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: 10549674
• 负责人: Sachin Patel
• 金额: $ 55.22万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 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 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10549674
• 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.

项目摘要压力是情绪和焦虑症发展的主要风险因素， 创伤后应激障碍(PTSD)的病因。与应激相关的精神病理学的发展 不同个体之间的差异，并涉及有利于 防止心理发展的精神病理学和复原力机制的发展 逆境中的病痛。了解分子、细胞和电路级别的机制 应激暴露转化为情感病理可能对理解 与应激相关的精神障碍的病理生理学和新治疗方法的发展。 我们建议检验最重要的假设，即内源性大麻素2-花生四烯基甘油(2-AG) 是应激适应的关键调节因子，建议通过以下途径阐明突触和细胞机制 其中2-AG信号转导系统起到减轻应激反应的作用。我们将首先测试 2-AG信号抑制杏仁核与腹侧双向兴奋性偶联的假说 海马体--调节先天危险回避和后天恐惧泛化的关键神经回路 回应。我们将测试应激导致2-AG信号的功能崩溃这一假设 回路导致突触加强，产生更多的回避，和恐惧泛化。我们会 也要测试应激暴露导致杏仁核不同回路中2-AG释放增加的假设 以神经活动依赖的方式，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力学和活动依赖的调节机制。 应激诱导杏仁核环路内的内源性大麻素动员。最后，我们将使用体内单细胞 钙成像方法验证2-AG是神经元动态变化所必需的假说 对发生在恐惧学习、表达、概括、 和灭绝。综上所述，这些数据将为2-AG信号如何调控提供新的机械性见解 与包括创伤后应激障碍在内的神经精神障碍相关的应激相关生物行为过程，并可能揭示 有助于将应激暴露转化为情感病理的新的病理生理机制。