The principal goal of this work is to better understand a curious naturally occurring phenomenon: the widespread loss of synaptic circuits in the developing nervous system. This synaptic reorganization, occurs in postnatal life and has the effect of redistributing a neuron's synapses to strongly activate a subset of its synaptic partners while at the same time completely disconnecting from the rest. Several lines of evidence suggest that early experience may play a role in deciding which connections are maintained and which are lost. Thereforethis phenomenon may provide insight into the still largely mysterious ways experience causes long lasting alterations in the function of the brain, i.e., the physical changes that underlie learning and memory. We have developed methods to follow these events in living mice that express different colored fluorescent proteins in individual neurons. Some of what we have learned suggests the idea that the decisions about which connections are kept and which are lost are related to competitive interactions between neurons that are vying to remain in contact with the same target cells. We would like to put this idea to the test by seeing if some branches that would otherwise be lost can be rescued by eliminating putative competitors. In addition we would like to follow the interactions between different neurons over time to see if one neuron physically attempts to push nearby neurons away. Because we can now visualize the entire branching tree of one neuron, even at embryonic ages, we will be able to see how many branches a neuron starts with and how many are lost. Using new computational and automated imaging methods and transgenic mice that express many different colors of fluorescent protein we plan to see for the first time, the final product of the developmental reorganizations: the complete set of connections of all the nerve cells that project to a single target tissue. This """"""""connectome"""""""" should provide insight into the developmental mechanisms that regulate number and complexity of axon branching. Because our present understanding of these events is rudimentary, we still know very little about the way these events go awry in disease. It is my hope however that these experiments will provide essential and fundamental insights into the mechanisms by which experience normally shapes our nervous systems and how this process may be disregulated in pathological conditions such as learning disorders, memory disabilities, and autism.
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