PROJECT SUMMARY - OVERALL Psychiatric illnesses, including schizophrenia, affect a significant proportion of the population, yet current treatments are only partially effective for many individuals and, in the case of SZ, do little to address disabling cognitive and negative symptoms. Thus, there is a pressing need to develop biomarkers to identify at-risk individuals for early intervention and new molecular pathways to target for development of novel therapies. An increasingly compelling pathway associated with SZ is immune dysregulation. This proposed renewal of the UC Davis Conte Center brings together investigators with a unique combination and wide range of complementary expertise to address a critical gap in knowledge related to the potential links between immune dysregulation and psychiatric illness. During the previous funding period, we took a multi-pronged approach to test our Center hypothesis that early activation of the maternal immune system alters brain development in offspring leading to structural and functional changes in connectivity that are associated with the emergence of psychopathology in adolescence and young adulthood. Four important findings emerged from those studies that serve as the premise for this renewal application. First, we discovered two factors in the mouse model that predict susceptibility and resilience of offspring to MIA, allowing us to study why MIA causes aberrant outcomes in only a subset of pregnancies and how it can lead to diverse phenotypes in offspring. Second, we found signatures of abnormal brain development in our male MIA NHP offspring as early as 6 months of age, indicating that the early postnatal period is critical for understanding the impact of MIA on brain development. Third, combined results from NHP and mouse models point to cortico-striatal circuitry as central to behavioral outcomes in MIA offspring. Finally, convergence between MIA NHP imaging findings and recent onset SZ support the clinical relevance of the MIA models. In this renewal, we will continue to test our original Center hypothesis across species (mouse and NHP MIA models and humans with SZ), through three specific aims: (i) Identify immune signaling pathways in females before and during pregnancy that confer susceptibility or resilience to distinct subsets of MIA-induced behavioral phenotypes in offspring, (ii) Determine the contribution of cortico-striatal circuits to susceptibility, resilience and phenotypic heterogeneity in MIA mouse and NHP offspring and in individuals with SZ, and (iii) Determine how sex contributes to susceptibility, resilience and phenotypic heterogeneity in MIA offspring and individuals with SZ. Successful completion of these Aims, which could only be accomplished in a highly integrated interdisciplinary Center as proposed, will identify causal molecular pathways in specific neural circuits critical for guiding the development of interventions optimized for the developmental age and sex of at-ris...