PROJECT 2 There is a lack of understanding in the field of mental health of the mechanisms by which environmental or maternal factors influence disease susceptibility, specifically with neurodevelopmental disorders such as schizophrenia (SZ). The long-term objective of Project 2 is to connect the molecular pathways disrupted in the offspring after maternal immune activation (MIA) in the mother to cellular, circuit and neurobehavioral alterations that lead to SZ and perhaps other allied neurodevelopmental disorders. To accomplish this objective, the project will undertake four specific aims. First, the Geschwind lab, in collaboration with the Nonhuman Primate (NHP) Core, will identify the transcriptional signature of MIA in the PFC, ACC, HC and VC in an extensively characterized NHP model. The lab will use advanced, next-generation sequencing methods to measure genome-wide transcriptome changes in four relevant brain regions in a well-characterized 4-year-old cohort of NHPs exposed in utero to MIA and compare this with matched controls. Second, the research team will characterize and integrate the transcriptional signature caused by MIA in the PFC, ACC, HC, and VC in a validated mouse model at four developmental ages to compare to changes observed during psychosis and to determine the developmental progression of changes in gene expression. The work will focus on the same 4 regions as in the NHP using RNAseq methods, but have the additional advantage of spanning the full time course over the development of molecular and behavioral alterations so as to develop causal models and identify changes shared across species. Third, the project will identify changes in the transcriptome in the PFC, ACC, HC, and VC in well-characterized individuals with SZ and matched controls. The same RNAseq methods used in Aims 1 and 2 will be applied so as to ensure direct comparability between the species, SZ patients and controls for the first time. In the fourth aim, a systems biology framework (WGCNA) will be used to integrate NHP, mouse and human transcriptional data. Using a powerful network analysis, WGCNA, the project will identify key co-expression modules associated with MIA across species and time, as well as the regulatory network that drives these changes, and determine whether these changes in gene expression correlate with the magnitude of cortical inflammation (Project 1), dysregulation of subcortical DA (Project 1), changes in anatomical and functional connectivity (Project 2), changes in synaptic connectivity (Project 4), and changes in expression of immune molecules in the brain (Project 4). This will enable development of true causal models that connect molecular pathway alterations at the level of gene expression to the ontogeny of cellular changes, anatomical changes and behavioral changes that follow in utero exposure to MIA. The single-platform, cross-species design will enable a more-definitive determination of the relationship of these changes to SZ in humans and provide a framework for assessment of other neuropsychiatric disorders, such as Austism Spectrum Disorder.
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