Hippocampal PACAP signaling activation triggers a rapid antidepressant response

作者：Hailou Zhang, Yan Sun, Zhangjie Wu, Ying Yin, Ruiyi Liu, Ji‐chun Zhang, Zhang‐Jin Zhang, Suk‐Yu Yau, Haoxin Wu, Ti‐Fei Yuan, Li Zhang, Miroslav Adžić, Gang Chen · 发表于：Military Medical Research · 年份：2024 · DOI：10.1186/s40779-024-00548-1 · 被引用次数：24 · 研究领域：Neuropeptides and Animal Physiology、Neuroendocrine regulation and behavior、Tryptophan and brain disorders

BACKGROUND: The development of ketamine-like rapid antidepressants holds promise for enhancing the therapeutic efficacy of depression, but the underlying cellular and molecular mechanisms remain unclear. Implicated in depression regulation, the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is investigated here to examine its role in mediating the rapid antidepressant response. METHODS: The onset of antidepressant response was assessed through depression-related behavioral paradigms. The signaling mechanism of PACAP in the hippocampal dentate gyrus (DG) was evaluated by utilizing site-directed gene knockdown, pharmacological interventions, or optogenetic manipulations. Overall, 446 mice were used for behavioral and molecular signaling testing. Mice were divided into control or experimental groups randomly in each experiment, and the experimental manipulations included: chronic paroxetine treatments (4, 9, 14 d) or a single treatment of ketamine; social defeat or lipopolysaccharides-injection induced depression models; different doses of PACAP (0.4, 2, 4 ng/site; microinjected into the hippocampal DG); pharmacological intra-DG interventions (CALM and PACAP6-38); intra-DG viral-mediated PACAP RNAi; and opotogenetics using channelrhodopsins 2 (ChR2) or endoplasmic natronomonas halorhodopsine 3.0 (eNpHR3.0). Behavioral paradigms included novelty suppressed feeding test, tail suspension test, forced swimming test, and sucrose preference test. Western blott...