This lecture is intended to provide an overview of some very basic principles of early brain development. Human brain development begins during the third week after conception and continues at least until late adolescence, but arguably extends throughout life. The processes that contribute to brain development range from the molecular events of gene expression to environmental input, and the interactions between them. Both gene expression and environmental input are essential for normal brain development, but neither is prescriptive or determinative of outcome. Brain development can be characterized as a complex series of dynamic and adaptive processes that operate throughout the course of development to promote the emergence and differentiation of new neural structures and functions. At the end of the second week after conception the embryo is a simple, oval shaped structure. The structure contains two-layers, the epiblast and the hypoblast. This is the starting point of the phase of gastrulation. During this phase 3 layers of cells are formed, called germ cells, from which all tissues and structures are formed during development.
To illustrate we first remove the side and then take a look inside. In the layer of epiblast cells that is now visible, first a slit-like opening appears, that is called the primitive streak. What happens next is best seen from a cross-sectional look at this picture. Epiblast cells migrate via the primitive streak under the upper layer of epiblast cells. The migrating cells form two new layers of cells. The deepest layer of cells displace the hypoblast cells and form the endodermal cell layer that will later develop into the gut and respiratory tract. The intermediate layer of cells is called the mesoderm, which will develop into structures like muscle, bone, and the vascular system. They then move in the direction of what is to become the head of the baby. The first migrating cells move the furthest in this direction, and later migrating cells will move to take position behind the cells who migrated just before. When cells migrate to their new position, they pass the primitive node, located at the “head-side” of the primitive streak. The primitive node is a molecular signaling center, that provides two important set of signals to the migrating cells. The first triggers the migrating cells to the produce and secrete proteins that induce the overlying epiblast cells to differentiate into neuro progenitor cells. These cells will give rise to the brain and central nervous system. The second set of signals from the primitive node, changes over the course of gastrulation and serves to establish the basic organization of the nervous system. Early migrating cells are triggered to produce molecular signal causing overlying cells to differentiate into neuro progenitor cells that can produce forebrain structures, while later migrating cells are triggered to induce neuro progenitor cells that can produce hindbrain and spinal cord structures. The region of the embryo containing the neuro progenitor cells is called the neural plate. You can see the neural plate depicted here from above and from a cross sectional view.
The second phase in brain development is called neurulation: The formation of the neural tube. First, two ridges appear at the side of the neural plate. These ridges arise, fold inward and fuse, beginning in the center and progressing outwards in both directions. The result is a hollow tube lined at the inside with a single layer of neuro progenitor cells. The cells that lie at the “head-side” eventually give rise to the brain, while the cells at the “bottom-side” give rise to the hindbrain and spinal cord.
Over the next month the embryo undergoes rapid growth and increases in size tenfold. During this period the shape of the primitive nervous system changes dramatically, and specific subdivisions of the brain begin to develop. These changes reflect an important and ongoing process during brain development, called neural patterning.
The mature brain is partitioned into well-defined structurally and functionally distinct areas, that are differentiated by their cellular organization and patterns of neuronal connectivity. Neural patterning refers to the process of specification and refinement of those various brain areas over the course of development. The process is influenced by gene activity resulting in specific combinations and concentrations of proteins that in turn induce progenitors to produce neurons suited for specific brain areas, like the motor or the visual cortex.
Nine weeks after conception, the fetal period begins in which the initially smooth brain structure gradually develops the mature pattern of folds.
Much of brain development during the fetal period centers around the processes of neuron production, migration, and differentiation.
In order to facilitate the production of the vast numbers of neurons that will eventually make up the brain, the initial population of progenitor cells lining the neural tube starts dividing symmetrically in the period between day 25 and 42. As each symmetric division leads to two new progenitor cells, their numbers grow exponentially. After day 42, the progenitor cells gradually shift to asymmetric division. Each division then results in one progenitor cell, that remains in place and continues to divide, and one neuron that migrates to the developing neocortex.
Newly produced neurons migrate radially from the center of the brain out to the neocortex. The first neurons do this by extending a protrusion which attaches to the surface of the developing brain. The protrusion then shortens “pulling” the neuron to its new position. As the brain grows and the distances that need to be travelled increase, new neurons start using another method. Some progenitor cells also have a protrusion attached to the surface progenitor cells. New neurons use these special progenitor cells, called Radial glial cells, as a scaffold along which they migrate. Thus each new wave of neurons assumes the most superficial position.
In this picture shows an overview of te migration. The outer layer of the fetal brain, the marginal zone, contains special cells that control the positioning of neurons into the right layer of cortex, using molecular signals. When migrating neurons enter this layer, these signals make them stop. The migration of neurons eventually results in an orderly 6-layered structure, each of which contains different types of neurons.
While most production and migration of neurons takes place before birth, the differentiation and maturation of these cells continues throughout childhood. The time course of these events remains largely uncertain.
When the neurons are in place they need to connect to other cells, to become integrated in the neural networks that allow information processing. They do so by developing extensions meant for sending and receiving information. Most neurons have many extensions used for receiving signals from neighboring neurons, called dendrites. In addition, most neurons have one extension used for sending signals, called the axon. Just like electric wires, the axons are then insulated to increase the velocity with which signals can be relayed. This insulation called myelin is delivered by special cells that form protective sheets around nearby axons. In doing so these cells also provide support. Myelination continuous throughout development and is only finished when the individual is around 18 year old.
At first the developing brain seems overenthusiastic in the formation of vast numbers of new neurons and the connections they make. Then, however, a process called synaptic pruning starts. Through this process precise and efficient connections between neurons are retained, while less efficient, damaged or unnecessary connections are eliminated, or pruned. In this way the structural and functional connections are formed that are required for normal functioning.
This process is strongly influenced by the inputs the developing brain receives from the environment. This input leads to competition between neural connections, and those connections that are used and work best remain. The initial overproduction of neurons and connections thus serves an adaptive function, making the developing brain malleable. Studies show that animals reared in complex environments, offering much and varied input, show increased numbers of cortical synapses and brain support cells. Animals reared in deprived environments on the other hand show deviant neural organization in those sensory systems that were deprived. Thus the developing brain requires certain inputs from the environment to be able to develop normally.
Brains do not develop normally in the absence of critical genetic signaling and they do not develop normally in the absence of essential environmental input. Rather, at each point in development, factors inside and outside the organism interact to support the increasingly complex and elaborate structures and functions of the brain.
