Ventral Tegmental Area Cholinergic Mechanisms Mediating Susceptibility to Stress

 描述（由申请人提供）：抑郁症仍然是一个严重的健康问题，在美国影响大约六分之一的人，并大大降低生活质量 为那些与疾病作斗争的人。然而，仍然有一个很大的需要，以提高对介导抑郁症发病机制的神经生物学过程的理解。还需要更有效的治疗干预来治疗抑郁症。来自临床和临床前研究的证据有力地表明，多巴胺能和胆碱能机制可能在抑郁症的发病机制中起重要作用。因此，正在进行的调查，以确定神经回路的基础上的重度抑郁症（MDD）。最近在啮齿动物模型中的工作揭示了腹侧被盖区（VTA）到丘脑核（NAc）通路中的阶段性多巴胺活性在介导对压力的敏感性和恢复力中的新的因果作用。然而，仍然迫切需要确定调节阶段性多巴胺活性的机制是否也介导对压力的反应。我们的初步研究结果表明，VTA毒蕈碱乙酰胆碱受体（mAChR）机制有力地调节阶段DA活性和应激敏感性，通过大鼠的神经化学和行为研究。然而，关键的差距仍然在确定特定的腹侧被盖区mAChR亚型（S）和主要胆碱能输入到腹侧被盖区，介导这种易感性。本提案中的工作将使用综合实验方法（利用行为药理学，体内快速扫描循环伏安法和雄性和雌性Sprague-Dawley大鼠的体内光遗传学）来解决科学理解中的这些差距。行为检查将包括使用慢性不可预测的压力（CUS）模型，该模型具有较强的结构和表面效度作为抑郁症的模型。目的1将使用行为药理学和在体伏安法来鉴定介导行为和多巴胺能应激反应的特定中脑mAChR亚型。目的2将使用体内光遗传学和行为分析来鉴定介导慢性应激的易感性和恢复力的特定中脑桥脑至中脑胆碱能通路。这项工作的首要目标是确定介导压力行为和生理反应的神经生物学机制，以促进抑郁症新型治疗干预措施的开发。

 DESCRIPTION (provided by applicant): Depression remains a serious health concern that affects approximately 1 in 6 individuals in the U.S. and dramatically decreases the quality of life for those struggling with the illness. However, there is still a great need for improved understanding of the neurobiological processes that mediate the pathogenesis of depression. There is also a need for more effective therapeutic interventions to treat depression. Evidence from clinical and preclinical studies strongly suggests that dopaminergic and cholinergic mechanisms likely play important roles in the pathogenesis of depression. Thus, ongoing investigations have sought to identify the neurocircuitry underlying major depressive disorder (MDD). Recent work in rodent models has revealed a novel, causal role for phasic dopamine activity in the ventral tegmental area (VTA) to nucleus accumbens (NAc) pathway in mediating susceptibility and resilience to stress. However, there remains a critical need to determine whether the mechanisms that regulate phasic dopamine activity also mediate responses to stress. Our preliminary findings demonstrate that VTA muscarinic acetylcholine receptor (mAChR) mechanisms powerfully regulate both phasic DA activity and susceptibility to stress, as revealed through neurochemical and behavioral studies in rats. However, critical gaps remain in identifying both the specific VTA mAChR subtype(s) and the primary cholinergic input into the VTA that mediates this susceptibility. The work in this proposal will use an integrative experimental approach (utilizing behavioral pharmacology, in vivo fast scan cyclic voltammetry, and in vivo optogenetics in male and female Sprague-Dawley rats) to address these gaps in scientific understanding. Behavioral examination will include the use of the chronic unpredictable stress (CUS) model, which has strong construct and face validity as a model of depression. Aim 1 will use behavioral pharmacology and in vivo voltammetry to identify the specific midbrain mAChR subtype(s) that mediate behavioral and dopaminergic responses to stress. Aim 2 will use in vivo optogenetics and behavioral analyses to identify the specific mesopontine to midbrain cholinergic pathway(s) that mediates susceptibility and resilience to chronic stress. The overarching goal of this work is to identify the neurobiological mechanisms that mediate behavioral and physiological responses to stress in order to facilitate the development of novel therapeutic interventions for depression.