Project Summary/Abstract Adaptation to environmental cues is essential to survival. For example, learning to associate certain scents with food availability is critical to C. elegans deciphering nutritious bacteria from pathogenic bacteria. While we know that long-term potentiation (LTP) and long-term depression (LTD) underlie learning and long- term memory consolidation, we lack an understanding of the molecular mechanism by which memory is encoded within a neural circuit. Transient receptor potential vanilloid-type (TRPV) channels have been implicated in promoting both LTP and LTD.1 Furthermore, the upregulation of TRPV1 has been shown to rescue loss of neural plasticity and learning in Alzheimer's mouse models.2 Interestingly, our lab has shown that instead of acting as a primary sensory receptor, its classic function, OSM-9, a TRPV-like channel, is downstream of several nuclear events required for olfactory adaptation. The goal of this study is to probe the mechanism by which OSM-9 promotes long-term memory formation in live animals. The proposed aims will test the hypothesis that OSM-9 expression mediates olfactory adaptation non-cell autonomously by promoting Ca2+ influx during both learning and long-term memory consolidation, but not during development. To help delineate the role of OSM-9 in each stage of long-term memory consolidation, we will first probe endogenous OSM-9 expression patterns in worms who have been trained to associate an innately attractive odor, butanone, with starvation both after training and post-training recovery. (Aim 1A) We will then utilize the auxin-inducible degradation (AID) system to degrade endogenous OSM-9 and ask in what neurons and at what stages OSM-9 expression is functional for adaptation. (Aim 1B and 1C) To further study if OSM-9 produces an activating or attenuating response in the olfactory circuit after learning and memory, we will first ask how patterns of Ca2+ activity evolve in the known olfactory circuit in response to odor after learning and 16-hr recovery. (Aim 2A) We will then ask if OSM-9 is required for these changes in activity by visualizing Ca2+ activity in OSM-9 expressing neurons in trained wild-type and OSM-9 depleted worms. (Aim 2B) Taken together, this proposal will help resolve the role of OSM-9 in neural plasticity and may guide its use as a druggable target in Alzheimer's, schizophrenia, Parkinson's, anosmia, epilepsy, Charcot-Marie-Tooth disease, and other neurological and sense disorders caused by TRP channel dysfunction.3,4