Neuronal and theoretical analysis of spatial orientation

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DESCRIPTION (provided by applicant): The long-term objective of this research is to understand how the nervous system controls behavior. This objective is significant because mental illness is a disease of behavior. The challenge is to understand how the healthy nervous system produces normal behavior in order to understand how the diseased nervous system produces abnormal behavior. This research question will be pursued in the context of understanding the genetic and neuronal basis of behavior in a simple organism: the round worm Caenorhabditis elegans. The existence of the complete sequence of the C. elegans genome, together with the complete description of the synaptic connectivity of the 302 neurons of the C. elegans brain, makes it well-suited to the proposed studies. The present proposal focuses on one of several behaviors in C. elegans: chemotaxis, the ability of an animal to orient its locomotion with respect to a chemical gradient. A worm placed on an agar surface makes sinusoidal swimming movements that are occasionally interrupted by a brief tum. Orientation in C. elegans is known to involve a simple rule--turn more frequently when going down the gradient and turn less frequently when going up the gradient. Neurons that control the switch between swimming and turning have been identified, but it is not yet known how they function in chemotaxis. The proposed research addresses this question using a remarkable combination of genetics, electrophysiology, calcium imaging, behavioral analysis, and mathematical modeling. There are three specific aims. Specific Aim 1 is to elucidate the neuronal mechanism for switching between swimming and turning by testing a mathematical model of the switching neurons, Specific Aim 2 is to identify the interneurons that comprise the pathways from chemosensory neurons to the switching network by killing various neurons with a laser and testing for defects in orientation. Specific Aim 3 is to investigate how taste receptor neurons in C. elegans encode and transduce chemosensory information by recording the activity of chemosensory neurons in worms that have mutations in likely taste genes. Specific Aim 3 will promote a better understanding of taste transduction mechanisms and could lead to new treatments for chemosensory disorders affecting an estimated two million Americans.