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

 描述(申请人提供)：压力是情绪和焦虑症发展的主要风险因素，也是创伤后应激障碍(PTSD)的致病因素。应激相关精神病理学的发展因个体而异，涉及促进精神病理学发展的易感机制和面对逆境时防止精神疾病发展的弹性机制之间的复杂相互作用。阐明弹性因子阻止从应激暴露向精神病理学转变的新机制可能对预防和治疗应激相关的神经精神障碍具有广泛的意义。在这里，我们将测试全球 假设内源性大麻素2-花生四烯基甘油(2-AG)是一种压力弹性因子，起到平衡作用，缓冲应激暴露的不良行为后果。2-AG是通过激活1型大麻素受体(CB1)在中枢突触逆行抑制突触的关键介质。重要的是，压力增加了包含前额叶皮质(PFC)和杏仁核的关键边缘焦虑回路中2-AG的水平，在那里2-AG信号抑制谷氨酸的释放。重要的是，我们和其他人最近表明，2-AG信号的药理增强可以防止一些应激诱导的行为病理，而阻断CB1受体会恶化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起关键作用，但支持2-AG信号在焦虑调节和压力适应中的因果证据在文献中严重缺乏。为了明确地验证2-AG是生理焦虑调节和压力适应所必需的假设，我们产生了缺乏主要2-AG合成酶二酰甘油脂肪酶α(DAGLα)的结构性和条件性突变小鼠。我们将首次使用条件性DAGLα小鼠和电路特异性病毒Cre注射，以及新产生的慢病毒-DAGLα过表达系统，测试PFC-杏仁核回路中2-AG信号在应激适应调节中的必要性和充分性。我们将使用体外光发生电生理学方法和神经元活动成像来验证2-AG信号用于抑制PFC-杏仁核回路中相互的谷氨酸能信号的假设。如果成功，这些实验将为2-AG信号在调节焦虑和抑郁行为以及压力适应中提供因果证据，并揭示2-AG信号缓冲应激暴露的不良行为后果的电路和突触水平的机制。本文建议的药理学研究的完成也将验证2-AG增强作为治疗包括创伤后应激障碍在内的情感障碍的可行方法。

 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.