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：
9265958
负责人：
Nii A Addy
金额：
$ 41.54万
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/9265958
关键词：
Address Affect Agonist 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 Periodicity Phase 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 Treatment Efficacy Ventral Tegmental Area Work 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（由适用提供）：抑郁症仍然是一个严重的健康问题，影响了美国六分之一的人，并大大降低了生活质量对于那些挣扎着疾病的人。但是，仍然需要改善对介导抑郁发病机理的神经生物学过程的理解。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强烈表明，多巴胺能和胆碱能机制可能在抑郁发病机理中起重要作用。这是持续的调查试图确定基本的重大抑郁症（MDD）的神经记录。在啮齿动物模型中的最新工作揭示了腹侧段段区域（VTA）对核伏隔（NAC）途径（NAC）途径的新型灾难性作用，从而介导了易感性和对压力的弹性。但是，仍然需要确定调节阶段多巴胺活性的机制是否也介导对压力的反应。我们的初步发现表明，VTA毒蕈碱乙酰胆碱受体（MACHR）机制有力地调节了阶段性DA活性和应激的易感性，如大鼠的神经化学和行为研究所示。然而，临界差距在识别特定的VTA MACHR亚型和对VTA中的主要胆碱能输入均介导了这种敏感性。该提案中的工作将采用综合实验方法（利用行为药理学，体内快速扫描循环伏安法和男性和雌性Sprague-Dawley大鼠的体内光遗传学）来解决这些差距，以解决科学理解。行为检查将包括使用慢性不可预测的应力（CUS）模型，该模型具有强大的结构和面部有效性作为抑郁症模型。 AIM 1将使用行为药理学和体内伏安法来识别介导对压力的行为和多巴胺能反应的特定中脑MACHR亚型。 AIM 2将使用体内光遗传学和行为分析来识别介导易感性和对慢性应激的韧性的特定中桥到中脑胆碱能途径。这项工作的总体目标是确定介导对压力的行为和身体反应的神经生物学机制，以促进新型抑郁症治疗干预措施的发展。