The amazing capabilities of the human brain arise from
exquisitely intricate communication among its billions
of interacting brain cells. Although the specific patterns
of connectivity are forged by the ever-changing interplay
between a person’s genes and his specific environment,
much of the development of brain cells occurs during the
prenatal period. Understanding the processes underlying
how brain cells are formed, become specialized, travel to
their appropriate location, and connect to each other in
increasingly elaborate adaptive networks is the central
challenge of developmental neurobiology.
Advances in the study of brain development have
become increasingly relevant for medical treatments.
For example, several diseases that most scientists
once thought were purely disorders of adult function,
such as schizophrenia, are now being considered in
developmental terms; that is, such disorders may occur
because pathways and connections to the brain did
not form correctly early in life. Other research suggests
that genes important for brain development may also
play a role in susceptibility to autism spectrum disorders.
And by applying knowledge about how connections
form during development, regeneration following injury
to the brain is now viewed as a future possibility.
Knowing how the brain is constructed is essential for
understanding its ability to reorganize in response to external
influences or injury. As the brain evolves from the embryo
to the adult stage, unique attributes evolve during infancy
and childhood that contribute to differences in learning
ability as well as vulnerability to specific brain disorders.
Neuroscientists are beginning to discover some general
principles that underlie developmental processes, many of
which overlap in time.
The Journey of Nerve Cells
The development of neurons occurs through a delicate
process. Signaling molecules “turn on” certain genes and “turn
off” others, beginning the process of nerve cell induction.
Even more astonishing is that this process takes place as the
embryo is developing. Induction and proliferation are followed
by migration, during which the newly formed neurons travel
to their final destination. Throughout life, the nervous system
is active, making new connections and fine-tuning the way
messages are sent and received. The activities of the everchanging
nervous system are explained in more detail in the
following sections.
Induction During the early stages of embryonic
development, three layers emerge — the endoderm, the
ectoderm, and the mesoderm. These layers undergo many
interactions to grow into organ, bone, muscle, skin, or
nerve tissue. How does this process of differentiation occur,
especially since each cell contains 25,000 genes, the entire
sequence of DNA instructions for development? The answer
lies in signaling molecules released by the mesoderm. These
molecules turn on certain genes and turn off others, triggering
some ectoderm cells to become nerve tissue in a process called
neural induction. Subsequent signaling interactions further
refine the nerve tissue into the basic categories of neurons or
glia (support cells), then into subclasses of each cell type. The
remaining cells of the ectoderm, which have not received the
signaling molecules diffusing from the mesoderm, become skin.
The proximity of cells to the signaling molecules largely
determines their fate. That’s because the concentration of
these molecules spreads out and weakens the farther it moves
from its source. For example, a particular signaling molecule,
called sonic hedgehog, is secreted from mesodermal tissue
lying beneath the developing spinal cord. As a result, the
adjacent nerve cells are converted into a specialized class of
glia. Cells that are farther away, however, are exposed to lower
concentrations of sonic hedgehog, so they become the motor
neurons that control muscles. An even lower concentration
promotes the formation of interneurons, which relay messages
to other neurons, not muscles. Interestingly, the mechanism of
chaPter 2:
the develoPiNg BraiN
in this chapter
n The Journey of Nerve Cells
n Critical Periods
n Plasticity
chaPter 2:
14 BraiN factS | introduction to the brain Society for NeuroScieNce
this basic signaling molecule is very similar in species as diverse
as flies and humans.
Migration Once neural induction has occurred, the
next step for new neurons is a journey to the proper position
in the brain. This process is called migration, and it begins
three to four weeks after a human baby is conceived. At
this time, the ectoderm starts to thicken and build up along
the middle. As the cells continue to divide, a flat neural
plate grows, followed by the formation of parallel ridges,
similar to the creases in a paper airplane, that rise across its
surface. Within a few days, the ridges fold in toward each
other and fuse to form a hollow neural tube. The top of the
tube thickens into three bulges that form the hindbrain, the
midbrain, and the forebrain. Later in the process, at week
seven, the first signs of the eyes and the brain’s hemispheres
appear. As neurons are produced, they move from the neural
tube’s ventricular zone, or inner surface, to near the border of
the marginal zone, or outer surface.
After neurons stop dividing, they form an intermediate
zone, where they gradually accumulate as the brain develops.
The neurons then migrate to their final destination— with
the help of a variety of guidance mechanisms. The most
common guidance mechanism, accounting for about 90
percent of migration in humans, are glia, which project
radially from the intermediate zone to the cortex. In this way,
glia provide a temporary scaffolding for ushering neurons to
their destination. This process of radial migration occurs in an
“inside-out” manner; that is, the cells that arrive the earliest
(the oldest ones) form the deepest layer of the cortex, whereas
the late-arriving (the youngest) neurons form the outermost
layer. Through another mechanism, inhibitory interneurons,
small neurons with short pathways usually found in the central
nervous system, migrate tangentially across the brain.
Migration is a delicate process and can be affected by
different factors. External forces, such as alcohol, cocaine,
or radiation, can prevent proper migration, resulting in
misplacement of cells, which may lead to mental retardation
or epilepsy. Furthermore, mutations in genes that regulate
migration have been shown to cause some rare genetic forms
of retardation and epilepsy in humans.
Making Connections Once the neurons reach their
final location, they must make the proper connections so
that a particular function, such as vision or hearing, can
emerge. Unlike induction, proliferation, and migration, which
occur internally during fetal development, the next phases of
brain development are increasingly dependent on interactions
with the environment. After birth and beyond, such activities
as listening to a voice, responding to a toy, and even the
reaction evoked by the temperature in the room lead to more
connections among neurons.
Neurons become interconnected through (1) the growth
of dendrites — extensions of the cell body that receive signals
from other neurons and (2) the growth of axons — extensions
from the neuron that can carry signals to other neurons.
Axons enable connections between neurons at considerable
distances, sometimes at the opposite side of the brain, to
develop. In the case of motor neurons, the axon may travel
from the spinal cord all the way down to a foot muscle.
The human brain and nervous system begin to develop at about three weeks’ gestation with the closing of the neural tube (left image). By four weeks, major
regions of the human brain can be recognized in primitive form, including the forebrain, midbrain, hindbrain, and optic vesicle, from which the eye develops.
Ridges, or convolutions, can be seen by six months.
Society for NeuroScieNce introduction to the brain | BraiN factS 15
Growth cones, enlargements on the axon’s tip, actively
explore the environment as they seek out their precise
destination. Researchers have discovered many special
molecules that help guide growth cones. Some molecules
lie on the cells that growth cones contact, whereas others
are released from sources found near the growth cone. The
growth cones, in turn, bear molecules that serve as receptors
for the environmental cues. The binding of particular signals
with receptors tells the growth cone whether to move
forward, stop, recoil, or change direction. These signaling
molecules include proteins with names such as netrin,
semaphorin, and ephrin. In most cases, these are families of
related molecules; for example, researchers have identified at
least fifteen semaphorins and at least nine ephrins.
Perhaps the most remarkable finding is that most of
these proteins are common to many organisms—worms,
insects, and mammals, including humans. Each protein
family is smaller in flies or worms than in mice or people,
but its functions are quite similar. As a result, it has been
possible to use the simpler animals as experimental models
to gain knowledge that can be applied directly to humans.
For example, the first netrin was discovered in a worm and
shown to guide neurons around the worm’s “nerve ring.”
Later, vertebrate netrins were found to guide axons around
the mammalian spinal cord. Receptors for netrins were then
found in worms, a discovery that proved to be invaluable in
finding the corresponding, and related, human receptors.
Once axons reach their targets, they form connections
with other cells at synapses. At the synapse, the electrical
signal of the sending axon is transmitted by chemical
neurotransmitters to the receiving dendrites of another
neuron, where they can either provoke or prevent the
generation of a new signal. The regulation of this transmission
at synapses and the integration of inputs from the thousands
of synapses each neuron receives are responsible for the
astounding information-processing capacity of the brain.
For processing to occur properly, the connections
must be highly specific. Some specificity arises from the
mechanisms that guide each axon to its proper target area.
Additional molecules mediate target recognition when
the axon chooses the proper neuron. They often also
mediate the proper part of the target once the axon arrives
at its destination. Over the past few years, several of these
recognition molecules have been identified. Dendrites also
are actively involved in the process
of initiating contact with axons and
recruiting proteins to the “postsynaptic”
side of the synapse.
Researchers have successfully
identified ways in which the synapse
differentiates once contact has been made.
The tiny portion of the axon that contacts
the dendrite becomes specialized for the
release of neurotransmitters, and the tiny
portion of the dendrite that receives the
contact becomes specialized to receive and
respond to the signal. Special molecules
pass between the sending and receiving
cells to ensure that the contact is formed
properly and that the sending and receiving
specializations are matched precisely.
These processes ensure that the synapse
can transmit signals quickly and effectively.
Finally, still other molecules coordinate
the maturation of the synapse after it has
formed so that it can accommodate the
changes that occur as our bodies mature
and our behavior changes. Defects in some
This is a cross-sectional view of the occipital lobe, which processes vision, of a three-month-old monkey
fetus brain. The center shows immature neurons migrating along glial fibers. These neurons make
transient connections with other neurons before reaching their destination. A single migrating neuron,
shown about 2,500 times its actual size (right), uses a glial fiber as a guiding scaffold.
16 BraiN factS | introduction to the brain Society for NeuroScieNce
of these molecules are now thought to make people susceptible
to disorders such as autism. The loss of other molecules may
underlie the degradation of synapses that occurs during aging.
A combination of signals also determines the type of
neurotransmitters that a neuron will use to communicate
with other cells. For some cells, such as motor neurons, the
type of neurotransmitter is fixed, but for other neurons, it is
not. Scientists found that when certain immature neurons
are maintained in a dish with no other cell types, they
produce the neurotransmitter norepinephrine. In contrast, if
the same neurons are maintained with specific cells, such as
cardiac, or heart, tissue, they produce the neurotransmitter
acetylcholine. Just as genes turn on and off signals to regulate
the development of specialized cells, a similar process leads
to the production of specific neurotransmitters. Many
researchers believe that the signal to engage the gene, and
therefore the final determination of the chemical messengers
that a neuron produces, is influenced by factors coming from
the location of the synapse itself.
Myelination Insulation covering wires preserves
the strength of the electrical signals that travel through
them. The myelin sheath covering axons serves a similar
purpose. Myelination, the wrapping of axons by extensions
of glia, increases the speed at which signals may be sent
from one neuron to another by a factor of up to 100x. This
advantage is due to how the sheath is wrapped. In between
the myelin are gaps, called nodes of Ranvier, that are not
covered in myelin. The electrical signal moves faster over
the insulated portion, jumping from one node to another.
This phenomenon, known as saltatory conduction (the word
“saltatory” means “to jump”), is responsible for the rapid
transmission of electrical signals. The process of myelination
occurs throughout the lifespan.
Paring Back After growth, the neural network is
pared back to create a more efficient system. Only about
half the neurons generated during development survive to
function in the adult. Entire populations of neurons are
removed through apoptosis, programmed cell death initiated
in the cells. Apoptosis is activated if a neuron loses its
battle with other neurons to receive life-sustaining chemical
signals called trophic factors. These factors are produced
in limited quantities by target tissues. Each type of trophic
factor supports the survival of a distinct group of neurons.
For example, nerve growth factor is important for sensory
neuron survival. Recently, it has become clear that apoptosis
is maintained into adulthood and constantly held in check.
On the basis of this idea, researchers have found that injuries
and some neurodegenerative diseases kill neurons not by
directly inflicting damage but rather by activating the cells’
own death programs. This discovery — and its implication
that death need not follow insult — have led to new avenues
for therapy.
Brain cells also form excess connections at first. For
example, in primates, the projections from the two eyes
to the brain initially overlap and then sort out to separate
territories devoted to one eye or the other. Furthermore, in
the young primate cerebral cortex, the connections between
neurons are greater in number and twice as dense as those
in an adult primate. Communication between neurons
with chemical and electrical signals is necessary to weed
out the connections. The connections that are active and
generating electrical currents survive, whereas those with
little or no activity are lost. Thus, the circuits of the adult
brain are formed, at least in part, by sculpting away incorrect
connections to leave only the correct ones.
Neurons communicate with electrical and chemical signals at special
contact points called synapses. [Credit: Meagan A. Jenkins, et al., The Journal of
Neuroscience 2010, 30(15): 5125-5135]
Society for NeuroScieNce introduction to the brain | BraiN factS 17
Critical Periods
Genes and the environment converge powerfully
during early sensitive windows of brain development to form
the neural circuits underlying behavior. Although most
neuronal cell death occurs in the embryo, the paring down
of connections occurs in large part during critical periods
in early postnatal life. During these moments in time, the
developing nervous system must obtain certain critical
experiences, such as sensory, movement, or emotional input,
to mature properly. Such periods are characterized by high
learning rates as well as enduring consequences for neuronal
connectivity.
After a critical period, connections diminish in number
and are less subject to change, but the ones that remain are
stronger, more reliable, and more precise. These turn into
the unique variety of sensory, motor, or cognitive “maps”
that best reflect our world. It is important to note that
there are multiple critical periods, organized sequentially,
as individual brain functions are established. The last step
in the creation of an adult human brain, the frontal lobes,
whose function includes judgment, insight, and impulse
control, continues into the early 20s. Thus, even the brain of
an adolescent is not completely mature.
Injury or deprivation of environmental input occurring
at specific stages of postnatal life can dramatically reshape
the underlying circuit development, which becomes
increasingly more difficult to correct later in life. In one
experiment, a monkey raised from birth to 6 months of age
with one eyelid closed permanently lost useful vision in that
eye because of diminished use. This gives cellular meaning
to the saying “use it or lose it.” Loss of vision is caused by the
actual loss of functional connections between that eye and
neurons in the visual cortex. This finding has led to earlier
and better treatment for the eye disorders of congenital
cataracts and “lazy eye” in children. Similarly, cochlear
implants introduced in infancy are most effective in restoring
hearing to the congenitally deaf. Cognitive recovery from
social deprivation, brain damage, or stroke is also greatest
early in life. Conversely, research suggests that enriched
environments or stimulation may bolster brain development,
as revealed by animals raised in toy-filled surroundings. They
have more branches on their neurons and more connections
than isolated animals.
Many people have observed that children can learn
languages or develop musical ability (absolute pitch) with
greater proficiency than adults. Heightened activity in the
critical period may, however, also contribute to an increased
incidence of certain disorders in childhood, such as epilepsy.
Fortunately, as brain activity subsides, many types of epilepsy
fade away by adulthood.
Plasticity
The ability of the brain to modify itself and adapt to
challenges of the environment is referred to as plasticity.
Plasticity itself is not unique to humans, but the degree to
which our brains are able to adapt is the defining attribute
of our species. Plasticity can be categorized as experienceexpectant
or experience-dependent.
Experience-expectant plasticity refers to the integration
of environmental stimuli into the normal patterns of
development. Certain environmental exposures during limited
critical, or sensitive, periods of development are essential for
healthy maturation. For example, finches need to hear adult
songs before sexual maturation in order for them to learn to
sing at a species-appropriate level of intricacy.
Scientists hope that new insight into brain development
will lead to treatments for those with learning disabilities,
brain damage, and neurodegenerative disorders, as well
as help us understand aging. If we can figure out a way
to lift the brakes that restrict adult plasticity — either
pharmacologically or by circuit rewiring — it may be possible
to correct damage done through mistimed critical periods
or other means. By understanding normal functions of the
brain during each developmental stage, researchers hope to
develop better age-specific therapies for brain disorders.
This chapter discussed how cells differentiate so that
they can perform specific functions, such as seeing and
hearing. Those are just two of the senses we rely on to learn
about the world. The senses of taste, smell, and touch also
provide key information. Through intricate systems and
networks, the brain and the nervous system work together
to process these sensory inputs. Part 2, called Sensing,
Thinking, and Behaving, describes how these systems work
and complement each other. It begins with a look at senses
and perception.
