THE BRAIN FROM TOP TO BOTTOM

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From Embryo to Ethics

Identifying Pathways in the Brain

Homeotic Genes

When the neural tube closes early in the development of the embryo, some of the cells on its dorsal side separate themselves from this tube to form the neural crest. These cells then migrate throughout the embryo. Those in the rostral portion of the crest form the cranial nerve ganglia, the parasympathetic ganglia, the Schwann cells, etc. The cells in the caudal portion give rise to the dorsal root ganglia, sympathetic ganglia, intestinal ganglia, etc.

Though the migration route of these cells is determined by their position along the neural crest, the specific final position of the neurons is not determined at the start of migration but is instead strongly influenced by the environment encountered in the course of it.

Experiments with neural crest cells isolated and grown in vitro have also shown that the choice of the neurotransmitter that a neuron will synthesize is not completely preprogrammed either. On the contrary, the environment in which the neuron develops will affect the expression of its capabilities for synthesizing neurotransmitters. Thus, some extrinsic chemical factors are needed to activate or deactivate the genes that control certain neurotransmitters.

Researchers have developed special strains of mice with certain mutations that help provide a better understanding of neuron migration. One of the best known examples of these strains is the weaver mouse, which has a tentative, trembling posture. In this mutant mouse, the granular cells of the cerebellum die before they can migrate in the inner granular layer and form their parallel fibres. Contrary to what was initially believed, this mutation does not seem to affect the radial glia that guide the migration of these granular cells. Instead, it seems to affect a component of a potassium channel in the granular cells themselves. The result is catastrophic for all of the circuits of the cerebellum and leads to the motor problems observed in this mutant mouse.

The time at which a neuron is generated helps to determine its final position in the brain and therefore influences all of its future connections. The first neurons generated within a given proliferative unit are located in the deepest layers of the cortex. Because these deeper layers will thus already be occupied, the neurons generated later will migrate farther, to constitute layers closer and closer to the surface of the cortex. It therefore follows that neurons that occupy the same layer are approximately the same age.

The first neurons form at the end of the 4th week of gestation. Starting on the 33rd day, differentiated development of the spinal cord and the brain can be observed. Between the 2nd and the 5th month, the formation of neurons reaches its peak; it is completed a few months after the baby is born.

The rudimentary structures of the cortex begin to appear after 6 weeks. Around the 10th week, the neurons begin to form connections. This is the start of the communication network that will enable the individual to generate appropriate behaviours.

HOW STEM CELLS FORM NEURONS

Starting with its very first mitosis, the zygote begins a long process of cell differentiation. As it proceeds through the various phases of its development, the potentialities of its various cells gradually become more limited.

The totipotent zygote, which is capable of producing the entire organism, will first divide into pluripotent cells that do not have this ability but can nevertheless produce all the tissues of the organism. Next will come multipotent cells, which can produce various cells within a particular tissue. And last will come specialized cells.

Since all of the cells in a person’s body contain the same genetic inheritance from that person’s parents, the factors that determine the location, morphology, and function of a future neuron are necessarily linked not only to the presence of specific genes but also to their expression and, ultimately, to their products: special proteins called transcription factors (follow Advanced Tool Module link to the left).

In the layers of the telencephalic vesicles that will form the cortex, a veritable cellular choreography takes place during the proliferation phase that produces the neurons and glial cells.

The cell proliferation phase begins when a cell in the ventricular zone of the neural tube sends an extension through its marginal zone to its outer surface, at the pia mater. The nucleus of the cell itself then migrates into the marginal zone along this extension while replicating its DNA. Next the nucleus, which now contains two copies of its genetic material, heads back into the ventricular zone. The cell then retracts its extension and divides in two.

The fate of the resulting two daughter cells depends on many factors. The first of these is the orientation of the plane of cleavage during cell division. If the cleavage takes place in the vertical plane, the two daughter cells will remain in the ventricular zone and divide again. But if the cleavage takes place in the horizontal plane, then the daughter cell that is farther from the ventricular zone will no longer divide and will begin migrating to its ultimate location. The other daughter cell will remain in the ventricular zone and continue dividing.

Hence, during the early stages of development, vertical cleavage predominates, to increase the population of neuronal precursors. Later, the pattern reverses, and horizontal cleavage becomes the rule. In this latter case, the uneven distribution of some transcription factors in the parent cell contributes to this differentiation (see the explanation below the following diagram, and follow the link below for a discussion of more recent results that call this hypothesis into question).

If certain transcription factors are not uniformly distributed in the cell before it divides, then when division takes place, the cleavage plane may be such that one of the daughter cells receives all of a given transcription factor while the other receives none. This difference will affect their futures.

One such case involves two kinds of proteins, Notch1 and Numb, which migrate to different poles of the neurons in the ventricular zone. When these neurons divide vertically, both proteins are distributed symmetrically between the two daughter cells. But if the neurons divide horizontally, then the Notch1 proteins end up in the daughter cell that begins migrating to its final position, while the Numb proteins remain in the daughter cell that stays in place and divides again. Notch1 therefore seems to be the trigger for the genetic program that causes cells to cease dividing and to migrate toward their final locations.

Most of the neuroblasts migrate over distances that are appreciable when measured on the scale of the embryo. These distances range from just a few millimetres (for cells migrating to the pia mater in the primate cortex) to far greater distances (for cells migrating from the neural crest to the peripheral nervous system).

Depending on their areas of origin and their destination, neuroblasts use different methods to guide themselves during their migration. The cells that come from the neural crests and migrate to the peripheral nervous system, as well as those neurons that will form clusters called nuclei in the brain, orient themselves chiefly by means of cell adhesion molecules. These molecules are located either in the extracellular matrix or on the surface of other cells that these migrating nerve cells encounter along their way. In addition, each migration pathway thus determined provides opportunities for the migrating neuroblasts to interact with various cell environments that emit inductive signals which alter the neuroblasts and contribute to their differentiation.

The other major method of migration is observed in those brain structures where the cells stratify, such as the cerebral cortex, hippocampus, and cerebellum. In these structures, the neurons reach their final destination by climbing along glial cells of a particular type, known as radial glial cells. The migrating neurons use these glial cells as highways and are pulled along them by the affinities between the neurons’ own adhesion molecules and those of the glial cells.

However, one-third of the neuroblasts do not take this radial migration route, which can lead to a certain horizontal dispersion of the cortical neurons derived from the same precursor.

The first neuroblasts that migrate from the venrtricular zone are destined to form a layer called the cortical subplate, which disappears in a later phase of development. The neuroblasts that are destined to form the six layers of the cerebral cortex then cross through this subplate and form a new layer called the cortical plate. The first cells to reach the cortical plate form layer VI in the cortex; next come the cells that form layer V, then layer IV, and so on, from the inside out.

As a result, the neurons that are born first are located in the deepest layers of the cortex, whereas the younger ones are located in the layers closer to the cortical surface. This migration guided by the radial glia also provides an embryological explanation of the columnar structure of the cortex. Each group of stem cells in the ventricular zone naturally gives rise to a column of closely interrelated neurons in the cortex.

Eventually, once the cortical neurons have reached their destinations, the radial glial cells will retract their extensions. By the end of the process of corticogenesis, the ventricular zone has become nothing more than a single layer of ependymal cells that marks the boundary of the cerebral ventricles.

Not all neurons complete their migration successfully. In fact, the experts believe that only one-third do so. The other neurons either die and disappear during the two to three weeks that the migration lasts, or they never differentiate,or they survive and differentiate, but not in the right location. This last group of cells may be the cause of various disorders, ranging from learning disorders and dyslexia to epilepsy and schizophrenia.

Each cell individually is not required to undertake the entire journey that leads from the activation of specific genes to the fulfilment of this cell’s function in the organism. Many decisions are made very early in development and throughout the differentiation process. Because differentiation is a process that does not reverse, the cells begin by activating genes responsible for general functions of a given type of organ, but save until the end the precise adjustments needed to place the cell in its final position in the organ.

Apoptosis

A continuous decline in our ability to remodel our neuronal connections through selective stabilization of the synapses is probably the cellular basis of the critical periods for various kinds of learning, including language learning. More generally, the malleability of the brain’s synapses probably constitutes the neurobiological foundation for our ability to adapt our behaviours, and the decline in this malleability with age probably explains why this adaptability is greater in the earlier stages of life.

HOW NEURONS CONNECT TO ONE ANOTHER

Once the neurons have migrated to their final locations, their axons must reach their target cells and make synaptic connections with them. The decisions that a neuron must make to establish these connections depend essentially on the communication that takes place between the axon’s growth cone and the signalling molecules that are either secreted by the surrounding cells or carried on their surface. This communication can take several forms: direct cell-to-cell contact, contact between the axon and the extracellular secretions of other cells, remote communication between cells by means of diffusible chemicals, and so on.

There are two major phases in the forming of neuronal connections. The first phase consists of the selective recognition of the right paths and the right targets by the growth cones of the axons.

During this phase, three main mechanisms come into play:

molecular markers identify the neurons according to their position, thus enabling the right populations of neurons to recognize one another;
the growing axons are guided by molecular signals distributed along the migration path that they must follow;
the axon’s growth cones chemically recognize the target cells with which they must make connections.

Various strategies enable the axon to reach its target cell.

In the second major phase in the development of synaptic connections, the presynaptic and postsynaptic components adjust to each other to increase the accuracy and efficiency of the neural circuits. Two mechanisms play an active role in this process:

the adjustment of the size of the neuronal population by the death of certain neurons. (neuronal death is also called apoptosis; for more about it, follow the Tool Module link to the left);
the fine adjustment of the neuronal circuits through the selective stabilization of some synapses and the selective elimination of others.

The elimination of unneeded synapses depends not only on trophic factors secreted by the target cells but also on the sensory stimuli received by the brain. It is as if the brain were designed to have redundant synapses initially so that it could deal with the huge amount of learning that it has to do during the first few months of life.

Indeed, a subtractive mechanism of this kind represents an elegant solution to the difficult question of how the brain decides what connections it must make to acquire a new piece of knowledge or a new motor skill. By forming a multitude of synapses in the earliest stages of its development, the brain can then select the combinations that will work best to refine its circuitry.

In humans, the first simple synaptic contacts appear during the fifth month of gestation. During the seventh month, extensive synaptic development takes place in all areas of the brain. After birth, synapses continue to form at a very rapid pace; they reach their highest density when the infant is between six and twelve months old.

The brain’s post-natal growth is attributable to the development of these synapses and of the neurons’ dendritic extensions, as well as to increases in the size of the neurons and the number of glial cells.

The phase in which synapses are selectively eliminated begins around age 1. By the time a person reaches mature adulthood, his or her brain will have lost 60% of the synapses it once had.

The myelination of the cortex begins just after birth and continues to around age 18, but some part of the brain are fully myelinated long before that.

The complexity of the branching of the dendrites of the cortical neurons depends on various environmental factors, such as the presence of other neurons. Some experiments have shown, for example, that axons projecting from the neurons of the thalamus influence the cell architecture of many parts of the cortex.

How do these projections from the thalamus organize their structure in the cortex , when they have to be there before the cortical neurons are differentiated? The answer may lie in the cortical subplate. This is the first layer formed by the neuroblasts as they migrate, and it might therefore attract the axons from the thalamus.

Various cortical regions would thus attract the axons of the specific thalamic nuclei from which they need to receive connections (for instance, the visual cortex would attract axons from the lateral geniculate nucleus of the thalamus). Subsequently, when the cortical plate forms and the neurons of the various layers are put into place, the correct thalamic terminations would already be positioned to guide the fine differentiation of the cortical neurons’ dendrites. The neurons of the cortical subplate can thus be said to contain the instructions needed for the detailed assembly of the various areas of the cortex.