Key contribution of prefrontal inhibition to passive coping behaviour: chronic stress and fast-acting antidepressant

Persistent passive coping behaviour is a hallmark feature in major depression and is reversed by fast-acting antidepressants (such as ketamine). This behaviour is regulated by a specific cortico-midbrain circuit. However, whether the prefrontal cortex (PFC), especially inhibition in PFC, contributes to the modulation of passive coping, and whether this modulation is important for mediating the impacts of chronic stress and/or fast-acting antidepressants, are poorly understood. Here, we found that rostral prelimbic cortex (rPL) bidirectionally controls the occurrence of passive coping behaviour where excitatory and inhibitory neurons play opposite roles. Chronic stress leads to reduced excitation/inhibition (E/I) ratio, reflected as alterations in in vivo spiking rate, synaptic inputs and intrinsic excitability of both excitatory and inhibitory neurons. A fast-acting antidepressant, (2R, 6R)-hydroxynorketamine (HNK), reduced passive coping behaviour, restored rPL E/I ratio and partially reversed altered properties in rPL neurons, in chronically stressed mice. Importantly, chronic stress and HNK mostly affected fast-spiking/parvalbumin inhibitory neurons instead of other inhibitory neurons, indicating the important role of this subtype of inhibitory neurons in the above processes. These findings demonstrate the importance of rPL E/I balance in regulating passive coping, which can be modulated by chronic stress and rapidly restored by fast-acting antidepressant.