BNST PACAP signaling in the dorsal medial habenula mediates depression- related behavioral responses after chronic stress.

BACKGROUND: Hallmark behaviors associated with depression-related disorders include reduction in reward responsivity and increased despair. However, the neurocircuits and mechanisms underlying reward responding and despair-like behavior have remained unclear. Our current studies show that pituitary adenylate cyclase activating polypeptide (PACAP, ADCYAP1) connections from the bed nucleus of the stria terminalis (BNST) to the dorsal medial habenula (dMHb) may contribute to depression-like behaviors. METHODS: Viral tracing of BNST afferents was examined in PACAP-Cre mice; MHb immunocytochemical staining for PACAP and the PAC1 receptor was also performed. Reward responsiveness was measured using the sucrose preference test (SPT) following MHb-targeted infusions of PACAP, PAC1 receptor antagonist (PACAP(6-38); N-terminally truncated PACAP peptide), or vasoactive intestinal peptide (VIP) in rats. Despair-like behavior was measured in rats using the forced swim test following PACAP infusions. The ability PACAP(6-38) to blunt chronic stress-induced depression-like responses was also evaluated. Finally, the BNST → dMHb PACAPergic pathway was chemogenetically activated and the effect on the SPT was measured. RESULTS: PACAP and PAC1 receptors are both expressed in the MHb, and BNST PACAP neurons have afferent projections to the dMHb. PACAP signaling in the MHb is necessary and sufficient for depression-like behaviors in rats and chemogenetic activation of the BNST → dMHb PACAPergic pathway reduces sucrose preference score in mice. CONCLUSIONS: We identify a novel PACAPergic BNST → dMHb pathway and characterize its involvement in depression-like responses. These results further our understanding of the neurocircuitry underlying depression-like behaviors, particularly the behavioral roles of BNST PACAP → dMHb signaling.