Laminar dissection of cortical human brain gene expression in neuropsychiatric disorders

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Project Summary/Abstract The DLPFC is a true six layered neocortex, and neurons in different cortical layers show distinct expression patterns, morphology, physiology and patterns of connectivity. Converging evidence suggests that impairments in the formation or maintenance of synapses may be involved in schizophrenia and other neuropsychiatric disorders. Studies in the postmortem brains of subjects have pointed to specific cell types and revealed differences in neuronal and synaptic structure that are localized to specific layers, suggesting that genetic risk for schizophrenia may manifest with laminar specificity. Given the close relationship between brain structure and function, precisely assigning gene expression to the spatial coordinates of individual cell populations within this cortical cytoarchitecture would significantly advance our understanding of how dysregulation in these areas contributes to debilitating neuropsychiatric disorders. In this application, we propose to generate detailed spatial transcriptomics maps of the human DLPFC in patients with schizophrenia (SCZD), bipolar (BPD), major depressive (MDD) and autism spectrum (ASD) disorders, and contrast these laminar expression patterns to those derived from matched neurotypical controls (CONT). We will use the 10x Genomics Visium platform, which combines transcriptome-wide RNA sequencing with detailed high-resolution histology and immunofluorescence imaging, to generate these spatial transcriptomics profiles. We will combine these topographic and cell type-specific maps to implicate layer- and cell type-specific populations in psychiatric disorder genetic risk and illness state that will be validated using complementary quantitative in situ hybridization techniques. These layer-specific and cell type-specific expression profiles can refine the molecular causes and consequences of debilitating neuropsychiatric disorders that can be targeted for prevention and treatment.