Brain Facts - Brain Development

The cells of the nervous system

connect with one another in trillions of remarkably specific patterns

that form and change over the course of an organism’s life.

These connections develop among various types of neurons, a process

that begins in the embryo. First, appropriate types of neurons

must arise in appropriate numbers and migrate to appropriate places.

The axons and dendrites that form the connections then extend

from these nerve cells, and the growth of axons must be guided over

long distances so they reach the appropriate targets. Axons must

recognize specific target cells. The connections that form initially

then mature, with the activity and experience of early postnatal life

playing a key role in their refinement. The degree of complexity in

the brain, and therefore the amount of interaction required to regulate

its development, is far greater than in other organs of the body.

Scientists studying development are working to reveal how these

complicated processes of connecting and reshaping occur.

Many initial steps in brain development are similar across species,

although later steps are different. By studying these similarities

and differences, scientists can learn about normal human brain development

and can learn how brain abnormalities, such as mental

retardation and other disorders, can be prevented or treated.

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 are now being considered in developmental terms,

including schizophrenia. Other research suggests that genes that are

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 now is viewed as distinctly possible.

Knowing how the brain is put together is essential for understanding

its ability to reorganize in response to external influences

or injury. These studies also shed light on brain functions such as

learning and memory. The brain evolves from the embryo to the

adult stage, and during infancy and childhood it possesses unique

attributes 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.

Birth of neurons and brain wiring

Three to four weeks after conception, one of the two cell layers

of the gelatinlike human embryo, about one-tenth of an inch long,

starts to thicken and build up along the middle. As the cells continue

to divide and this flat neural plate grows, parallel ridges, similar to

the creases in a paper airplane, rise across its surface. Within a few

days, the ridges fold in toward each other and fuse to form the hollow

neural tube. The top of the tube thickens into three bulges that form

the hindbrain, midbrain, and forebrain. The first signs of the eyes and

the hemispheres of the brain appear later in development.

Brain Development

The human brain and nervous system begin to develop at about three weeks’ gestation with the closing of the neural tube. 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). Irregular ridges, or convolutions, are clearly seen by six months.

The embryo has three layers that undergo many interactions in

order to grow into organ, bone, muscle, skin, or neural tissue. Skin

and neural tissue arise from one layer, the ectoderm, in response to

signals provided by the adjacent layer, the mesoderm.

A number of molecules interact to determine whether the

ectoderm becomes neural tissue or develops in another way to

become skin. Studies of spinal cord development in frogs show that

one major mechanism depends on specific proteins that inhibit

the activity of other proteins. In areas where no inhibition occurs,

the tissue becomes skin. In areas where proteins secreted from the

mesoderm do lead to inhibition, the tissue becomes neural.

Once the ectodermal tissue has acquired its neural fate, more

signaling interactions determine which type of brain cell forms. The

mature nervous system contains a vast array of cell types, which can

be divided into two main categories: the neurons, responsible primarily

for signaling, and supporting cells called glial cells.

Researchers are finding that the destiny of neural tissue depends

on a number of elements, including cell position within the

nervous system, that define the environmental signals to which

the cells are exposed. For example, a key factor in spinal cord development

is a secreted protein called sonic hedgehog that is similar to a

signaling protein found in flies. The protein, initially secreted from

mesodermal tissue lying beneath the developing spinal cord,

marks directly adjacent neural cells to become a specialized class

of glial cells. Cells farther away are exposed to lower concentrations

of sonic hedgehog, and 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.

A combination of signals also determines the type of chemical

messages, or 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 a

matter of choice. Scientists found that when certain 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 other cells, such as cardiac, or heart, tissue,

they produce the neurotransmitter acetylcholine. Since all neurons

have the genes required to produce these molecules, it is the turning

on of a particular set of genes that begins 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 targets themselves.

NEURON MIGRATION. 

A cross-sectional view of

the occipital lobe (which

processes vision) of a

three-month-old monkey

fetus brain (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. To move, it needs

adhesion molecules, which

recognize the pathway,

and contractile proteins to

propel it along.

Neurons are initially produced along the central canal in the

neural tube. These neurons then migrate from their birthplace to a

final destination in the brain. They collect together to form each

of the various brain structures and acquire specific ways of transmitting

nerve messages. Their axons grow long distances to find and

connect with appropriate partners, forming elaborate and specific

circuits. Finally, sculpting action eliminates redundant or improper

connections, honing the specific purposes of the circuits that remain.

The result is a precisely elaborated adult network of 100 billion

neurons capable of body movement, perception, emotion,

and thought.

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 migration of neurons occurs in most structures of the

brain but is particularly prominent in the formation of a large

cerebral cortex in primates, including humans. In this structure,

neurons slither from the place of origin near the ventricular surface,

along non-neuronal fibers that form a trail, to their proper destination.

Proper neuron migration requires multiple mechanisms,

including the recognition of the proper path and the ability to

move long distances. One mechanism for long-distance migration is

the movement of neurons along elongated fibers that form transient

scaffolding in the fetal brain. In another mode, inhibitory interneurons

migrate tangentially across the brain. Many external forces,

such as alcohol, cocaine, or radiation, prevent proper neuronal

migration and result 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.

Once the neurons reach their final location, they must make

the proper connections for a particular function to occur; for example,

vision or hearing. They do this through their axons. These

thin appendages can stretch out a thousand times longer than the

cell body from which they arise. The journey of most axons ends

when they meet thicker appendages, called dendrites, on other

neurons. These target neurons can be located at a considerable

distance, sometimes at the opposite side of the brain. In the case of

a motor neuron, the axon may travel from the spinal cord all the

way down to a foot muscle.

Axon growth is directed by growth cones. These enlargements

of 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

15 semaphorins and at least 10 ephrins.

Perhaps the most remarkable finding is that most of these

proteins are common to 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. It has therefore

been possible to use the simpler animals 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

found in worms and proved invaluable in finding the corresponding,

and related, human receptors.

Once axons reach their targets, they form synapses, which

permit electric signals in the axon to jump to the next cell, 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, whereby the axon chooses the proper

neuron, and often the proper part of the target, once it arrives at

its destination. Several of these recognition molecules have been

identified in the past few years.

Researchers also have had success identifying the 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

precisely matched. 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 of these molecules are

now thought to confer susceptibility to disorders such as autism,

and the loss of others may underlie the degradation of synapses that

occurs during aging.

Many axons in the brain require a sheath of myelin to enhance

the speed of conduction. The process of wrapping axons in myelin

occurs last and can take years to complete in some areas of the brain.

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 directly by the damage they inflict 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 too many 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

than and twice as dense as those in an adult primate.

SPINAL CORD AND NERVES. 

The mature

central nervous system (CNS) consists of the brain

and spinal cord. The brain sends nerve signals

to specific parts of the body through peripheral

nerves, known as the peripheral nervous system

(PNS). Peripheral nerves in the cervical region

serve the neck and arms; those in the thoracic

region serve the trunk; those in the lumbar region

serve the legs; and those in the sacral region

serve the bowels and bladder. The PNS consists

of the somatic nervous system that connects

voluntary skeletal muscles with cells specialized

to respond to sensations, such as touch and

pain. The autonomic nervous system is made

of neurons connecting the CNS with internal

organs. It is divided into the sympathetic nervous

system, which mobilizes energy and resources

during times of stress and arousal, and the

parasympathetic nervous system, which conserves

energy and resources during relaxed states.

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.

Critical periods

Although most of the neuronal cell death occurs in the

embryo, the paring down of connections occurs in large part during

critical periods in early postnatal life. These are windows of time

during development when the nervous system must obtain certain

critical experiences, such as sensory, movement, or emotional

input, to develop properly. These periods are characterized by high

learning rates.

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. Injury or deprivation, either

sensory or social, occurring at a certain stage of postnatal life may

affect one aspect of development, whereas the same injury at a

different period may affect another aspect.

In one example, if a monkey is raised from birth to 6 months

of age with one eyelid closed, the animal permanently loses 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 “crossed

eyes” in children.

Research also shows that enriched environments can bolster

brain development. For example, studies show that animals brought

up in toy-filled surroundings have more branches on their neurons

and more connections than isolated animals. In one recent study,

scientists found that enriched environments resulted in more neurons

in a brain area involved in memory.

Many people have observed that children can learn languages

with greater proficiency than adults, and recent research suggests

that the heightened activity of the critical period may contribute

to this robust learning. Interestingly, compared with adults, children

have an increased incidence of certain disorders that involve

excessive brain activity, such as epilepsy. Many epilepsy syndromes

appear during childhood and fade away by adulthood. Brain development

in people continues into the early 20s — even the brain

of an adolescent is not completely mature. One of the later aspects

of brain development is the completion of myelination of the

axons connecting one brain area to another. This process starts

around birth and moves from the back of the brain to the front:

The frontal lobes are the last to become “connected” with fastconducting

myelinated axons. Major functions of the frontal lobes

are judgment, insight, and impulse control, and so the acquisition

of these attributes becomes the last step in the creation of an adult

human brain.

Scientists hope that new insight into brain development

will lead to treatments for those with learning disabilities, brain

damage, and neurodegenerative disorders and will help us understand

aging. Research results indicate the need to understand

processes related to normal function of the brain at each of its

major stages and suggest that this information might lead to better

age-specific therapies for brain disorders.