Npbwr1 signaling mediates fast antidepressant action

Chronic stress is a major risk factor for depression, a leading cause of disability and suicide. Because current antidepressants work slowly, have common side effects, and are only effective in a minority of patients, there is an unmet need to identify the underlying molecular mechanisms. Here, we identify the receptor for neuropeptides B and W, Npbwr1, as a key regulator of depressive-like symptoms. Npbwr1 is increased in the nucleus accumbens of chronically stressed mice and postmortem in patients diagnosed with depression. Using viral-mediated gene transfer, we demonstrate a causal link between Npbwr1, dendritic spine morphology, the biomarker Bdnf, and depressive-like behaviors. Importantly, microinjection of the synthetic antagonist of Npbwr1, CYM50769, rapidly ameliorates depressive-like behavioral symptoms and alters Bdnf levels. CYM50769 is selective, well tolerated, and shows effects up to 7 days after administration of a single dose. In summary, these findings advance our understanding of mood and chronic stress and warrant further investigation of CYM50769 as a potential fast-acting antidepressant. Overall design: Total mRNA sequenced 1) for 8 brain NAc (Nucleus accumbens) samples of 8 weeks old mice after stereotaxic surgery to infect NAc by empty Adeno-associated virus constructs (GFP control) and AAVs to overexpress (OE) Npbwr1. And 2) for 64 NAc samples at four time points in a 12L:12D light cycle and from two genotypes (C75BL/6J wild type and T75A-DARPP-32 mutant), 2 hours after injection with 7.5 mg/kg caffeine or saline at an injection volume of 10ml/kg body.

慢性应激是抑郁症的主要危险因素，而抑郁症是致残与自杀的首要诱因。当前抗抑郁药物普遍存在起效迟缓、不良反应常见，且仅对少数患者有效的局限，因此亟需阐明抑郁症发生的潜在分子机制。本研究鉴定出神经肽B与W的受体（neuropeptides B and W receptor, Npbwr1）是抑郁样症状的关键调控因子。在慢性应激小鼠的伏隔核（nucleus accumbens, NAc）以及确诊抑郁症患者的死后脑组织中，Npbwr1的表达均显著上调。本研究通过病毒介导的基因转移技术，证实了Npbwr1、树突棘形态、生物标志物脑源性神经营养因子（Brain-derived neurotrophic factor, Bdnf）与抑郁样行为之间存在因果关联。值得注意的是，显微注射Npbwr1的合成拮抗剂CYM50769，可快速改善抑郁样行为症状，并改变Bdnf的表达水平。CYM50769具有选择性强、耐受性良好的特点，单次给药后其药效可持续长达7天。综上，本研究结果加深了我们对情绪与慢性应激的认知，同时支持将CYM50769作为潜在快速起效抗抑郁药物开展进一步研究。整体实验设计：对总mRNA进行测序，样本分为两组：1）8只8周龄小鼠的脑伏隔核（nucleus accumbens, NAc）样本，这些小鼠经立体定位手术，分别用空载腺相关病毒（Adeno-associated virus, AAV）载体（绿色荧光蛋白（Green Fluorescent Protein, GFP）对照）及过表达Npbwr1的AAV感染伏隔核；2）64份伏隔核样本，取自12小时光照:12小时黑暗光照周期下的两种基因型小鼠（C75BL/6J野生型及T75A-DARPP-32突变型），在以10ml/kg体重的注射体积给予7.5mg/kg咖啡因或生理盐水处理2小时后采集，实验共涵盖4个时间点。