Convergence of clinically relevant manipulations on dopamine-regulated prefrontal activity underlying stress-coping responses

Background: Depression is a pleiotropic condition that can be produced or ameliorated by diverse genetic, environmental, and pharmacological manipulations. In this context, identifying patterns of circuit activity on which many of these manipulations converge would be important, because studying these patterns could reveal underlying biological processes related to depression and/or new therapies. In particular, the prefrontal cortex and dopaminergic signaling have both been implicated in depression. Nevertheless, how dopamine influences disease-relevant patterns of prefrontal circuit activity remains unknown. Methods: We used calcium imaging in brain slices to identify depression-relevant patterns of activity in prefrontal microcircuits, and measure how these are modulated by dopamine D2 receptors (D2Rs). Then, we used optogenetic and genetic manipulations to test how dopamine and D2Rs contribute to stress-coping behavior in a paradigm commonly used to assay how manipulations promote or ameliorate depression-like states. Results: Patterns of correlated activity in prefrontal microcircuits are enhanced by D2R stimulation as well as by two mechanistically distinct antidepressants: ketamine and fluoxetine. Conversely, this D2R-driven effect was disrupted in two etiologically distinct models of depression: a genetic susceptibility model and chronic social defeat. Phasic stimulation of dopamine afferents to prefrontal cortex increased effortful responses to tail suspension stress. Conversely, deleting prefrontal D2R receptors reduced the duration of individual struggling episodes. Conclusions: Correlated prefrontal microcircuit activity represents a point of convergence for multiple depression-related manipulations. Prefrontal D2Rs enhance this activity. Through this mechanism, prefrontal dopamine signaling may promote network states associated with antidepressant actions that manifest as effortful responses to stress.