Orbitofrontal and Prelimbic Cortices Serve Complementary Roles in Adapting Reward Seeking to Learned Anxiety

Background: Anxiety is a common symptom of several mental health disorders and adversely affects motivated behaviors. Anxiety can emerge from associating risk of future harm while engaged in goal-guided actions. Using a recently developed behavioral paradigm to model this aspect of anxiety, we investigated the role of 2 cortical subregions, the prelimbic medial frontal cortex (PL) and lateral orbitofrontal cortex (lOFC), which have been implicated in anxiety and outcome expectation, in flexible representation of actions associated with harm risk.

Methods: A seek-take reward-guided instrumental task design was used to train animals (N = 8) to associate the seek action with a variable risk of punishment. After learning, animals underwent extinction training for this association. Fiber photometry was used to measure and compare neuronal activity in the PL and lOFC during learning and extinction.

Results: Animals increased action suppression in response to punishment contingencies. This increase dissipated after extinction training. These behavioral changes were associated with region-specific changes in neuronal activity. PL neuronal activity preferentially adapted to the threat of punishment, whereas lOFC activity adapted to safe aspects of the task. Moreover, correlated activity between these regions was suppressed during actions associated with harm risk, suggesting that these regions may guide behavior independently under anxiety.

Conclusions: These findings suggest that the PL and lOFC serve distinct but complementary roles in the representation of learned anxiety. This dissociation may provide a mechanism to explain how overlapping cortical systems are implicated in reward-guided action execution during anxiety.