2-Arachidonoylglycerol signaling in anxiety, depression, and stress adaptation

焦虑、抑郁和压力适应中的 2-花生四烯酰甘油信号传导

• 批准号: 9099424
• 负责人: Sachin Patel
• 金额: $ 45.31万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-15 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9099424
• 关键词: 2-arachidonylglycerol; Address; Adult; Adverse effects; Affective; Amygdaloid structure; Animals; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Behavioral; Brain; Buffers; CNR1 gene; CNR2 gene; Complex; Data; Development; Economic Burden; Electrophysiology (science); Endocannabinoids; Environmental Risk Factor; Exposure to; Fright; Glutamates; Goals; Homeostasis; Image; Immediate-Early Genes; Individual; Injection of therapeutic agent; Link; Lipids; Literature; LoxP-flanked allele; Major Depressive Disorder; Measures; Mediating; Mediator of activation protein; Mental Depression; Mental disorders; Metabolism; Monoacylglycerol Lipases; Mood Disorders; Mus; Neurons; Outcome; Pathogenesis; Pathology; Peripheral; Phenotype; Physiological; Post-Traumatic Stress Disorders; Predisposition; Prefrontal Cortex; Psychopathology; Recruitment Activity; Regulation; Risk Factors; Role; Schizophrenia; Signal Transduction; Signaling Molecule; Stress; Substance Addiction; Synapses; System; Testing; Time; Viral; activity marker; adverse outcome; anxiety states; base; clinical investigation; comparative; conditional mutant; depressive behavior; depressive symptoms; glutamatergic signaling; in vivo; lipoprotein lipase; mood regulation; neural circuit; neuropsychiatric disorder; novel; novel strategies; optogenetics; overexpression; prevent; public health relevance; reconstitution; relating to nervous system; research study; response; synthetic enzyme; transmission process; treatment strategy

 DESCRIPTION (provided by applicant): Stress is a major risk factor for the development of mood and anxiety disorders and the causative agent in posttraumatic stress disorder (PTSD). Development of stress-related psychopathology is variable among individuals and involves complex interactions between susceptibility mechanisms favoring development of psychopathology and resiliency mechanisms protecting against the development of mental illness in the face of adversity. Elucidating novel mechanisms by which resiliency factors prevent the transition from stress exposure to psychopathology could have broad implications for preventing and treating stress-related neuropsychiatric disorders. Here we will test the global hypothesis that the endogenous cannabinoid 2- arachidonoylglycerol (2-AG) is a stress resiliency factor that serves a homeostatic role buffering against the adverse behavioral consequences of stress exposure. 2-AG is a key mediator of retrograde synaptic suppression at central synapses via activation of type-1 cannabinoid receptors (CB1). Importantly, stress increases 2-AG levels in a key limbic anxiety circuit containing the prefrontal cortex (PFC) and amygdala where 2-AG signaling suppresses glutamate release. Importantly, we and others have recently shown that pharmacological augmentation of 2-AG signaling can prevent some stress-induced behavioral pathology whereas blocking CB1 receptors worsens the behavioral consequences of stress exposure. Although these data suggest a key role of 2-AG in anxiety modulation and stress adaptation, causal evidence supporting 2-AG signaling in anxiety modulation and stress adaptation is critically absent from the literature. To explicitly test the hypothesis that 2-AG is required for physiological anxiety modulation and stress adaptation we have generated constitutive and conditional mutant mice lacking the primary 2-AG synthetic enzyme diacylglycerol lipase α (DAGLα). We will test for the first time the necessity and sufficiency of 2-AG signaling within the PFC- amygdala circuit in the regulation of stress adaptation using conditional DAGLα floxed mice and circuit-specific viral CRE injection, and a newly generated lentiviral-DAGLα overexpression system. We will test the hypothesis that 2-AG signaling serves to suppress reciprocal glutamatergic signaling within the PFC-amygdala circuit using ex vivo optogenetic electrophysiological approaches and neuronal activity imaging. If successful, these experiments will provide causal evidence for 2-AG signaling in modulation of anxiety and depressive behaviors and stress adaptation, and reveal circuit- and synaptic-level mechanisms by which 2-AG signaling buffers against the adverse behavioral consequences of stress exposure. Completion of pharmacological studies proposed herein will also validate 2-AG augmentation as a viable approach for the treatment of affective disorders including PTSD.

 描述（由申请人提供）：压力是情绪和焦虑障碍发展的主要风险因素，也是创伤后应激障碍（PTSD）的致病因素。压力相关的精神病理学的发展在个体之间是可变的，并且涉及有利于精神病理学发展的易感性机制和在逆境中保护免受精神疾病发展的弹性机制之间的复杂相互作用。阐明弹性因素阻止从压力暴露到精神病理学转变的新机制可能对预防和治疗压力相关的神经精神疾病具有广泛的意义。在这里，我们将测试全球 假设内源性大麻素2-花生四烯酰甘油（2-AG）是一种压力弹性因子，具有稳态作用，可缓冲压力暴露的不良行为后果。2-AG是通过激活1型大麻素受体（CB 1）在中枢突触处的逆行突触抑制的关键介质。重要的是，压力增加了包含前额叶皮层（PFC）和杏仁核的关键边缘焦虑回路中的2-AG水平，其中2-AG信号抑制谷氨酸释放。重要的是，我们和其他人最近表明，2-AG信号的药理学增强可以防止一些应激诱导的行为病理学，而阻断CB 1受体可以减轻应激暴露的行为后果。虽然这些数据表明2-AG在焦虑调节和压力适应中的关键作用，但文献中严重缺乏支持2-AG信号在焦虑调节和压力适应中的因果证据。为了明确验证生理焦虑调节和应激适应需要2-AG的假设，我们产生了缺乏主要2-AG合成酶二酰基甘油脂肪酶α（DAGLα）的组成型和条件性突变小鼠。我们将使用条件DAGLα固定小鼠和回路特异性病毒CRE注射以及新产生的慢病毒DAGL α过表达系统，首次测试PFC-杏仁核回路中2-AG信号传导在应激适应调节中的必要性和充分性。我们将使用离体光遗传电生理方法和神经元活动成像来测试2-AG信号传导用于抑制PFC-杏仁核回路内的相互的神经元能信号传导的假设。如果成功，这些实验将提供因果关系的证据2-AG信号在调节焦虑和抑郁行为和压力适应，并揭示电路和突触水平的机制，2-AG信号缓冲对不良行为后果的压力暴露。本文提出的药理学研究的完成也将验证2-AG增强作为治疗情感障碍包括PTSD的可行方法。