Project 2

Project 2 Abstract Pathological changes of the olfactory epithelium (OE) and smell deficits are reproducibly reported in schizophrenia (SZ) patients. Notably, smell deficits are tightly correlated with negative symptoms (e.g., avolition, anhedonia; due to impaired positive valence systems) and social cognitive deficits, but not with positive symptoms (e.g., hallucination, delusion) in SZ. However, a conceptual framework for explaining the impact of the olfactory system on higher brain functions (e.g., motivation, social process, and cognition) remains lacking. Olfactory sensory neurons (OSNs) in the OE project their axons to the olfactory bulb (OB), which then transmits the information to several olfactory cortices, including the anterior olfactory nucleus/taenia tecta (AON for simplicity) and the piriform cortex (Pir). These olfactory cortical regions subsequently project to the prefrontal cortex (PFC), which may participate in in emergence of negative symptoms as well as in deficits of social cognition in SZ and related disorders. Our preliminary results show that chronic local OE inflammation leads to reduced excitatory synaptic inputs into PFC pyramidal neurons (PNs), we propose that the olfactory- prefrontal circuits provide the causal link between OE perturbation and PFC functionality to impact higher brain functions. Because adolescence/young adulthood is a critical period for PFC maturation, which depends on its excitatory inputs, we will test the central hypothesis that chronic local OE perturbation during this period leads to prolonged PFC dysfunction through the olfactory-prefrontal circuits. Specifically, we will pursue three aims. First, we will determine the impact of OE perturbation on functional properties of PFC PNs in two inducible OE perturbation mouse models [in collaboration with Project 1 (P1) and P3]. Using patch clamp recordings, we will examine the effects of OE inflammation or OSN inactivation in two time windows covering adolescence to adulthood on intrinsic electrophysiological properties and synaptic connections of PFC PNs and aim to reverse the effects by chemogenetic activation of olfactory-prefrontal circuits. Second, we will determine the impact of OE perturbation on PFC activity (both olfactory cortical PN terminals in PFC and PFC PNs) via fiber photometry recording during specific mouse behaviors that assess motivation and social recognition (in collaboration with Project 1). Third, in collaboration with Core B and Core C, we will determine the impact of OE perturbation on functional connectivity of olfactory-prefrontal circuits in mice via in vivo electrophysiology and compare functional connectivity between control mice and human healthy subjects (via resting-state functional magnetic resonance imaging) to evaluate cross-species similarity. Overall, this project will fill a significant knowledge gap by establishing olfactory-prefrontal circuits as a novel contributory link between OE pathology and negative symptoms/social cognitive deficits in SZ that are currently treatment refractory (complement P1 and P3).