吻内侧被盖核孤啡肽及其受体在酒精成瘾共病抑郁症中神经机制研究

酒精成瘾是慢性反复发作性脑病，常共病抑郁症，与脑内多巴胺(DA)水平降低相关，但机制尚不明确。吻内侧被盖核（RMTg）中GABA能神经元接受外侧缰核(LHb)兴奋性传入后，通过抑制中脑DA能神经元调控情绪和药物成瘾。我们发现大鼠RMTg异常兴奋会驱动酒精成瘾共病抑郁的行为。而应用“双核团-双病毒”的化学遗传学手段特异性地抑制LHb-RMTg间谷氨酸环路能成功缓解症状，但具体分子机制不明。近期我们用RNA测序发现酒精成瘾RMTg内孤啡肽递质系统下调、钙调蛋白上调、M型钾离子通道下调。由此我们提出“酒精成瘾诱导RMTg孤啡肽功能下调→钙调蛋白-谷氨酸受体磷酸化水平↑、谷氨酸释放↑、M型钾离子电流↓→RMTg兴奋性↑→大脑DA↓→抑郁行为↑和饮酒动机↑”的科学假说，并拟在研究本项目中验证酒精成瘾共病抑郁的神经环路和分子机制，籍此研究为药物开发和治疗酒精成瘾提供新的理论依据和精准的分子靶标。

Alcohol use disorders (AUDs) is a chronic relapsing brain disease. AUDs are often comorbidity with depression. However, the underlying neural mechanism has not been fully elaborated. It has been well documented that the dopamine (DA) levels significantly decreased in alcoholic brains. Recently, a novel GABAergic brain region, the rostromedial tegmental nucleus (RMTg), has been identified, which mediates the inhibitory effect of the LHb on midbrain DA neurons. The RMTg neurons encode aversion, regulating mood disorder and drug abuse. We recently reported that the aberrant RMTg hyperactivity drives the depression-like behavior associated with AUDs. Moreover, using dual viral-mediated gene transfer of DREADDs, we show that chemogenetic inactivation of the LHb-RMTg circuit significantly attenuates morbidity of AUDs and depression of alcohol-dependent rats. Next, the bioinformatics analysis from the RNA sequencing in the RMTg of AUDs vs. naïve rats, revealed AUDs decreased N/OFQ-NOP receptor and M-channel function, whereas an increased CaMKII-AMPA phosphorylation. We raised a hypothesis that AUDs impairs the RMTg endogenous NOPr function, which is likely to be attributed to the robust glutamate release, upregulated CaMKII-AMPA receptor phosphorylation, and decreased membrane M-type potassium channel. The above molecular events cause the hypofunction of the mesolimbic DA level, driving the motivation for alcohol relapse and depression-like behavior. The current competitive grant proposal will investigate the neural circuit and molecular mechanism of alcohol addiction comorbidity depression, aim further to expand the Negative Reinforcement Theory of alcohol addiction, as well as to seek the precision molecular targets for drug development and clinical treatment for AUDs.