The Effect of Normal and Prolonged Sensory Activity on Neural Circuits

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DESCRIPTION (provided by applicant): The human central nervous system is composed of 100 billion neurons interconnected into precisely regulated circuits to mediate vital functions such as perception, thought, and behavior. Sensory activity has long been known to have important affects on synaptic plasticity. Understanding the molecular underpinnings of these processes may aid in understanding neurological disorders, such as autism and schizophrenia. However, much remains unknown about the molecular mechanisms by which normal activity and long-term activity affect synaptic plasticity. The discovery of molecules required in these pathways may be accelerated by the study of genetic model organisms, in which large-scale gene discovery techniques are feasible. To address this, we propose to take an innovative approach to studying the affects of sensory activity on synaptic plasticity, investigating all leves of the responses within two defined circuits in the genetic model organism C. elegans. We will assay behavioral output at the highest level, cellular-level calcium responses, specific synaptic connections between the neurons utilizing the trans-synaptic split-GFP based marker NLG-1 GRASP, and the individual molecules required for these events. This integrative proposal is relevant to the NINDS mission to support research that aims to reduce the burden of neurological disease by supporting basic research on the biology of the cells of the nervous system, nervous system development, genetics of the brain, behavior, neurodegeneration, brain plasticity, sensory function, synapses, and circuits. Using this approach, we have discovered a Galpha-olf-dependent pathway by which normal sensory activity maintains appropriate synaptic connections, and an EGL-4/PKG dependent pathway by which animals adapt to long-term sensory signaling. Our research will characterize the mechanism by which these pathways affect structural and functional synaptic plasticity. Our specific aims are to: 1) elucidate the molecular pathway by which normal sensory activity affects structural plasticity, and 2) determine the molecular basis for plasticity induced by long-term sensory activity. The robust prior characterization of these two circuits, in combination with the powerful tools we have available to study them, offers the unique potential to discover new and unexpected signaling pathways that mediate sensory activity dependent synaptic plasticity, which can then be explored in other systems.