Sunday, June 1, 2025
6/1/2025
Mechanisms underlying the development, evolution, and function of human-specific cortical dopaminergic interneurons - PROJECT SUMMARY/ABSTRACT Dopamine is a monoamine neuromodulator that is critical for the regulation of complex behaviors in the human brain. Dysregulation of dopaminergic neurotransmission has been implicated in a spectrum of psychiatric disorders, including attention deficit hyperactivity disorder (ADHD), bipolar disorder, and schizophrenia. Moreover, a substantial proportion of psychotropic medications, most notably antipsychotics, exert their therapeutic effects through the modulation of dopamine signaling. Elucidating the molecular, cellular, and physiological underpinnings of the human dopaminergic system will be essential in the development of novel and targeted therapeutic interventions for psychiatric illnesses. Recently, our lab has uncovered a population of inhibitory interneurons in the cerebral cortex that although present in non-human primate species, display unique molecular features in humans. We found that in humans, but not other mammalian species, these interneurons express the key components of dopamine synthesis and are capable of producing and releasing dopamine. Importantly, we identified that dopaminergic interneurons are completely absent from the cerebral cortices of our closest living relatives, the nonhuman African great apes (chimpanzee, bonobo, and gorilla species). These observed differences in the abundance of dopaminergic interneurons between species, along with their distinct molecular profile in the human cortex, suggests a human-specific role for these neurons within neocortical circuits. However, fundamental questions on the development and function of these interneurons remain unanswered. The objective of this proposal is to unravel the functional properties of human cortical dopaminergic interneurons and to identify the developmental and evolutionary mechanisms underlying the selective absence of dopaminergic interneurons in the cerebral cortices of nonhuman African great apes. To accomplish this, we will use human and chimpanzee stem cell-derived brain organoids to model developmental dynamics of brain development and assess the function of dopaminergic interneurons with simultaneous profiling of electrophysiology and transcriptomics in single cells (Patch-seq). The proposed experiments stand to significantly deepen our mechanistic and physiological understanding of a highly-derived neuronal subtype in the human cerebral cortex. Unraveling the function of cortical dopaminergic interneurons as well as the developmental and evolutionary mechanisms that underlie these functions will provide crucial insights into the human dopaminergic system and identify putative targets for intervention in dopamine-associated psychopathologies. In addition to this research, my training with the University of Wisconsin Medical Scientist Training Program will provide an exceptional foundation in the technical skills, responsible conduct of research, leadership, and clinical expertise to become a successful independent physician-scientist in Child and Adolescent Psychiatry.
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