Prefrontal contribution to passive coping behaviour in chronic stress and treatment by fast-acting antidepressant

Persistent passive coping (p-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, the contribution of inhibition in prefrontal cortex to p-coping modulation, and its relevance to chronic stress and/or fast-acting antidepressant effects, are poorly understood. Here, we found that rostral prelimbic cortex (rPL) bidirectionally controls p-coping behaviour where excitatory and inhibitory neurons play opposite roles. Chronic stress leads to a reduced excitation/inhibition (E/I) ratio, reflected as alterations of in vivo spiking rate, synaptic strength, and intrinsic excitability of rPL neurons. A fast-acting antidepressant, (2 R,6 R)-hydroxynorketamine (HNK), reduced p-coping, restored rPL E/I ratio, and partially reversed neuronal changes in chronically stressed mice. Notably, chronic stress and HNK significantly affected fast-spiking/parvalbumin inhibitory neurons which also bidirectionally regulate the passive coping behaviour, highlighting the critical roles of these neurons in the above processes. These findings underscore the importance of rPL E/I balance in regulating p-coping behaviour, which is disrupted by chronic stress and rapidly restored by fast-acting antidepressant.