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The Schmidt team employs high throughput molecular techniques to understand how the repertoire of genes expressed in discrete neuron populations contributes to normal brain function and underlies dysfunction in disease. Schmidt is particularly interested in elucidating why certain cell populations are selectively vulnerable to neurodegenerative disorders despite the fact that many disease-causing mutations are widely expressed. His work focuses on projection neurons in the cerebral cortex, where degeneration of different classes of these cells results in a loss of executive function, dementia, and death. Discovering cell type-specific genetic pathways dysregulated in susceptible populations is a crucial milestone for understanding pathological mechanisms and developing innovative therapies.

Schmidt has established a transgenic and viral tool set that provides reproducible genetic access to defined pyramidal cell populations, overcoming a historical lack of reliable markers to distinguish between different classes of these cells. By combining these with cell type-specific genome-wide profiling, anatomical techniques, and behavior, he has dissected cortical circuits underlying neuropsychiatric disease. This strategy led to the identification of a population of cells that mediates behavioral responses to antidepressant treatment, but not a depression-like phenotype, demonstrating a dissociation of the neural circuits underlying a pathological phenotype from those governing therapeutic responses.

Currently, Schmidt leads a translational effort to elucidate mechanisms underlying the selective neurodegeneration of spinal cord-projecting cortical “upper” motor neurons (UMNs) in amyotrophic lateral sclerosis (ALS). Schmidt discovered that increased expression of genes linked to oxidative phosphorylation is a defining feature of UMNs and differentiates them from a highly related population that does not degenerate in preclinical ALS models. Metabolic pathways are dysregulated in ALS, linking pathology to a fundamental property of vulnerable cells. Schmidt’s team is therefore utilizing biochemical and physiological approaches to directly compare mitochondrial function between the vulnerable and resilient cell populations during disease progression. Molecular profiling has also identified novel markers which he is utilizing to identify and characterize these cell populations in postmortem tissue from ALS patients.