the function of the
filopodia depends on large quantities of actin microfilaments in these processes. Agents that
can disrupt actin filaments result in loss of function of the growth cones.
Depending on the location of the adhering filopodia, the growth cone may lead the neurite
to which it is attached straight ahead or change its direction of outgrowth. This outgrowth
appears to be guided by four broad types of environmental influences: chemoattraction,
contact attraction, chemorepulsion, and contact repulsion.
Growth cones can respond to concentration gradients of diffusible substances or to weak
local electrical fields. A major family of attractant molecules is called netrins. The
repulsive counterparts are members of a family of secreted proteins called semaphorins.
Essential to the growth and maintenance of axons and dendrites is axonal transport.
Here, materials produced in the perikaryon or cell body are carried to the ends of the
neurites. The cytoskeletal backbone of the cell body and axon is made by microtubules
(tubulin dimers) and neurofilaments (intermediate filaments).
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Neurite/Target Relations
Developing neurites continue to elongate until they have contacted their appropriate end
organ. The end of the neurite must first recognize its proper target, and then it must make a
functional connection to it.
In the case of motor neurons "fast" axons are attracted to the precursors of fast muscle
fibers and "slow" axons to those of slow muscle fibers.
When a motor axon and a muscle fiber meet, a series of changes occurs that mark the
formation of a functional synapse or neuromuscular junction. The early changes consist of
(1) cessation of outgrowth of the axon, (2) the preparation of the nerve terminal for the
release of the appropriate neurotransmitter, and (3) modifications of the muscle fibers at the
site of nerve contact so that the neural stimulus can be received and translated into a
contractile stimulus.
Neuronal cell death (apoptosis) plays an important role in normal neural development.
For example, when a muscle is first innervated, far more numbers of neurons supply it than
would be in an adult. When one neuron establishes a neuromuscular junction, the rest of the
neurons vying for that muscle fiber are not allowed to make a functional synapse, hence,
massive numbers of neurons die.
Positional Changes of the Cord
In the third month, the spinal cord extends the total length of the vertebral column, but with
increasing age, the end of the cord is at a higher level. At birth the conus medullaris is at
the level of L3. The caudal end of the spinal cord is about the level of L2 in the adult.
Below L2 the peripheral nerves in the dural sac are in the form of a cauda equina. The pia
mater continues from the tip of the cord as the filum terminale, hanging freely in the dural
sac until it reaches the end of the sac at S2. Being intimate with each other, the pia and dura
terminate at the 1st coccygeal segment as the coccygeal ligament.
AUTONOMIC NERVOUS SYSTEM
Sympathetic Nervous System
Preganglionic neurons of the sympathetic nervous system arise from the intermediate horn of
the gray matter in the spinal cord. At levels from T1 to L2, their myelinated axons grow
from the cord through the ventral roots with the motor axons that supply skeletal muscles.
Just lateral to where the dorsal and ventral roots join forming a spinal nerve, the
preganglionic fibers (derived from neuroepithelium) leave the spinal nerve via a white
communicating ramus. They soon enter on of series of sympathetic ganglia (derived from
neural crest) that contain postganglionic neurons. Migrating sympathetic neuroblasts of the
intermediate column follow special pathways to their targets. Preganglionic axon of the
neuroblasts spread from the sympathetic chain ganglia cranially and caudally,
approximating what is seen in an adult. These preganglionic axons may terminate in local
ganglia or collateral ganglia. The adrenal medulla is considered to be a modified
sympathetic ganglion.
Axons of some postganglionic neuroblasts, which are unmyelinated, leave the chain
ganglia and reenter the nearest spinal nerve through the gray communicating ramus. Once
in the spinal nerve, theses axons continue to grow until they reach appropriate peripheral
targets, such as sweat glands, arrector pili muscles, and walls of blood vessels.
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Parasympathetic Nervous System
Preganglionic parasympathetic neurons originate in the visceroefferent column of the central
nervous system. However, the levels of origin of these neuroblasts are in the midbrain and
hindbrain and in the 2nd to 4th sacral segments. Axons of these preganglionic neuroblasts
grow long distances before they meet the neural crest derived postganglionic neurons.
Theses are typically embedded in scattered small ganglia or plexuses in the walls of the
organs that they innervate.
Differentiation of Autonomic Neurons
At early stages the neural crest cells have the option of differentiating into several types of
tissues. If they go down the line to become components of the autonomic nervous system
they may become part of either the sympathetic or parasympathetic system.
Typically, parasympathetic postganglionic neurons are cholinergic (acetylcholine),
whereas sympathetic neurons are adrenergic (noradrenergic). As they arrive at their final
destinations all autonomic neurons are noradrenergic. Then they enter a phase during which
they select the neurotransmitter substance that will characterize their mature state. An
example of a natural transition of the neurotransmitter phenotype from noradrenergic to
cholinergic occurs in the sympathetic innervation of sweat glands.
Congenital Aganglionic Megacolon (Hirschsprung's disease)
If a newborn has symptoms of constipation without obstruction, the cause is usually an
absence of parasympathetic ganglia in the sigmoid colon and rectum. Hirschsprung's disease
is attributed to an absence of colonization of the lower colon by neural crest-derived
parasympathetic neuronal precursors.
NEURAL TUBE DEFECTS
Neural tube defects (NTDs) may involve the meninges, vertebrae, muscles, and skin. NTDs
occur approximately in 1 /1000 births.
Spina Bifida
Spina bifida Occulta – this is a defect of the vertebra arches that is cover by skin and usually
does not involve the underlying neuronal tissue. It occurs in about 10% of the population.
The lumbosacral region is affected and is usually marked by a patch of overlying hair.
Spina bifida cystica – Here is a severe NTD in which the neural tissue and/or meninges
protrude through a defect in the vertebral arches. Most are in the lumbosacral area and in
some cases, only a fluid-filled meningeal sac protrudes through the defect: a meningocele.
In other instances there will be nervous tissue included in the sac: a meningomyelocele.
Occasionally the neural folds do not elevate, but remain as a flattened mass of neural tissue:
myeloschisis or rachischisis. Hydrocephaly occurs in almost every case of spina bifida
cystica because as the vertebral column lengthens, the cerebellum is pulled into the foramen
magnum.
Several causes of NTDs are hyperthermia, valproic acid, and hypervitaminosis A. Recent
evidence proves that folic acid (folate) reduces the incidence of NTDs by as much as 70% if
400 μg is taken daily beginning two months prior to conception and continuing throughout
gestation.
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BRAIN
Figure 1
A. Sketch of the developing brain at the end of the fifth week, showing the three primary divisions of
the brain and the brain flexures. B. Transverse section of the caudal part of the myelencephalon
(developing closed part of the medulla). C and D. Similar sections of the rostral part of the
myelencephalon (developing "open" part of the medulla), showing the position and successive stages
of differentiation of the alar and basal plates. The arrows in C show the pathway taken by
neuroblasts from the alar plates to form the olivary nuclei.
Functional Regions in the Spinal Cord and Brain
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ALAR PLATE (AFFERENT OR SENSORY)
Special somatic afferent: sensory from vision, hearing, and equilibrium
General somatic afferent: sensory input from the skin joints and muscles
Special visceral afferent: sensory input from the taste buds of tongue,
plate and pharynx
General visceral afferent: sensory input from the viscera and heart
BASAL PLATE (EFFERENT: MOTOR OR AUTONOMIC)
General visceral efferent: autonomic (two-neuron) links from the
intermediate horn to viscera and brainstem parasympathetics
Special visceral efferent: motor nerves to striated muscles of the
pharyngeal arches (I, II, III, IV, and VI)
General somatic efferent: motor nerves to the striated muscles other than
those of the pharyngeal arches
Rhombencephalon: Hindbrain
Myelencephalon
The myelencephalon is the most caudal subdivision of the rhombencephalon, developing
into the medulla oblongata. Alar (sensory) and basal (motor) plates are separated by the
sulcus limitans (Figure 1). The medulla is a conduit for many nerve tracts, but it also
contains centers for regulation of the heart rate and respiration.
In the basal plate, three groups of nuclei are positioned in a somewhat medial to lateral
placement. Most medial are the neurons of the somatic efferent motor column continuing
rostrally into the mesencephalon (midbrain). In the myelencephalon motor column forms the
hypoglossal nerve. In the metencephalon (pons) the motor column forms the abducens
nucleus and in the mesencephalon, the trochlear and oculomotor nuclei.
The special visceral efferent column extends into the metencephalon. Its motor neurons
supply striated muscles of the pharyngeal arches. In the myelencephalon, the column is
represented by the glossopharyngeal, vagus, and accessory nerves.
The general visceral efferent column contains motor neurons the supply involuntary
musculature of the respiratory and intestinal tracts, and the heart (dorsal motor nucleus of
the vagus nerve). In association with the glossopharyngeal nerve, the inferior salivatory
nucleus supplies preganglionic parasympathetic fibers to the otic ganglion.
In the alar plate there are three groups of sensory nuclei: four of the somatic afferent are
partitioned into separate special and general categories (see the above box). The most lateral
of these is the somatic afferent group. This group receives impulses from the
vestibulocochlear nerve (special somatic afferent) and trigeminal nerve (general somatic
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afferent) from the head. The intermediate, or special visceral afferent group (solitary
nucleus), receives taste sensation from the tongue, palate, oropharynx, and epiglottis. The
general visceral afferent group receives sensation from the gastrointestinal tract and heart.
The roof plate if the myelencephalon is a layer of ependymal cells covered with pia mater.
This combination forms the tela choroidea. Invaginations of the tela choroidea into the
fourth ventricle form a choroid plexus.
Metencephalon
Pons
Similar to the myelencephalon, the metencephalon is characterized alar and basal plates. The
components of the metencephalon are the cerebellum and the pons.
The basal plate of the metencephalon has a medial general somatic efferent group giving
rise to the abducens nerve. The special visceral efferent group contains motor nuclei for
the trigeminal and facial nerves (nerves supplying the 1st and 2nd pharyngeal arches). In
association with the facial nerve, the general visceral efferent group has preganglionic
parasympathetic neurons from the superior salivatory nucleus supplying the submandibular
and pterygopalatine ganglia.
The alar plates of the metencephalon contain three groups of sensory nuclei. The most
lateral is the somatic afferent for portions of the vestibulocochlear complex, plus neurons
for the trigeminal nerve. Also, there is a special visceral afferent group (rostral solitary
nucleus) for taste and general visceral afferent group (sensory to soft palate and pharynx).
Cerebellum
The future site of the cerebellum is first represented by the rhombic lips, which are
somewhat diamond-shaped. The cerebellum arises from the anterior (cerebellar) rhombic
lips. The migratory precursors of a variety of ventrally located nuclei are found in the
posterior (hindbrain) rhombic lips. These ventrally located nuclei are from the
rhombencephalon (olivary nuclei) and the metencephalon (pontine nuclei). Soon after the
induction of the rhombic lips, precursors of granule cells migrate anteriorly along the
cerebellar lips to a transitory location to form the external granular layer. After terminal
mitotic divisions, the external granule cells migrate from the external part of cerebellum to its
internal part. Along this route, these cells pass by the Purkinje cells, which are migrating
radially in the opposite direction. Once past the Purkinje cells, the migrating granule cells
permanently settle in the inner granular layer or granule layer. Cells in the granular layer
are granule and Golgi neurons. The outer (molecular) layer of the cerebellar cortex
contains basket and stellate neurons. Between the molecular and granule layers is the
Purkinje layer. Deep cerebellar nuclei (dentate, emboliform, globose, fastigial) reach their
final position before birth.
Mesencephalon: Midbrain
The basal plates form a neuron-rich area called the tegmentum. Here, there are two motor
nuclei: a medial somatic efferent group represented by the oculomotor and trochlear
nerves. A general visceral efferent group is represented by the Edinger-Westphal
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nucleus, which innervates the pupillary sphincter muscle. The marginal layer of each basal
plate forms the crus cerebri.
The alar plates form the sensory part of the midbrain and have two pairs of bulges called
corpora quadrigemina. The caudal pair, called inferior colliculi, is composed of neurons
that serve the auditory system. The rostral pair of bulges is the superior colliculi, whose
neurons subserve the visual system.
Prosencephalon: Forebrain
The prosencephalon consists of the telencephalon and diencephalon.
Diencephalon
Roof Plate and Epiphysis - The roof plate of the diencephalon consists of a single layer of
ependymal cells covered by vascular mesenchyme. Together they form the choroid plexus
of the 3rd ventricle. The most caudal part of the roof plate develops into the pineal body, or
epiphysis. The epiphysis serves as a channel through which light and darkness affect
endocrine and behavioral mechanisms. In adults it has calcifications (brain sand) that can be
seen on x-rays, hence it can be used as a landmark.
Alar Plate, Thalamus, and Hypothalamus - The alar plates form the lateral walls of the
diencephalon. The hypothalamic sulcus divides the plate into a dorsal and ventral region:
the thalamus and hypothalamus, respectively. Frequently, both sides of the thalamus fuse
in the midline, forming the massa intermedia.
The hypothalamus develops a number of neuronal areas that regulate visceral functions
(sleep, digestion, body temperature, and emotional behavior). One such group is the
mammillary bodies.
Hypophysis or Pituitary Gland - The pituitary gland develops from two sources of tissue.
One, from an ectodermal outpocketing of the stomodeum directly in front of the
buccopharyngeal membrane known as Rathke's pouch. Rathke's pouch develops at about
three weeks old and by the end of the second month, loses contact with the oral cavity. It is
in close contact with the infundibulum, a direct extension of the diencephalon.
The cells of Rathke's pouch form the adenohypophysis or pars distalis, plus the part of
the adenohypophysis in direct contact with the infundibulum, the pars tuberalis. The pars
intermedia is poorly developed in humans.
The second part of the pituitary gland, the infundibulum, gives rise to the stalk and pars
nervosa, or posterior lobe of the hypophysis.
Telencephalon
Cerebral Hemispheres - The cerebral hemispheres are bilateral evaginations of the
prosencephalon. The walls of the telencephalon are expanded with lateral ventricles. The
third ventricle is in the midline of the diencephalon. The two cerebral hemispheres never
meet in the dorsal midline because they are separated by the falx cerebri. Their surfaces
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remain smooth until the fourteenth week. With continued growth, the cerebral hemispheres
undergo several foldings. One is the formation of the temporal lobes. By the eighth month
the sulci and gyri take shape.
Internally, the telencephalon thickens to form the comma-shaped corpus striatum. With
differentiation, the corpus striatum is subdivided into lentiform and caudate nuclei. These
structures, along with several other nuclei, are part of the basal ganglia.
The other major component of the early telencephalon is the lamina terminalis, which
has connections between the two hemispheres. Associated with the lamina terminalis is the
anterior commissure, which connects the olfactory areas from two sides of the brain.
Another connection is the hippocampal commissure or fornix. The corpus callosum has
the most connections between the two hemispheres. Other commissures not related to the
lamina terminalis are the posterior and habenular commissures.
The oldest and most primitive component of the telencephalon is the rhinencephalon
(also the archicortex and paleocortex).
Questions
1.
The ____________is also called the midbrain.
a. prosencephalon
b. mesencephalon
c. metencephalon
d. myelencephalon
2.
The optic vesicles are the extension of the ______________.
a. telencephalon
b. diencephalon
c. metencephalon
d. myelencephalon
3.
When the production of neuroblasts ceases, the formation of __________ and
ependymal cells begins from neuroepithelial cells.
a. microglia
b. Schwann cells
c. gliablasts
d. satellite cells
4.
In the gray matter are found __________________.
a. fibrous astrocytes
b. oligodendrocytes
c. ependymal cells
d. protoplasmic astrocytes
5.
In the developing spinal cord, the intermediate stratum is called the _______ zone.
a. ventricular
b. mantle
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c. marginal
d. cortical
6.
You will tend to find cell bodies of neurons in the ______________ zone.
a. mantle
b. ependymal
c. marginal
d. medullary
7.
Which of the following is true?
a. The alar plate is associated with motor neurons.
b. The floor plate connects the alar plates.
c. The basal plate contains sensory neurons.
d. The sulcus limitans separates the basal and alar plates.
8.
During development, neurons become assembled into functional networks by growing
out axons and dendrites, collectively called ___________.
a. astrocytes
b. filopodia
c. growth cones
d. neurites
9.
The condition where both meninges and spinal cord protrude from the surface of the
body is __________.
a. spina bifida occulta
b. meningomyelocele
c. meningocele
d. rachischisis
10. The hindbrain is also called the ______________.
a. rhombencephalon
b. prosencephalon
c. diencephalon
d. mesencephalon
11. The outer layer of the cerebellar cortex is the ___________ layer.
a. Purkinje
b. granular
c. marginal
d. molecular
12. The Edinger-Westphal nuclei are found in the ______________.
a. telencephalon
b. diencephalon
c. mesencephalon
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d. metencephalon
13. The adenohypophysis develops from ___________ epithelium, also called
___________.
a. endodermal / the foramen cecum
b. ectodermal / the foramen cecum
c. endodermal / Rathke's pouch
d. ectodermal / Rathke's pouch