General Introduction, Abstract Smell deficits are one of the most reproducible changes in patients with schizophrenia (SZ). They are tightly correlated with specific clinical features, such as negative symptoms and some cognitive deficits (e.g., social cognitive deficits), but rarely with positive symptoms. Many studies have also observed molecular and cellular changes in the olfactory epithelium (OE) in living patients with SZ. Our group has accumulated evidence that the immune/inflammatory changes associated with redox imbalance may be major pathological changes in the OE of SZ patients. Nevertheless, whether and how the OE pathology mechanistically contributes to these specific clinical features has been a major knowledge gap. Using an inducible animal model, we have demonstrated that chronic local OE inflammation elicits a functional alteration in prefrontal cortex (PFC) pyramidal neurons, likely via the olfactory-prefrontal circuits. As a result, the mice showed behavioral deficits in the positive valence systems and social processes. Consistent with this basic science observation, we have recently obtained promising results that specific molecular changes in the inflammatory/redox signaling in the OE are directly correlated with negative symptoms (deficits of the positive valence systems) and smell deficits in SZ patients at the cross-sectional and longitudinal levels. Altogether, we hypothesize that molecular and cellular changes in the OE in SZ patients, or at least in a subset of them, significantly contribute to specific clinical manifestations that correlate with smell deficits. We expect that the OE pathology alters the olfactory- prefrontal circuits and PFC pyramidal neuron functionality, which in turn contributes to negative symptoms and social cognitive deficits in SZ patients. We hypothesize that the impact of OE pathology on the olfactory- prefrontal circuits is more robust in adolescence/young adulthood when the PFC maturation dynamically happens. We propose three Projects and three Cores. Project 1 (P1) will define how OE perturbation (e.g., chronic local OE inflammation) elicits the neuronal alteration in the OE and OB, which results in behavioral deficits; P2 will determine the circuitry mechanism(s) that links OE pathology to the PFC via the olfactory- prefrontal circuits, and identify the critical developmental period vulnerable to the OE influences; P3 will define OE pathology in early-stage SZ patients at the molecular/cellular levels, stratify patient groups depending on the specific mechanisms (e.g., molecular expression levels), and elucidate how the OE pathology influences specific clinical symptoms (e.g., negative symptoms and cognitive deficits) via the olfactory-prefrontal circuits. This molecular/circuitry mechanism cannot solely be causal for these clinical deficits. Nevertheless, we consider this mechanism as a significant contributory factor for them. Given that inflammation/redox-associated pathology in the OE...