Molecular and Cellular Mechanisms of a Neuronal Network that Regulates Olfactory

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DESCRIPTION (provided by applicant): We are interested to understand how individuals communicate with environment by olfaction and, particularly, how olfactory responses are shaped and modified by experience and environmental cues. To this end, we use a genetic model organism Caenorhabditis elegans and a new form of olfactory plasticity in this animal model to ask the following questions: What is the functional organization of the neuronal circuit underlying olfactory learning? How does experience generate modulatory cues to modify olfaction? How does the intrinsic property of the olfactory circuitry change in response to experience to generate olfactory learning? We previously showed that C. elegans learns to avoid the smell of pathogenic bacteria after ingestion of the pathogens. Serotonin signaling from a pair of serotonergic neurons ADF and an olfactory circuit are essential to direct this learning process. The physiological stress of infection enhances ADF serotonin signals through CaMKII and a Gq pathway; and the strengthened signaling promotes learning through a serotonin-gated channel in several interneurons. An olfactory neural circuit downstream of two pairs of sensory neurons is required for this learning to occur. We hypothesize that the enhanced serotonin signaling modulates the properties of the olfactory circuit, resulting in a change in olfaction. To test this hypothesis and characterize the molecular and cellular mechanisms of this learning process, we will first use genetic ablation and laser surgery to map the neural circuit underlying the olfactory learning and define the neuronal components of this network. Then we will use calcium imaging to examine the neuronal properties of the olfactory circuit in both na¿ve and learned animals. And finally we will use molecular genetics and biochemical tools to characterize how the training experience generates a neuromodulatory serotonin signaling through CaMKII and a Gq signaling pathway. PUBLIC HEALTH RELEVANCE: Olfactory learning is one of the fundamental forms of neural plasticity that enables us to interact with environment and to learn from experience. However, many people suffer from different forms of disabilities in learning and memory that are associated with varies devastating neurological diseases and are seriously compromised in their ability to develop or maintain their mental capacities, which often result in a marginal life quality. Little is known about the molecular and cellular pathology of these neurological defects. Our basic research on the mechanisms of olfactory learning will help us understand the physiological requirements of normal learning processes, provide insights into the basis of mental disability and guide potential treatments for these devastating neurological disorders.