Ventral Tegmental Area Cholinergic Mechanisms Mediating Susceptibility to Stress

腹侧被盖区胆碱能机制介导对压力的敏感性

基本信息

批准号：
9123840
负责人：
Nii A Addy
金额：
$ 41.43万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9123840
关键词：
Address Affect Animal Model Anti-Anxiety Agents Antidepressive Agents Behavior Behavioral Brain region Cell Nucleus Cells Chronic Chronic stress Clinical Research Collaborations Data Development Dimensions Dopamine Exposure to Face Female Foundations Future Glutamate Receptor Glutamates Goals Health Human Individual Infusion procedures Investigation Laboratories Major Depressive Disorder Mediating Mental Depression Mental disorders Midbrain structure Modeling Muscarinic Acetylcholine Receptor Negative Valence Neurobiology Nucleus Accumbens Optics Pathogenesis Pathway interactions Phenotype Physiological Physostigmine Pilocarpine Play Pre-Clinical Model Predisposition Process Quality of life Rattus Regulation Research Domain Criteria Rodent Model Role Scanning Scopolamine Signal Transduction Sprague-Dawley Rats Stress Sucrose Swimming System Testing Therapeutic Intervention Time Ventral Tegmental Area Work acetylcholine receptor agonist acute stress arm avoidance behavior base behavioral pharmacology behavioral response behavioral study cholinergic depression model depressive symptoms evidence base improved in vivo male neurobiological mechanism neurochemistry neuronal circuitry new therapeutic target novel novel therapeutic intervention optogenetics preclinical study preference public health relevance receptor resilience response therapeutic target

项目摘要

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.

描述（由申请人提供）：抑郁症仍然是一个严重的健康问题，影响着美国大约六分之一的人，并极大地降低了生活质量然而，对于那些与疾病作斗争的人来说，仍然非常需要提高对介导抑郁症发病机制的强烈神经生物学过程的了解，还需要来自临床和临床前研究的更有效的治疗干预措施。表明多巴胺能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重度抑郁症（MDD）背后的神经回路，最近在啮齿动物模型中的研究揭示了一种新的，腹侧被盖区（VTA）到伏隔核（NAc）通路中的阶段性多巴胺活动在介导应激敏感性和恢复力中的因果作用然而，仍然迫切需要确定调节阶段性多巴胺活动的机制是否也介导应激反应。我们的初步研究结果表明，VTA 毒蕈碱乙酰胆碱受体 (mAChR) 机制可以有力地调节阶段性 DA 活性和敏感性。然而，在识别特定的 VTA mAChR 亚型和介导这种易感性的 VTA 的主要胆碱能输入方面仍然存在关键差距。综合实验方法（利用雄性和雌性斯普拉格-道利大鼠的行为药理学、体内快速扫描循环伏安法和体内光遗传学）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应激 (CUS) 模型，该模型作为抑郁症模型具有很强的结构和表面效度，目标 1 将使用行为药理学和体内伏安法来识别特定的中脑 mAChR 亚型。介导对压力的行为和多巴胺能反应，目标 2 将使用体内光遗传学和行为分析来识别介导易感性的特定中脑桥到中脑胆碱能通路。这项工作的首要目标是确定介导对压力的行为和生理反应的神经生物学机制，以促进针对抑郁症的新型治疗干预措施的开发。