Project 3: ABSTRACT Smell deficits detected by established psychophysical measures are reproducibly reported in patients with schizophrenia (SZ). Importantly, smell deficits are correlated with specific clinical features, such as negative symptoms (e.g., avolition, anhedonia) and some cognitive deficits (e.g., social cognitive deficits), but not with positive symptoms (e.g., hallucination, delusion). Smell deficits are found in SZ from the early stages of the disease, and to a milder extent, in the first-degree relatives, indicating that smell deficits are a reflection of fundamental disease pathophysiology rather than mere secondary outcomes of confounding factors (e.g., medications) in SZ. The olfactory epithelium (OE) is the most peripheral component of the olfactory system, located outside the cranium. Thus, OE is highly influenced by environmental stressors, such as viral infection and air pollution. Molecular changes in the OE in SZ have been reported from many groups. Nevertheless, whether and how pathological changes in OE contributes to clinical manifestation in SZ still remains to be elucidated. We have recently obtained evidence that immune/inflammatory changes associated with redox imbalance may be one of the most prominent alterations in the OE pathology in SZ. Furthermore, we have observed that the OE molecular changes (inflammation, redox) are significantly correlated with OB volume changes and negative symptoms in SZ. In parallel, we observed that a mouse model of local chronic OE inflammation affects the pyramidal neurons in the prefrontal cortex (PFC) and resultant behavioral changes (including those in positive valence systems), which may be mediated by the olfactory-prefrontal circuits. Based on these compelling evidence, we hypothesize that molecular and cellular changes in the OE significantly contribute to specific clinical manifestations that correlate with smell deficits in SZ patients, which is mediated by the olfactory-prefrontal circuits. We expect that OE pathology in SZ is a major contributory mechanism for negative symptoms and social cognitive deficits. In this Project, we will define OE pathology in SZ patients at the tissue level via immunohistochemistry and single-cell RNA sequencing (Aim 1). By leveraging the homogeneity of olfactory neuronal cells (ONCs), we will further define OE pathology in SZ in greater detail using bulk RNA sequencing and aim to identify key molecules for OE pathology in SZ (Aim 2). By using the key molecules, we will aim to stratify SZ patients. Lastly, we will study the relationship between OE pathology and anatomical/clinical characteristics in SZ (Aim 3). We will conduct correlation analysis and mediation analysis by utilizing the multimodal data (OE, OB, PFC, and clinical data) from the same subjects. We will also perform a longitudinal cohort maintenance. Through this study, we plan to establish the OE pathology and its contributory role to negative symptoms and social cognitive def...