Dopaminergic regulation of prefrontal activity patterns during behavior

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PROJECT SUMMARY / ABSTRACT Dopaminergic projections from ventral tegmental area (VTA) to medial prefrontal cortex (mPFC), underlie critical functions disrupted across many neuropsychiatric conditions. However, the circuit-level mechanisms by which prefrontal dopamine modulates specific behaviors remain poorly understood. The scientific objective of this project is to determine how particular patterns of neural activity relate to distinct behavioral states and how prefrontal dopamine alters these patterns to influence behavior. My preliminary studies have shown that activating dopamine D2 receptors (D2Rs) in prefrontal brain slices enhances a positively correlated activity state. D2Rs are preferentially activated by the high dopamine state induced by phasic bursting of VTA neurons. I find that phasic, but not tonic stimulation of VTA-mPFC projections elicits active coping in the tail suspension test (TST). Finally, I show using in vivo imaging of activity that correlations between neurons fall over the course of active coping bouts, culminating in a transition to immobility. These data suggest the main hypothesis of the proposed project, that passive coping results from a breakdown of correlated activity and active coping is maintained by D2R-driven increases in correlations. In aim 1, I will employ optogenetics to further define how phasic and tonic patterns of activity in VTA-mPFC afferents influence different behaviors. In aim 2, I will use head-mounted miniscopes to confirm and expand the initial finding that correlations degrade during struggling, imaging activity in D1 and D2R expressing subnetworks. In aim 3, I will directly alter activity in elements of VTA-mPFC circuitry to establish causal relationships between dopamine and circuit activity-behavior relationships. These results will establish a foundation for my future work as this award allows me to start an independent laboratory. In addition to conducting the proposed studies, I will be mentored towards independence by Dr. Vikaas Sohal in whose laboratory this work will be accomplished. My scientific development will be aided by specific aspects of the mentoring plan, including coursework, workshops, journal clubs and presentations at conferences. As a physician, I will continue to expand my expertise in treating depression by learning cutting-edge techniques to modulate activity in the brain. By the completion of the award, I will have obtained a professorship and successfully applied for an R01 grant to launch an independent research program in neural circuits related to mood disorders.