Ventral Tegmental Area Cholinergic Mechanisms Mediating Susceptibility to Stress

 描述(申请人提供)：抑郁症仍然是一个严重的健康问题，在美国大约每6个人中就有一个受到影响，并显著降低生活质量 为那些与疾病作斗争的人。然而，对抑郁症发病机制的神经生物学过程的了解仍有很大的需要。还需要更有效的治疗干预措施来治疗抑郁症。来自临床和临床前研究的证据有力地表明，多巴胺和胆碱能机制可能在抑郁症的发病机制中发挥重要作用。因此，正在进行的研究试图确定严重抑郁障碍(MDD)背后的神经回路。最近在啮齿动物模型中的工作揭示了腹侧被盖区(VTA)到伏核(NAC)通路中的多巴胺活动在调节对应激的敏感性和弹性中的一个新的因果作用。然而，仍然迫切需要确定调节相多巴胺活性的机制是否也介导了对压力的反应。我们的初步研究结果表明，大鼠的神经化学和行为学研究表明，VTA M胆碱型乙酰胆碱受体(MAChR)机制对时相DA活性和应激敏感性具有很强的调节作用。然而，在确定特定的VTA mAChR亚型(S)和介导这种易感性的VTA的初级胆碱能输入方面仍然存在关键差距。这项提案中的工作将使用一种综合的实验方法(利用行为药理学、体内快速扫描循环伏安法和体内光遗传学在雄性和雌性Spraogue-Dawley大鼠中)来解决科学理解中的这些差距。行为检查将包括慢性不可预测压力(CUS)模型的使用，该模型作为抑郁症的模型具有很强的结构和表面有效性。目的1利用行为药理学和体内伏安法鉴定介导应激行为和多巴胺能反应的中脑mAChR亚型(S)。目的2将利用体内光遗传学和行为分析来确定介导对慢性应激易感性和弹性的特定中脑桥到中脑胆碱能途径(S)。这项工作的首要目标是确定调节行为和生理应激反应的神经生物学机制，以促进新的抑郁症治疗干预措施的发展。

 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.