Active avoidance behavior, in which an animal performs an action to avoid a stressor, is crucial for survival and may provide insight into avoidance behaviors seen in anxiety disorders. Active avoidance requires the dorsomedial prefrontal cortex (dmPFC), which is thought to regulate avoidance via downstream projections to the striatum and amygdala. However, the endogenous activity of dmPFC projections during active avoidance learning has never been recorded. Here we utilized fiber photometry to record from the dmPFC and its axonal projections to the dorsomedial striatum (DMS) and the basolateral amygdala (BLA) during active avoidance learning in both male and female mice. We examined neural activity during conditioned stimulus (CS) presentations and during clinically relevant behaviors such as active avoidance or 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 and decreased patterns of activity during avoidance and cued freezing, respectively. Finally, dmPFC-DMS and dmPFC-BLA projections show divergent encoding of active avoidance behavior, with the dmPFC-DMS projection showing increased activity and the dmPFC-BLA projection showing decreased activity during active avoidance. Our results demonstrate task-relevant encoding of active avoidance in projection-specific dmPFC subpopulations that play distinct but complementary roles in active avoidance learning.

The dorsomedial prefrontal cortex (dmPFC) has been linked to avoidance and decision-making under conflict, key neural computations altered in anxiety disorders. However, the heterogeneity of prefrontal projections has obscured identification of specific top-down projections involved. 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. Using fiber photometry recordings in both male and female mice during the elevated zero maze task, we show heightened neural activity in frontostriatal but not frontoamygdalar projection neurons during exploration of the anxiogenic open arms. Additionally, using optogenetics, we demonstrate that this frontostriatal projection preferentially excites postsynaptic D₁ receptor-expressing neurons in the DMS and causally controls innate avoidance behavior. These results support a model for prefrontal control of defensive behavior in which the dmPFC-amygdala projection controls reflexive fear behavior and the dmPFC-striatum projection controls anxious avoidance behavior.SIGNIFICANCE STATEMENT The medial prefrontal cortex has been extensively linked to several behavioral symptom domains related to anxiety disorders, with much of the work centered around reflexive fear responses. Comparatively little is known at the mechanistic level about anxious avoidance behavior, a core feature across anxiety disorders. Recent work has suggested that the striatum may be an important hub for regulating avoidance behaviors. Our work uses optical circuit dissection techniques to identify a specific corticostriatal circuit involved in encoding and controlling avoidance behavior. Identifying neural circuits for avoidance will enable the development of more targeted symptom-specific treatments for anxiety disorders.