BIO254:Chemoaffinity

Introduction
The Chemoaffinity Hypothesis proposes that axons differentially recognize chemical signals produced by target matching cells. In this way, neurons connect only to specific cells or groups of cells. This selective recognition is the basis for establishing proper functional neuronal connections. The Chemoaffinity Hypothesis was first proposed by the neuropsychologist Roger Wolcott Sperry (August 20, 1913 - April 17, 1994), and is based on classic experiments performed on frogs.

When first proposed, the Chemoaffinity Hypothesis stood in contrast to a competing model called the Resonance Hypothesis. The Resonance Hypothesis predicts nonspecific neuronal connections during early developmental stages. Functional circuits are created by activity dependent rewiring of the initial random connections. Both classic and modern experiments seem to support the Chemoaffinity Hypothesis over the Resonance Hypothesis, making it the most widely accepted model of neuronal wiring.

Early Experiments
In the early 1940, Roger Sperry performed a series of experiments on the visual system of frog. In his experiments, the eye of a frog is severed from the original connection to the tectum, and then rotated 180o and re-implanted. The retinal ganglion cells are able to re-generate axons that project back to the tectum, and re-establish functional synapses. Insterestingly, this rotation of the eye resulted in a subjectively inverted visual world for these frogs: when attracted by a fly in its upper visual field, the frog always lunges downwards. This inappropriate behavior strongly implied that the frog behaves as if its entire visual world is inverted.

These experiments led to the conclusions that when original optic connections were severed, the regenerating axons of the retina grow back to their original location in the tectum and re-established these well-organized connections. Based on these conclusions, Sperry proposed that spatial gradients of chemical cues expressed by tectal cells likely mediate this process during development, i.e. each optic fiber and each tectal neuron possessed chemical cues that uniquely determined their neuronal type and position and optic fibers could utilize these cues to selectively navigate to their predetermined target cell. This inference was subsequently formulated into a general explanation of how neurons form well-organized connections during development and became known as the chemoaffinity hypothesis.

Trophic Interactions in Chemoaffinity
Neurotrophic signaling has two major functions: 1) determining the survival of a specific subset of neurons from an initial larger population, and 2) forming and maintaining axonal connections. Neurons depend on a minimum amount of trophic factors to survive and for preserving their target connections. If the chemoaffinity hypothesis states that nerve cells bear chemical labels to help determine their connectivity, then where and when are these chemical components produced? Trophic factors are synthesized by target tissues and made available to developing neurons in order to guide their potential axonal pathway. In addition, these targets produce trophic factors only in limited amounts, such that developing neurons must compete for the available factor to maintain survival (See Fire Together, Wire Together section for more). One commonly studied trophic molecule, nerve growth factor (NGF), is a protein that has given support to the above assumptions of how axons are attracted to target synapses.

Rita Levi-Montalcini and Viktor Hamburger discovered NGF at Washington University in the 1950s (later got Nobel Prize). Their experiments provided evidence that targets play a major role in determining neuronal populations. Hamburger et al. removed a limb bud from a chick embryo, and at later embryonic stages, he saw a striking reduction in the number of nerve cells in the corresponding portains of the spinal cord where the bud was removed. Hence, it seemed that neurons in the spinal cord competed with one another for a limited chemical resource at the target, since the original amount of "target compound" was greatly reduced following amputation of the limb bud. However, neurons that would have died were then rescued by manually providing the target trophic factor (in this case, by transplanting a limb bud back to the embryo). In support of this idea, adding an extra limb bud to the embyro resulted in an abnormally large number of limb motor neurons. Levi-Montalcini then used a bioassay to isolate and characterize the target molecule: NGF.

More than four decades of work throughout various laboratories have demonstrated that NGF mediates cell survival and neurite growth (The term neurite is used to describe neuronal branches when it is unclear whether they are axons or dendrites) among two neuronal populations: sympathetic and sensory (a subpopulation) ganglions. Observations of the effects of NGF as a chemotrophic molecule have defined four criteria that must be satisfied before concluding that a certain molecule is a trophic factor:

1.) There is death of relevant neurons in the absence of this trophic factor;

2.) There is survival of a surplus of neurons when levels of this trophic factor are augmented;

3.) There is presence and production of this trophic factor in neuronal targets;

4.) There exists receptors for this trophic factor in innervating nerve terminals.