Project 1 Abstract Smell deficits have been reproducibly shown to be associated with negative symptoms and impaired social cognitive processes in schizophrenia (SZ). Smell deficits are found from the early stage of SZ. Olfactory epithelium (OE) pathology including molecular and cellular changes (e.g., immune/inflammatory changes in association with redox imbalance) are directly associated with smell deficits, olfactory bulb (OB) volume reduction, and negative symptoms in SZ. Nevertheless, it is not yet known how OE perturbation induces pathological signatures of the OE and OB changes, which may lead to negative symptoms and impaired social cognition. In the OE, olfactory sensory neurons (OSNs) can be continuously produced from stem cells such as horizontal basal cells (HBCs) even in adulthood. OSNs transmit sensory information to the OB via direct neuronal connections, which projects to the primary olfactory cortical regions. These brain regions directly connect with the prefrontal cortex (PFC) that regulate higher brain functions. Using a mouse model, we have previously reported that OE inflammation affects cell cycle/fate control of HBCs, leading to OSN dysfunction. Our preliminary data also show that OE inflammation leads to a volume reduction and layer structure changes of the OB, reduced excitatory synaptic inputs to the OB and PFC principal neurons, and deficits in motivation and social recognition. Based on these findings, we hypothesize that chronic local OE perturbation during adolescence/young adulthood, a critical period for PFC maturation, induces pathological signatures of the OE, which may be a contributory factor to impair olfactory-prefrontal circuits, leading to behavioral deficits in positive valence systems and social processes. To address these hypotheses, we will leverage our mouse models to produce local OE perturbation. Using the inducible OE inflammation model and inducible OSN inactivation model, we will identify the impact of OE perturbation (i.e., OE inflammation and OSN inactivation) on pathological signatures of the OE and OB changes (Aim 1). We will also identify the impact of OE perturbation on behavioral outcomes (Aim 2). Finally, we will determine specific molecules that contribute to the impact of OE pathological signatures on OB changes and behavioral phenotypes (Aim 3). Overall, this project will identify molecular and cellular mechanisms underlying the impact of chronic local OE perturbation during adolescence/young adulthood on the olfactory-prefrontal circuits (focusing on the OB) and behavioral domains in positive valence systems and social processes.