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: 10223545
• 负责人: Sachin Patel
• 金额: $ 62.85万
• 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 2022-01-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10223545
• 关键词: 2-arachidonylglycerol; 2-arachidonylglycerol signaling; Acute; Affect; Affective; Amygdaloid structure; Anxiety; Anxiety Disorders; Award; Behavior; Behavioral; Biosensor; CNR1 gene; Calcium; Cells; Complex; Coupling; Cues; Data; Development; Disease; Economic Burden; Effectiveness; Electrophysiology (science); Endocannabinoids; Enzymes; Extinction (Psychology); Fright; Functional disorder; G-Protein-Coupled Receptors; Generations; Genetic; Glutamates; Goals; Hippocampus (Brain); Image; Impairment; Individual; Learning; Link; Lipids; Long-Term Depression; Major Depressive Disorder; Mediating; Mental Depression; Mental disorders; Metaplasia; Molecular; Monoacylglycerol Lipases; Mood Disorders; Neurons; Pathologic; Pathology; Pharmacology; Physiological; Play; Population; Population Dynamics; Post-Traumatic Stress Disorders; Predisposition; Prefrontal Cortex; Process; Psychopathology; Regulation; Risk Factors; Role; Shapes; Signal Transduction; Specificity; Stress; Substance Use Disorder; Synapses; Techniques; Testing; Time; Translating; Translations; Viral; Work; anxiety-related behavior; avoidance behavior; base; biobehavior; biological adaptation to stress; conditioned fear; endocannabinoid signaling; endophenotype; genetic approach; imaging approach; in vivo; innovation; insight; lipoprotein lipase; mental development; mood regulation; neural circuit; neuropsychiatric disorder; novel; novel strategies; optogenetics; physiologic stressor; psychological stressor; relating to nervous system; resilience; response; stress related disorder; stress resilience; synthetic enzyme

PROJECT SUMMARY 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. Understanding the molecular, cellular, and circuit-level mechanisms by which stress exposure is translated into affective pathology could have broad implications for understanding the pathophysiology of stress-related psychiatric disorders and for the development of novel treatment approaches. We propose to test the overarching hypothesis that the endogenous cannabinoid 2-Arachidonoylglycerol (2-AG) is a critical regulator of stress adaptation and propose to elucidate the synaptic and cellular mechanisms by which 2-AG signaling serves to mitigate pathological responses to stress exposure. We will first test the hypothesis that 2-AG signaling inhibits bi-directional excitatory coupling between the amygdala and ventral hippocampus, a neural circuit critical for mediating innate danger avoidance and generalization of learned fear responses. We will test the hypothesis that stress causes a functional collapse of 2-AG signaling within this circuit leading to synaptic strengthening, the generation of increased avoidance, and fear generalization. We will also test the hypothesis that stress exposure leads to increases in 2-AG release within distinct amygdala circuits in a neural activity-dependent manner using a novel virally encoded GPCR-based endocannabinoid biosensor. These studies will reveal, for the first time, the temporal dynamics and activity-dependent mechanisms mediating stress-induced endocannabinoid mobilization within amygdala circuits. Lastly, we will use in vivo single-cell calcium imaging approaches to test the hypothesis that 2-AG is required for the dynamic changes in neuronal ensemble representations to threat predictive cues that occur during fear learning, expression, generalization, and extinction. Taken together, these data will provide new mechanistic insight into how 2-AG signaling regulates stress-related biobehavioral processes relevant to neuropsychiatric disorders including PTSD and could reveal novel pathophysiological mechanisms contributing to the translation of stress exposure into affective pathology.

压力是情绪和焦虑障碍发展的主要危险因素， 创伤后应激障碍（PTSD）的病因。压力相关精神病理学的发展 个体之间存在差异，涉及易感性机制之间的复杂相互作用， 心理病理学和弹性机制的发展， 面对逆境时的疾病了解分子，细胞和电路水平的机制， 压力暴露转化为情感病理可能对理解 应激相关精神障碍的病理生理学和新的治疗方法的发展。 我们建议测试的总体假设，内源性大麻素2-花生四烯酸甘油（2-AG） 是应激适应的关键调节因子，并提出通过以下方式阐明突触和细胞机制： 该2-AG信号传导用于减轻对应激暴露的病理反应。我们将首先测试 2-AG信号抑制杏仁核和腹侧核之间的双向兴奋性耦合的假说 海马体，一个调节先天危险回避和习得性恐惧泛化的关键神经回路 应答我们将测试这一假设，即压力导致2-AG信号转导的功能崩溃， 回路导致突触强化，产生增加的回避和恐惧泛化。我们将 同时也验证了压力暴露导致不同杏仁核回路中2-AG释放增加的假设 以神经活性依赖的方式使用一种新的病毒编码的基于GPCR的内源性大麻素生物传感器。 这些研究将首次揭示，时间动态和活动依赖机制介导 杏仁核回路内应激诱导的内源性大麻素动员。最后，我们将使用体内单细胞 钙成像的方法来测试的假设，2-AG是所需的动态变化，神经元 在恐惧学习，表达，概括， 和灭绝。总之，这些数据将为2-AG信号如何调节 压力相关的生物行为过程与神经精神疾病，包括创伤后应激障碍，并可能揭示 新的病理生理机制有助于翻译的压力暴露到情感病理。