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CHAPTER 3 Constructing the Nervous System 51
Dierentiating at Journey’s End
As development progresses the RGCs give rise to cells that are postmitotic and
committed to a neuronal or glial fate. The committed cells then dierentiate into
specic types of neurons and glia. Dierentiation involves regulation of gene
expression, which determines the cell’s phenotype. Chapter 2 examines the
mechanisms that control gene expression.
As the neural tube develops, morphogens are released by specic groups of cells
in the embryo, and gradients of morphogens are formed along the anterior poste-
rior and dorsal ventral axes of the developing tube. The morphogen receptors in
the NECs, RGCs, and developing neurons and glia lead to the control of gene
expression. Through their receptors, these morphogens help to determine the
types of neurons and glial cells that will develop in specic CNS areas. One way
that gene expression is controlled is through transcription, which we describe in
the following sections.
Switching programs with
transcription factors
Researchers have identied several important morphogens and transcription in
the developing neocortex. Following neurulation, inhibition of the Wnt (ligand in
the wingless pathway) pathway is required for specication of the cerebral cortex
in the telencephalon. Initially, in the developing neural tube, the delta-notch sig-
naling pathway, which regulates a family of basic helix-loop-helix transcription
factors, promotes the self-renewal of NECs and RGCs.
After enough NECs and RGCs are produced, inhibition of delta-notch signaling in
RGCs is then required to activate specic proneural gene expression and the for-
mation of neurons. Proneural genes also contribute to the neuron–glia fate deci-
sion. The initial self-renewal and then the switch to neurogenesis and gliogenesis
are essential for generation of brain structures of appropriate size and shape by
controlling the timing of proliferation and dierentiation.
In the developing neocortex, additional transcription factors, including members
of the Otx, Emx, Sox, and Pax families, show dierential expression and contrib-
ute to the development of functional areas of the cerebral cortex, including sen-
sory, motor, and cognitive regions.
Dierentiation has an important impact on the morphology of neurons and glia.
When neurons dierentiate, they also synthesize proteins and activate pathways
that lead to the outgrowth of axons and dendrites, and later to the formation of
synapses.
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52 PART 1 Getting Started with Neurobiology
Establishing cortical neurons
Pyramidal (glutamatergic) neurons are located in the cerebral cortex (including
neocortex, mesocortex, and allocortex such as the hippocampus). They have
pyramid-shaped somas, one large apical and several basal dendrites, and many
dendritic spines. Pyramidal neurons are the main output neurons from the
neocortex. The other glutamatergic neurons in the neocortex are stellate neurons,
which also have dendritic spines but extend their axons locally within the
neocortex.
Inhibitory (GABAergic) interneurons have dense, local inhibitory connections.
Researchers have identied numerous types of neocortical inhibitory interneu-
rons that dier in their neuropeptide expression and morphologies. Inhibitory
interneurons provide modulation of neural activity in diverse ways that endow
neocortical circuits with enhanced computational power. Chapter11 describes the
inputs to, outputs from and connections among neurons in the neocortex.
Neural progenitor cells dierentiate during cortical development into dierent
neuronal types and locations in the neocortex that have specic connections and
functions.
The organization of the neocortex allowed the brain to enlarge rapidly during evo-
lution because of its ability to represent dierent types of inputs, process those
inputs, and communicate with other areas of cortex in a standard way. Cognitive
enhancements in multiple senses and motor control evolved by devoting more
area at a given stage of processing for higher acuity and more areas for greater
sophistication of processing.
Extending and Guiding Axons
and Dendrites
When newly generated neurons arrive at their specic cortical layer during develop-
ment (or even before they arrive), they begin to dierentiate and extend an axon
and form dendrites. As the axon and dendrites grow out, they also branch. These
branches are essential for the formation of synapses and functional neural circuits.
A specialized structure at the tip of the axon is the growth cone. It senses molecular
cues in the environment through specic receptors and guides the axon toward its
target. Activated receptors signal to the actin and microtubule cytoskeletons and
their motor proteins. This results in the movement of the growth cone. Dendrites
also contain growth cones at their ends and may employ similar mechanisms for
outgrowth.
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CHAPTER 3 Constructing the Nervous System 53
The majority of inhibitory neurons and many excitatory neurons connect locally
within the neocortex. Extracellular matrix proteins and cell adhesion molecules
are involved in axon guidance and targeting for connections among neurons
within the neocortex. The next sections delve deeper into axon guidance cues.
Detecting the cues
Cortical pyramidal neurons extend their axons out to other cortical or subcortical
regions. Little is known about the factors that guide axons into or out of the mam-
malian neocortex. Studies in animal models, such as the developing chick spinal
cord and frog retina, have identied axon guidance cues. Cues can act as attrac-
tants that guide the axon toward its correct target or as repellants that push the
axon away from the wrong target.
Guidance cues include both short- and long-range types. Short-range (tethered)
cues are proteins in the extracellular matrix, such as laminin and bronectin, or
plasma-membrane located proteins such as the cell-adhesion proteins like cad-
herins. Long-range cues are secreted proteins that form gradients in the extracel-
lular environment. Identied diusible guidance cues (and their receptors)
include netrins (DCC and Unc5), Slit (Robo), ephrins (Eph receptors), and sema-
phorins (plexins and neuropilins). Some morphogens such as BMPs, FGF, and
Wnts also participate in growth cone guidance.
Morphological dierentiation involves elaborating and branching a neuron’s axo-
nal projection. This process is mediated by molecular cues in the environment
that are detected by receptors on the axon growth cone. The axon elongates and
the growth cone moves toward attractants or away from repellents.
Competing for survival
During development, more neurons are produced than will be needed in the adult
nervous system. In order to survive, neurons depend on survival factors and/or
forming synaptic connections. Neurons that don’t receive survival factors or syn-
aptic connections undergo a type of programmed cell death called apoptosis. An
estimated one third to one half of all neurons initially produced in the brain may
undergo apoptosis. This loss ensures the right match between the neuronal popu-
lation and its targets and prevents the formation of unnecessary or inecient
synapses, and erroneous circuits.
Trophic factors bind to receptors and support neuronal survival. Developing axons
compete for binding of target-derived trophic factors. Axons (and the neurons
they are connected to) that don’t receive enough trophic signaling or don’t form
synapses don’t survive. Target-derived trophic factors include the neurotrophins,
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54 PART 1 Getting Started with Neurobiology
such as nerve growth factor, neurotrophin 3 and 4, and brain-derived neuro-
trophic factor (BDNF), as well as several morphogens, growth factors, and even
neurotransmitters and neuropeptides.
As soon as functional synaptic connections have formed, activity can also contrib-
ute to neuronal survival, possibly through the release of additional trophic factors.
Some trophic factors, such as BDNF, have been shown to function in neuroplasti-
city in the adult brain.
Establishing the Synapses
As neurons dierentiate, their dendrites undergo extensive branching and form
dendritic trees. Many dendrites protrude dendritic spines. This morphology
increases the area and number of synapses that can form on the dendrite. Den-
dritic branches and spines express specic cell adhesion and secreted proteins
that attract a growing axon branch.
In invertebrates, this wiring process is almost completely genetically programmed,
with several thousand identically laid neurons with almost the same synapses
from animal to animal. In vertebrates, however, and mammals, in particular,
things are more complicated.
After an axon has reached its correct target, a synapse can form in a process called
synaptogenesis that occurs prenatally and postnatally, and even in adulthood. The
synapse is the place where communication occurs between a neuron and its tar-
get, which can be another neuron, a muscle cell, or a gland. Synapses between
neurons are the basis of pathways, systems, and circuits that mediate sensory
perception, motor output that produces behaviors, and cognitive functions such
as language and memory.
Chapters5 and6 provide more information on synaptic transmission. The follow-
ing sections describe the mechanisms of how synaptogenesis occurs and how
synapses are rened.
Beginning the contact
In synaptogenesis in the CNS, the axonal growth cone contacts the postsynaptic
neuron. If the growth cone approaches a dendrite, a small protrusion on the den-
drite called a lopodium attracts the growth cone and helps initiate synapse for-
mation. This contact sends a signal back along the axon that instructs the growth
cone to develop into a presynaptic region.
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CHAPTER 3 Constructing the Nervous System 55
Both the presynaptic and postsynaptic regions become specialized by localizing
proteins in and near the plasma membrane. Some presynaptic proteins, such as
the synaptic vesicle, release machinery and ion channels, and some postsynaptic
proteins, like receptors and scaolds, are delivered to the developing synapses in
preassembled packets.
Formation of the synapse also involves attachment of cell adhesion molecules
across the cleft. These include neuroligin and neurexin, synCAMs, cadherins,
ephrins, and Eph receptors, which connect the presynaptic to the postsynaptic
region. Some synapses can become active rapidly after synapse formation, but it
typically takes several hours or longer for synapses to mature and become
functional.
Rening synapses
Axon guidance and targeting aren’t perfect. Neurons may form synapses with
both their intended and unintended targets, or more synaptic connections may
form than are needed. It’s important that the right connections be maintained and
the wrong or redundant connects be removed. During development, newly formed
synapses are modied through a process called synaptic renement where they can
be strengthened, weakened, or eliminated.
Initial synapse formation doesn’t depend on neuronal activity. However, activity
is required to maintain a synapse. The inactive or low activity synapses are
removed. Active synapses are maintained and may be strengthened. Sensory input
and behavioral circuits lead to activity-dependent mechanisms for the develop-
ment of neural circuits and connectivity maps. Many inactive or low activity syn-
apses that form during prenatal and postnatal periods will be removed between
early childhood and adolescence.
During development, there are specic windows of time when experiences have a
greater impact on the development of particular systems and circuits, referred as
developmental sensitive periods and critical periods. These are the time windows
when experiences and neuronal activity strengthen important connections.
They’re also the time windows when a lack of experience and neuronal activity
can lead to loss of synapses and possible permanent loss of circuits in specic
brain regions for a particular skill or function.
Synaptic renement and circuit formation occur and peak at dierent developmen-
tal times for dierent brain systems and circuits. The critical period for develop-
ment of the auditory and visual systems is during the rst postnatal 6 to 9 months.
The critical period for development of language is between 6 to 12 months. Higher
cognitive functions continue to develop throughout childhood and adolescence.
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56 PART 1 Getting Started with Neurobiology
Strengthening synapses
The nervous system, including the brain, develops by pruning neurons and con-
nections that don’t end up with signicant activity. Researchers don’t know
exactly how the nervous system determines what is signicant in the connectivity
of individual neurons. It may be the total number of connections compared to
neighbors. The brain also develops by altering the strength of connections between
neurons.
The idea that synapses can change strength was proposed by Donald Hebb in the
1940s and the type of change he envisioned is called Hebbian plasticity. The con-
cept in Hebbian plasticity is that coincident presynaptic and postsynaptic activity
leads to changes in the strength of synapses. It’s widely accepted as a mechanism
by which information can be encoded and retained in neurons in the brain. Heb-
bian plasticity is proposed to play an important role in development and memory.
Synapse renement and Hebbian plasticity also occur in the adult brain, where
they’re often referred to as synaptic plasticity. Synaptic plasticity is proposed as an
essential mechanism that underlies the encoding of memory by the hippocampus,
amygdala, and cerebellum and may be involved in cortical remapping following
practice and injury. Disruption of synaptic plasticity may also occur in disorders
such as depression. Chapter15 describes the mechanisms of synaptic plasticity.
Mapping out the cortex
The primary visual cortex contains a map in which adjacent retinal ganglion cells
relay through the thalamus to adjacent cortical cells. Similarly, the somatosensory
system has an orderly, although distorted, map of the body and face on the neo-
cortex. Early in development, projections are produced from dierent sensory
nuclei in the thalamus to the appropriate part of the neocortex. These genetically
specied maps are later rened by activity-dependent mechanisms.
Competing for cortical space
Within any given sense, and between senses, there’s competition for cortical area.
Research shows that if one area of a cortical map is deprived of its input, other,
usually adjacent, inputs will begin to activate it. Important research today is ask-
ing the question of whether this new activation comes from inputs that were
always there, but silent, or whether new inputs grow into a denervated area. The
answer depends on whether the deprivation occurs during development before
critical periods, or afterward.
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CHAPTER 3 Constructing the Nervous System 57
Wiring in the visual system
Synaptic modication occurs according to correlated activity in the pre- and post-
synaptic elements of synapses. In the case of cortical maps, consider two ganglion
cells that are adjacent to each other in the retina with receptive elds that overlap
to some degree. Objects projected onto this area of the retina tend to aect both
nearby ganglion cells and produce similar light distributions in the receptive elds
of both nearby ganglion cells, so that their ring tends to be correlated.
When the axons of these ganglion cells reach the thalamus, they initially branch
extensively and try to innervate many targets. But over time, because the axons of
adjacent ganglion cells tend to be correlated with each other and with target cells
they both innervate, their synaptic weights onto those target cells are increased.
Meanwhile, the weights of distant uncorrelated ganglion cells don’t get weight
increases when they innervate the same target.
The initial projection from the retina to the thalamus is approximately ordered by
the guidance cues. Coincident activity ensures that the nal wiring forms a good
map. During development of the visual system — before the retina even has
photoreceptors — waves of organized self-induced spontaneous ring move
across the retina constantly to produce a position-dependent internally generated
correlated ring. This process repeats itself at every level of the nervous system,
through many stages of neocortical processing.
In humans, after infancy, activity dependent synaptic renement leads to changes
in synaptic numbers and strengths. Myelination of axon tracts also has a signi-
cant developmental timescale that extends through early adulthood. In the adult
brain synaptic plasticity occurs in several regions and has been implicated in
learning and memory and recovery following injury.
Myelinating into Adulthood
In axon myelination, axons are wrapped with myelin membranes to make action
potential conduction faster, more ecient, and more reliable. Myelination begins
in the late prenatal period and continues until early adulthood. The last parts of
the brain to be fully myelinated are the frontal lobes, the areas of the brain most
needed for abstract thought and judgment.
Oligodendrocytes are the myelinating cells of the CNS. They develop from
oligodendrocyte precursor cells (OPCs) during gliogenesis in development and in
the adult. Axons that are larger than 1 micrometer in diameter and long axons
from projection/principal neurons are usually myelinated. One oligodendrocyte
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58 PART 1 Getting Started with Neurobiology
can myelinate multiple axons. The majority of oligodendrocytes are located in
white matter, but a few are also found in gray matter. They also provide metabolic
and trophic support of axons.
Damage to an oligodendrocyte or its myelin membranes can lead to loss of motor
or sensory functions. The most common demyelinating disorder is multiple scle-
rosis (MS), an autoimmune disorder that leads to myelin degeneration. We exam-
ine MS in Chapter12.
Here we discuss the meninges, which are membranes that form around the CNS
during development and provide protection and regulation of the cerebrospinal
uid (CSF).
Covering the CNS with meninges
The meninges, three membrane layers that form around the developing neural
tube and that form the mesoderm, protect the CNS:
»
Outermost layer: This layer is the dura mater, which is composed of dense
brous tissue and is attached to the skull in specic places. It contains a few
large blood vessels.
»
Middle layer: This layer is the arachnoid matter that consists of a membrane
of brous tissue that resorbs (transports) CSF.
»
Innermost layer: This thin membrane is the pia mater and follows the brain
surface and spinal cord. Blood vessels pass through the pia mater to the brain
and spinal cord.
The meninges may also play a role in the development of the nervous system.
They release diusible factors that aect neural progenitor cells. They also help
set up the pial basement membrane that forms a base for radial bers of neuro-
epithelial stem cells. Errors in development, injuries, or infections that aect the
meninges may contribute to hydrocephalus.
Hydrocephalus is caused by an abnormal accumulation of CSF in the brain’s ven-
tricles, which leads to high intracranial pressure. Hydrocephalus can be caused by
the following:
»
Congenital malformations that block normal drainage of the uid from
the meninges
»
Overproduction of CSF
»
Complications of head injuries or brain infections
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CHAPTER 3 Constructing the Nervous System 59
Symptoms in less severe cases include nausea, vomiting, and sleepiness. In more
severe cases, hydrocephalus can be associated with mental disability, convulsions,
and even death from brainstem compression.
Completing the PNS
Neurons and glia of the PNS are produced from neural crest cells (NCCs) induced
from ectoderm as the neural tube closes (see Figure3-1). NCCs dierentiate as
they migrate away from the dorsal neural tube.
The location of NCCs along the neural tube determines the adult structure they
will form. Cranial NCCs form components of cranial nerves and cranial ganglia
while trunk NCCs give rise to components of spinal nerves and ganglia outside the
spinal cord. NCCs give rise to a variety of neurons, including somatosensory and
visceral sensory neurons in dorsal root ganglia and cranial ganglia, neurons in the
sympathetic and parasympathetic (autonomic) ganglia, and enteric nervous
system.
NCCs produce the glial cells in the PNS, Schwann cells, and satellite cells. NCCs
also give rise to numerous non-neural cells, including the pigmented melanocytes
of the skin, the adrenal medulla, the thymus gland, facial structures, cartilage,
and connective tissue in the heart.
During development, small islands of neural ectoderm are also located in regions
of non-neural ectoderm after the neural tube closes, called neural placodes. They
give rise to olfactory and auditory sensory neurons, lens of the eye, and anterior
pituitary, and contribute to several cranial ganglia.
Disrupting Development
The developing nervous system is built using intrinsic genetic programs, but cells
are also inuenced by their environment. Development has incredible delity, but
it’s also fragile. Both genetic changes that are inherited or arise spontaneously,
and environmental insults can disrupt brain development.
The embryo is particularly susceptible to foreign chemicals, pathogens, and meta-
bolic disruption because the developing cells are responding to chemical gradients
in the environment, regulating gene expression, and forming new structures.
Environmental substances or infectious agents that have little eect on adults or
late fetal development can have profound eects on early embryonic develop-
ment. The general term for a substance or eector that causes birth defects is a
teratogen.
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60 PART 1 Getting Started with Neurobiology
Congenital brain disorders are dened asstructural or functional anomalies that
occur during prenatal development. Neural tube defects, cerebral palsy and hydro-
cephalus are three examples.
Neurodevelopmental disorders area group of conditions in which the growth and
development of the brain is aected. They can impact an individual’s behavior,
self-control, emotions, and cognitive functions including language, executive
functions, and learning and memory. Neurodevelopmental disorders include
attention-decit/hyperactivity disorder (ADHD), autism spectrum disorder, intel-
lectual disability, cerebral palsy, and sensory impairments. Many neurodevelop-
mental disorders result from interactions between genetic and environmental
factors. Chapter18 describes neurodevelopmental disorders in more detail. These
sections discuss several processes that occur during aging and their eects on the
function of the brain.
Aging cells
Aging is a complex process. It involves mechanisms that range from the subcel-
lular level to the whole organism. The telomeres at the end of chromosomes inside
the nucleus of cells appear to be capable of only a nite number of divisions. In the
body, each time a cell divides, the telomeres shorten until they become too short
for the cell to divide any more. The cell then may become inactive or die. Because
most neurons in the brain are postmitotic, telomere shortening probably isn’t a
mechanism in brain aging. Joints wear out and blood vessels harden or get clogged
with deposits at the whole organism level. Tissues and organs of the body can mal-
function, which can adversely aect other parts of the body including the brain.
During normal adulthood, cell numbers and structure in the brain are generally
stable. The encoding of memories primarily involves modication of synaptic
strengths, although neurons in areas such as the hippocampus continue to be
replaced at low levels. The number of neurons starts to decline at middle age
because of the accumulation of protein aggregates, toxins, and metabolic errors.
These can be inuenced by genetic and environmental factors that accelerate
neuronal injury and degeneration.
Aging and brain dysfunction
Most athletic and raw cognitive ability functions peak in the mid- to late 20s.
Cognitive capabilities, such as executive functions associated with knowledge and
wisdom, continue to increase beyond this age. Aging is a major risk factor for
neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease,
and vascular disease that aects the brain. Both genetic and environmental
factors appear to be involved in these disorders. We provide more details about
Parkinson’s disease in Chapter12 and Alzheimer’s disease in Chapter15.
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