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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

基本信息

批准号：
9297389
负责人：
Sachin Patel
金额：
$ 43.17万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/9297389
关键词：
2-arachidonylglycerol 2-arachidonylglycerol signaling 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 Immunologics 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 Mutant Strains Mice Neurons Outcome Pathogenesis Pathology Peripheral Pharmacology Pharmacology Study Phenotype Physiological Post-Traumatic Stress Disorders Predisposition Prefrontal Cortex Psychopathology Receptor Signaling 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 cannabinoid receptor clinical investigation comparative conditional mutant depressive behavior depressive symptoms endocannabinoid signaling experimental study glutamatergic signaling in vivo lipoprotein lipase mental development mood regulation neural circuit neuropsychiatric disorder novel novel strategies optogenetics overexpression prevent public health relevance receptor reconstitution relating to nervous system resilience response stress resilience synthetic enzyme transmission process treatment strategy

项目摘要

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.