2-Arachidonoylglycerol Signaling Relieves Stress-induced Anxiety

2-花生四烯酰甘油信号传导可缓解压力引起的焦虑

• 批准号: 9225234
• 负责人: Rebecca J Bluett
• 金额: $ 1.87万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2017-05-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9225234
• 关键词: 2-arachidonylglycerol; 2-arachidonylglycerol signaling; Address; Adverse effects; Amygdaloid structure; Anxiety; Anxiety Disorders; Behavior; Behavioral; Biomedical Research; Brain; Buffers; Cells; Chronic stress; Corticosterone; Darkness; Data; Development; Development Plans; Disease; Disinhibition; Electrophysiology (science); Endocannabinoids; Enzymes; Exhibits; Foundations; Fright; Functional disorder; Generations; Glutamates; Goals; Grant; Hyperactive behavior; Impairment; Individual; Injection of therapeutic agent; Intervention; Journals; Knock-out; Knockout Mice; Lentivirus Vector; Ligands; Light; Major Depressive Disorder; Manuscripts; Mass Spectrum Analysis; Measures; Mediating; Mental Depression; Mental disorders; Monoacylglycerol Lipases; Mood Disorders; Moods; Mus; Neurons; Operative Surgical Procedures; Pathologic; Pathology; Pharmacology; Phenotype; Physiological; Physiology; Post-Traumatic Stress Disorders; Probability; Production; Psychopathology; Research; Retreatment; Risk Factors; Rodent; Rodent Model; Role; Signal Transduction; Signaling Molecule; Solid; Stress; Sucrose; Supervision; Symptoms; Synapses; Tail Suspension; Testing; Therapeutic; Time; Training; Translating; Treatment Efficacy; Viral Vector; Virus; Work; Writing; acute stress; anandamide; anxiety-like behavior; base; biological adaptation to stress; cannabinoid receptor; career; clinical application; depressive behavior; depressive symptoms; effective therapy; endogenous cannabinoid system; experience; imaging study; inhibitor/antagonist; lipoprotein lipase; meetings; neurobiological mechanism; novel; novel strategies; novel therapeutic intervention; overexpression; patch clamp; post-traumatic stress; preference; presynaptic; public health relevance; reconstitution; response; skills; stress management; success; symposium; synthetic enzyme; tool; transmission process; treatment strategy

 DESCRIPTION (provided by applicant): While stress is a major risk factor for mood and anxiety disorders, the neurobiological mechanisms by which stress is translated into psychopathology are poorly understood. Current therapeutics that augment monoaminergic transmission ease symptoms but likely do not correct underlying dysfunction as they exhibit long-term success rates of only 40-60%. Novel therapeutic approaches to reduce pathological effects of stress could have broad clinical applications. Anxiety disorders are associated with amygdala hyperactivity. In rodents, stress increases excitatory drive to the basolateral amygdala (BLA). Interventions which temper excitatory drive to the BLA, a key modulator of fear and anxiety, may reduce stress-induced psychopathology. Cannabinoid receptors (CBR) are expressed on glutamatergic terminals within the BLA and activation of CBRs reduces presynaptic release probability. Thus, the endogenous cannabinoid (eCB) system is perfectly poised to buffer stress-induced excitatory drive to the BLA and thereby reduce stress-induced pathology. Enhanced signaling of the eCB, anandamide (AEA), in the BLA reduces stress-induced anxiety-like behavior. However, the role of 2-arachidonoylglycerol (2-AG), the most abundant eCB in the brain, in regulating stress, anxiety, and mood is poorly understood. The relatively recent development of JZL-184, a specific inhibitor of the primary 2-AG degrading enzyme, monoacylglycerol lipase, has spurred progress on this front, but several critical questions remain unanswered. Can 2-AG signaling buffer stress-induced behavioral dysregulation? Does impaired 2-AG signaling exacerbate stress-induced behavioral dysregulation? By what synaptic mechanisms does 2-AG signaling influence stress responses? We have developed novel tools to address these questions from multiple angles. We have functionally validated a lentiviral vector to overexpress the 2- AG synthetic enzyme diacylglycerol lipase a (DAGLa). We have also generated DAGLa knockout (KO) and DAGLa conditional KO (DAGLaf/f) mice. These novel tools permit us to test, for the first time, a causal relationship between 2-AG signaling and stress-induced anxiety- and depressive-like behaviors. Completion of these studies could validate enhancing 2-AG signaling as a viable therapeutic approach for mood and anxiety disorders. This proposal also constitutes a rigorous technical and professional training plan. I will be trained in stereotaxic surgery, mass spectrometry, whole-cell electrophysiology, and viral vector generation. I will present monthly in lab meetings, biannually in Synaptic Journal Club, and yearly in a departmental seminar and retreat. I will gain writing, presentation, and networking experience by presenting my work at 2 conferences per year. I will prepare at least 1 manuscript per year, edit the work of my colleagues, and practice reviewing manuscripts and grants under the supervision of Dr. Patel. Yearly completion of an individual development plan will facilitate formal discussion of my progress and goals with Drs. Colbran and Patel. This training constitutes a solid foundation from which to pursue postdoctoral opportunities and an independent research career.

 描述（由申请人提供）：虽然压力是情绪和焦虑障碍的主要危险因素，但人们对压力转化为精神病理学的神经生物学机制知之甚少。目前增加单胺能传递的疗法缓解了症状，但可能无法纠正潜在的功能障碍，因为它们表现出的长期成功率仅为40- 60%。新的治疗方法，以减少应激的病理影响可能有广泛的临床应用。焦虑症与杏仁核过度活跃有关。在啮齿类动物中，压力增加了对基底外侧杏仁核（BLA）的兴奋性驱动。调节BLA的兴奋性驱动的干预措施可能会减少压力引起的精神病理学。BLA是恐惧和焦虑的关键调节剂。大麻素受体（CBR）在BLA内的多巴胺能末梢上表达，CBR的激活降低突触前释放概率。因此，内源性大麻素（eCB）系统完全准备好缓冲对BLA的应激诱导的兴奋性驱动，从而减少应激诱导的病理。BLA中eCB，anandamide（AEA）的增强信号传导减少了应激诱导的焦虑样行为。然而，2-花生四烯酰甘油（2-AG），大脑中最丰富的eCB，在调节压力，焦虑和情绪的作用知之甚少。JZL-184是主要2-AG降解酶单酰基甘油脂酶的特异性抑制剂，其相对较新的发展推动了这方面的进展，但几个关键问题仍未得到解答。2-AG信号能缓冲应激诱导的行为失调吗？受损的2-AG信号会加重应激诱导的行为失调吗？2-AG信号通过哪些突触机制影响应激反应？我们开发了新的工具，从多个角度解决这些问题。我们已经在功能上验证了过表达2- AG合成酶二酰基甘油脂肪酶a（DAGLa）的慢病毒载体。我们还产生了DAGla敲除（KO）和DAGla条件性KO（DAGlaf/f）小鼠。这些新的工具使我们能够首次测试2-AG信号与压力诱导的焦虑和抑郁样行为之间的因果关系。这些研究的完成可以验证增强2-AG信号传导作为情绪和焦虑症的可行治疗方法。这项建议也是一项严格的技术和专业培训计划。我将接受立体定位手术、质谱、全细胞电生理学和病毒载体生成方面的培训。我将在每月的实验室会议上，每半年在新立得期刊俱乐部，每年在部门研讨会和务虚会上发表演讲。我将通过每年在2次会议上展示我的作品来获得写作，演讲和网络经验。我将每年至少准备一份手稿，编辑我的同事的工作，并在Patel博士的监督下练习审阅手稿和赠款。每年完成个人发展计划将有助于与Colbran博士和Patel博士正式讨论我的进展和目标。这种培训构成了一个坚实的基础，从追求博士后的机会和独立的研究生涯。