Antidepressant Response and Stress Resilience Are Promoted by CART Peptides in GABAergic Neurons of the Anterior Cingulate Cortex

A key challenge in the understanding and treatment of depression is identifying cell types and molecular mechanisms that mediate behavioral responses to antidepressant drugs. As treatment responses in clinical depression are heterogeneous, it is crucial to examine treatment responders and nonresponders in preclinical studies. We utilized the large variance in behavioral responses to chronic treatment with multiple class of antidepressant drugs in different inbred mouse strains and classified the mice into responders and nonresponders based on their response in the forced swim test. Medial prefrontal cortex tissues were subjected to RNA sequencing to identify molecules that are consistently associated across antidepressant responders. We developed and employed virus-mediated gene transfer to induce the gene of interest in specific cell types and performed forced swim test, sucrose preference, social interaction, and open field tests to investigate antidepressant-like and anxiety behaviors. Cocaine- and amphetamine-regulated transcript peptide ( Cartpt ) expression was consistently upregulated in responders to four types of antidepressants but not in nonresponders in different mice strains. Responder mice given a single dose of ketamine, a fast-acting non-monoamine-based antidepressant, exhibited high CART peptide expression. CART peptide overexpression in the GABAergic neurons of the anterior cingulate cortex (aCC) led to antidepressant-like behavior and drove chronic stress resiliency independently of mouse genetic background. These data demonstrate that activation of CART peptide signaling in GABAergic neurons of the aCC is a common molecular mechanism across antidepressant responders and that this pathway also drives stress resilience.