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How the mind develops
From Embryo to Ethics

Help Link : Three-Dimensional View of a Dendritic Filopodium and an Axon Link : cell and types of podia projections
Research : Mu-Ming POO

As the central nervous system develops, the axons of each retina’s ganglion cells form the optic nerve. When the growth cones of these axons reach the optic chiasm, they must “decide” whether or not to cross over to the other side of the brain. As the growth cones of these axons approach this decision point, they slow their advance and assume a more complex form.

The same phenomenon is observed in the development of the peripheral nervous system, where the growth cones of the motor neurons start to engage in more “seeking” behaviour when they enter the newly forming muscles of the arms and legs.


When the neuroblasts have completed their migration, or even while they are still making it, they send out extensions called neurites that grow from their tips. One of these neurites, which will become the axon, will have to grow a long distance before reaching its target. Its elongation will be made possible by a structure at its tip, called the growth cone.

The growth cone of an axon (or of a dendrite) is composed of flat, fanlike membranes, the lamellipodia, from which fine tubes called filipodia protrude. These filipodia extend and retract constantly to explore their surroundings. When a filipod, instead of retracting, attaches itself to the substrate, it makes the growth cone advance in that direction.

When axons are growing along a pathway already established by other axons, their growth cones are rather simple in form. But if an axon starts to open up a new pathway, or if it arrives at an intersection where it has to pick a direction, its growth cone becomes spectacularly complex. It flattens and sends out numerous filipodia to actively search for the signals that can guide it (see sidebar).


Actin is represented in light grey on the main drawing, and by the black V shapes ( >>>>>) in the enlargements. The white arrows in the enlargements represent the polymerization of the actin.

The growth cone responds to various molecular signals that show it what path to follow and, at the end of its journey, help the axon to form proper synaptic connections. In this process, as in neurotransmission, the affinity between these guidance molecules and their receptors on the growth cone membrane plays a vital role. The stimulation of these receptors causes the activation of second messengers that trigger the intracellular events responsible for determining the direction of this growth. These events are thought to involve reorganizations of elements in the axon’s cytoskeleton.


Link : Adhesion Molecules Involved in Axon Extension Link : Defining a Role and Mechanism for IgCAM Function in Vertebrate Axon Guidance Link : The Biochemistry of N-CAM
Research : Neurobiology

Proteins That Guide the Wiring of the Brain

One of the characteristics of almost all CAMs is that their extracellular portions contain repeated patterns of amino acids. CAMs are divided into two families, however, according to whether they need calcium to adhere to cells: cadherins do need calcium (they are “calcium-dependent”), whereas neural cell adhesion molecules (NCAMs) do not (they are “calcium-independent”).


Among the various kinds of molecules that act as signals to guide the growth cone, some, such as the large group known as cell adhesion molecules (CAMs), are classified as “non-diffusible”. These molecules mediate cell-to-cell contacts.


CAMs are transmembrane proteins that protrude from the surface of cells in the growth cones’ environment. CAMs can thus interact with CAM-specific receptors on the growth cones.


When a CAM and its receptor recognize each other, a biochemical cascade of second messengers is triggered within the growth cone. This cascade results in the activation of enzymes (kinases, phosphatases, proteases, etc.) whose effects will contribute to the elongation of the axon.


Some receptors on growth cones are also sensitive to proteins that are not located on cell membranes but are instead distributed in the extracellular matrix—an agglomeration of substances produced by cells but not directly attached to them.

The best known of these adhesion molecules in the extracellular matrix are the laminins, the collagens, and fibronectin. These molecules are specifically recognized by a class of growth cone receptors called integrins.

In addition to surface proteins, another important class of molecules can influence the direction in which the axon elongates. These molecules, called chemotropic factors, are secreted by the target cells in very small amounts and diffuse into the surrounding extracellular environment. They can be either chemoattractive and attract the axon or chemorepellent and repel it.

Note that these chemotropic factors are not the same thing as another class of diffusible molecules called trophic factors. The function of trophic factors, of which nerve growth factor (NGF) is one, is to keep the neuron alive and to facilitate the growth of its axons and dendrites.


Link : Nerve growth factor pathway (NGF) Link : The Role of Secreted Signaling Proteins in Establishing Neuronal Diversity in the Developing Vertebrate Central Nervous System Link : Evolution and the Internet: Toward A Networked Humanity?
Original modules
Tool Module: Apoptosis (Programmed Cell Death) Apoptosis (Programmed Cell Death)

BDNF is especially important for the survival of the neurons of the visual cortex. Most of the receptors to which neurotrophins bind, known as trk receptors, are kinase proteins that phosphorylate tyrosin residues found in other proteins that form their substrate. In other words, they add phosphorus atoms to the amino acid tyrosin in certain proteins to modify their form and hence their function. In the case of the development of the visual cortex, this phosphorylation ultimately has an effect on gene expression.

Neurotrophins, and in particular BDNF, which is very widely expressed in the central nervous system, appear to play a significant role in synaptic plasticity: the morphological and physiological changes that synapses undergo in response to changes in neuronal activity. We know, for example, that the synthesis and release of BDNF molecules by the neurons of the central nervous system are controlled by neuronal activity, which enables this neurotrophin to modulate the GABAergic and glutamatergic transmissions of certain brain structures such as the hippocampus and the visual cortex.


Trophic factors (also called growth factors) contribute to the development and maintenance of the body’s networks of neurons, but are not the same as axon guidance molecules. Trophic factors are another class of molecules that are secreted by target cells. The role of these molecules is not to help the axon orient itself, but rather to ensure its survival once it has formed certain functional synaptic connections.

Trophic factors are secreted in limited amounts by the target cells, so that only a subset of the neurons that innervate them receive enough to survive. In other words, every neuron needs a certain minimum amount of trophic factor to survive, and all indications are that the neurons compete for the trophic factors available. The neurons that fail to get enough simply disappear, by apoptosis, the body’s programmed process of cell death (for more on apoptosis, follow the Tool Module link to the left).

The first trophic factor ever discovered was nerve growth factor (NGF). NGF was identified as a protein composed of three sub-units, of which one in particular is truly indispensable for the neurons’ survival. This sub-unit, designated ß, is itself composed of two identical molecules of 118 amino acids).

The two green diagrams on the left represent the molecular structure of NGF, which consists of two symmetrical components connected to each other along their longitudinal axis. The blue diagram on the right shows an NGF molecule bound to the centre of an NGF receptor.

Though NGF is the prototypical trophic factor and probably the one that has been studied the most, it affects only certain categories of peripheral neurons. Since the mid-1980s, other trophic factors related to NGF have been identified in many studies. This family of molecules is now known as the neurotrophins. In addition to NGF, its includes three other molecules that have been well characterized: brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5).

The various trophic factors show substantial similarities in their amino acid sequences but differ in their specificity and in their affinity for different receptors. They contribute in important ways not only to the selection of populations of neurons, but also to the selective stabilization of synapses.

Indeed, experiments have shown that the growth of neurites can be controlled locally by growth factors, without necessarily involving the enzymatic mechanisms inside the cell body. Consequently, some of a neuron’s axons or dendrites may be extending at the same time as others are retracting, as is in fact seen during the formation of synapses.

Link : Concept: Epigenèse par stabilisation sélective de synapse ou le darwinisme neuronal Link : LES NEURONES DE LA RÉCOMPENSE Jean-Pierre Changeux dissèque «l'homme neuronal» aux Belles Soirées Link : Hebbian theory
Research : D. O. Hebb (1904 - 1985) Research : The Hebb Legacy

The affinity between an axon and its target cell is something like the colour coding used in multi-wire electrical cables so that the right wires can be connected to each other.

But whereas the coded colours in electrical wiring are designed to be mutually exclusive, research has shown that the affinity between neurons and their target cells is not highly selective. Certain axons do show a preference for certain target cells but can also establish synaptic connections with other neurons.

Associations between neurons and their target cells thus take place along a continuum of preferences. At one end of this continuum, axons are absolutely unable to make connections with glial cells, for example, while at the other end, axons can make connections to any cell at all within a given population.

When a neuromuscular junction is forming between the end plate of a motor neuron and a muscle fibre, even the biological properties of the nicotinic acetylcholine receptors on that fibre change. Their replacement rate decreases, their ability to pass ions increases, and the combination of sub-units that compose them is altered. All of these changes contribute to the fine-tuning of the neuromuscular junction.

When a growth cone first makes contact with its target cell, the synapse does not become functional immediately. The formation of a synapse is a gradual process. This process has been studied extensively in one particular class of synapses: neuromuscular junctions.

We know, for example, that the growth cone of a motor neuron secretes acetylcholine spontaneously, before even reaching the muscle fibre with which it will form a neuromuscular junction. We also know that initially, the nicotinic acetylcholine receptors on this muscle fibre’s membrane are distributed uniformly. But shortly after the motor neuron’s axon makes contact with the muscle fibre, nicotinic receptors accumulate rapidly on this fibre at the site where the neuromuscular junction will form, while the population of such receptors away from this site declines drastically.

One of the signals that guides the forming of these precisely fitted connections is a molecule called agrin. Agrin is synthesized by the cell body of the presynaptic neuron, transported down its axon, and released by the growth cone as the axon elongates. The agrin then binds to postsynaptic receptors whose activation enables acetylcholine receptors to concentrate at the future synaptic site.

In addition to redistributing its receptors, the postsynaptic cell forms new receptors in its membrane at this site. It follows logically that messenger RNA for these receptors is being synthesized in the cell nucleus closest to the developing neuromuscular junction.

Initially, the development of neural pathways is controlled by genetically programmed mechanisms. But the neural circuits formed by these intrinsic mechanisms are still only crudely laid out and contain myriad extremely redundant synapses. To reduce the number of synapses and refine these circuits, a selection process is required.

This selection process depends on the activity of the neurons; it is thus through the individual’s sensorimotor experience that the initial circuitry will be tested and the fine structure of the neural networks will be adjusted. But how exactly does the activity of the neurons as they respond to their environment affect the development of these circuits?

To answer this question, we must turn to Hebb’s postulate. Originally formulated to explain the cellular bases for learning and memory, this postulate also applies to the major synaptic changes that occur during the development of the nervous system. According to Hebb, the correlated activity of two neurons causes a synapse to be strengthened. As applied to development, this postulate means that if two neurons that are connected to the same target cell transmit co-ordinated signals, both of their synapses will be reinforced. Conversely, if their signals are out of phase, these synapses will be weakened.

Consequently, in the course of development, those synaptic endings whose activity is only rarely correlated with that of the postsynaptic neuron will gradually weaken until they disappear completely. This phenomenon was given the name selective stabilization of synapses by Changeux and Danchin (1976), who showed that only those synaptic connections that are incorporated into a functional neural circuit will survive.

In contrast to neuronal death, which serves to adjust the number of neurons to the number of target cells, the elimination of synapses serves to make the pattern of innervation more precise.

Throughout our lives, but especially during infancy, our synaptic connections are shaped by our sensory experience. Neurons can increase the efficiency of these connections through the process of long-term potentiation (LTP), or they can decrease it through the process of long-term depression (LTD). Both of these processes contribute to the fine-tuning of our neuronal connections, but LTD seems to play an especially important role in the selective elimination of synapses that characterizes certain critical periods of human development.

LTD leads to a reduction in the number of postsynaptic receptors, which would reduce the activity of the synapses concerned and could lead to their gradual elimination as observed during these critical periods.

Link : MIT researcher identifies mechanism in developing brain synapses

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