Anxiety evokes hypofrontality and disrupts rule-relevant encoding by dorsomedial prefrontal cortex neurons

Anxiety is a debilitating symptom of most psychiatric disorders, including major depression, post-traumatic stress disorder, schizophrenia, and addiction.Adetrimental aspect of anxiety is disruption of prefrontal cortex (PFC)-mediated executive functions, such as flexible decision making. Here we sought to understand how anxiety modulates PFC neuronal encoding of flexible shifting between behavioral strategies. We used a clinically substantiated anxiogenic treatment to induce sustained anxiety in rats and recorded from dorsomedial PFC (dmPFC) and orbito frontal cortex (OFC) neurons while they were freely moving in a home cage and while they performed a PFC-dependent task that required flexible switches between rules in two distinct perceptual dimensions. Anxiety elicited a sustained background “hypofrontality” in dmPFC and OFC by reducing the firing rate of spontaneously active neuronal subpopulations. During task performance, the impact of anxiety was subtle, but, consistent with human data, behavior was selectively impaired when previously correct conditions were presented as conflicting choices. This impairment was associated with reduced recruitment of dmPFC neurons that selectively represented task rules at the time of action. OFC rule representation was not affected by anxiety. These data indicate that a neural substrate of the decision-making deficits in anxiety is diminisheddm PFC neuronal encoding of task rules during conflict-related actions. Given the translational relevance of the model used here, the data provide a neuronal encoding mechanism forhow anxiety biases decision making when the choice involves overcoming a conflict. They also demonstrate that PFC encoding of actions, as opposed to cues or outcome, is especially vulnerable to anxiety.