Distinct downstream targets of the medial prefrontal cortex underlie discrete antidepressant responses to ketamine
Proceedings for Annual Meeting of The Japanese Pharmacological Society January 1, 2022 Ryota Shinohara, Brendan Hare, Rong-Jian Liu et al.
Ketamine, an NMDA receptor antagonist, rapidly relieves symptoms of depression within hours. While neuroplasticity in the medial prefrontal cortex (mPFC) is known to be critical for these effects, the downstream brain circuits involved were unclear. Using optogenetic and chemogenetic techniques in rodent models, researchers identified two distinct pathways. Activation of mPFC projections to the basolateral amygdala (BLA) and then to the ventral hippocampus mediated ketamine's effects on passive coping behavior, but not on anxiety or reward-seeking. In contrast, mPFC projections to the bed nucleus of stria terminalis (BNST) were necessary and sufficient for effects on anxiety-like and reward-seeking behaviors, but not passive coping. This suggests separate downstream circuits produce different antidepressant-like behavioral responses.