Distinct downstream targets of the medial prefrontal cortex underlie discrete antidepressant responses to ketamine

Abstract

Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is the prototype for a potential new generation of glutamate-based antidepressants that rapidly relieve symptoms of depression within hours of treatment. Studies in rodents have demonstrated that neuroplasticity in the medial prefrontal cortex (mPFC) is critical for the antidepressant actions of ketamine. However, effector circuits downstream of the mPFC underlying the rapid antidepressant responses remain unknown. To address this issue, we used optogenetic and chemogenetic circuit mapping in rodent models for studying depression, demonstrating the role of the basolateral amygdala (BLA) and bed nucleus of stria terminalis (BNST) as downstream targets of the mPFC mediating distinct behavioral effects of ketamine. By inhibiting isolated mPFC projections in the period immediately following ketamine administration, we found that mPFC-mediated activation of BLA principal neurons, and subsequent projections to the ventral hippocampus, mediate a subset of ketamine's persistent antidepressant-like effects on passive coping behavior but not on anxiety-like and reward-seeking behaviors. In contrast, mPFC projections to the BNST are necessary and sufficient to produce persistent antidepressant-like effects on anxiety-like and reward-seeking behaviors but not on passive coping behavior. Therefore, our data support a model where distinct downstream circuits of the mPFC contribute to producing separate antidepressant-like behavioral responses.