UCSF

The dorsomedial prefrontal cortex (dmPFC) has been linked to a variety of defensive behaviors, including approach-avoidance conflict and active avoidance, that are altered in anxiety disorders. However, the heterogeneity of prefrontal projections has hindered the identification of specific top-down projections. While the dmPFC-amygdala circuit has long been implicated in controlling reflexive fear responses, recent work suggests that dmPFC-dorsomedial striatum (DMS) projections may be more important for regulating avoidance. We utilized fiber photometry to record the neural pathways from the dmPFC and its downstream projections to the dorsomedial striatum (DMS) and the basolateral amygdala (BLA) during both approach-avoidance conflict and active avoidance in mice. We found heightened neural activity in the dmPFC-DMS and dmPFC-BLA projection neurons during the exploration of anxiogenic open arms (an approach-avoidance conflict task). Additionally, using optogenetics, we demonstrate dmPFC-DMS projection preferentially excites postsynaptic D1 receptor-expressing neurons in the DMS and causally controls innate avoidance behavior. We also examined neural activity during conditioned stimulus (CS) presentations, active avoidance, and cued freezing. Both prefrontal projections showed learning-related increases in activity during CS onset throughout active avoidance training. The dmPFC as a whole showed increased activity during avoidance and decreased activity during cued freezing. Finally, dmPFC-DMS and dmPFC-BLA projections showed divergent encoding of active avoidance behavior: activity increased in the dmPFC-DMS projection but decreased in the dmPFC-BLA projection. These results inform a model of the prefrontal control of defensive behavior, in which the dmPFC-DMS projection encodes and controls approach-avoidance conflict behavior. Additionally, our results reconcile the differential prefrontal encoding of active and passive coping behaviors within the same behavioral paradigm and demonstrate divergent encoding of active avoidance in projection-specific dmPFC subpopulations.