Keri Martinowich

Even among similar cell types, differences in synaptic connectivity and activity patterns render these populations functionally and molecularly distinct. While early cell type-specific investigations obtained molecular profiles on the basis of cell-type markers,   molecular genetic tools now allow researchers to target circuits of interest with high precision based on connectivity as well as neural activity patterns in animal models. While animal models have made progress in identifying some of  the neural substrates underlying neuropsychiatric disorders, they cannot recapitulate all aspects of human disease. Towards better understanding the molecular pathology of complex brain disorders, large-scale efforts are underway to characterize the human brain transcriptome within and across cell types of the human brain. For example, single nucleus RNA-sequencing (snRNA-seq) approaches have identified cell type-specific transcriptional changes in Alzheimer’s disease, autism spectrum disorder (ASD) and schizophrenia, and other analyses have identified cell type-specific enrichment of genome-wide association study (GWAS) signals. Our laboratory’s approach couples the power of circuit-manipulation, molecular profiling  and activity-mapping in mouse models of behavior with transcriptomic approaches in the postmortem human brain to better understand how programs of gene expression in defined populations of cells contribute to circuit function and control of behaviors that are relevant for neuropsychiatric disorders. We use genetic manipulation and viral transgenesis in combination with molecular, cellular and systems-level techniques in animals, and integrate these data with cell- and circuit-specific transcriptomic studies in the postmortem human brain and human-derived cell models. Work in our group is arranged into three broad themes: 1) molecular profiling in postmortem human tissue across spatial gradients and within specific cell types; 2) identification of how unique cell types within key neural circuits impact network activity to drive cognitive and social behaviors in animal models; 3) utilizing human-derived in vitro cell models to better understand the role of molecular variants on neural development. A recent focus of our group has been to develop and employ new molecular and imaging approaches for identifying molecular profiles of distinct cell types and to better understand the corresponding spatial molecular landscape using spatial transcriptomics in both the mouse and human brain. These studies provide novel approaches for defining the topography of gene expression in the rodent and human brain to better understand molecular mechanisms underlying psychiatric disorders.