Psychological stress reduces endocannabinoid tone: mechanisms and possible treatments

心理压力降低内源性大麻素张力：机制和可能的治疗方法

基本信息

批准号：
10292952
负责人：
Siqiong June Liu
金额：
--
依托单位：
SOUTHEAST LOUISIANA VETERANS HEALTH CARE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-10-01 至 2023-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10292952
关键词：
2-arachidonylglycerol 2-arachidonylglycerol signaling Adrenergic Agents Adrenergic Receptor Affect Animal Model Anxiety Anxiety Disorders Applications Grants Attenuated Behavioral Brain region Cerebellum Chronic stress Data Development Emotional Stress Endocannabinoids Enzymes Exhibits Extinction (Psychology)FDA approved Foxes Fright General Population Genetic Transcription Impairment Individual Interneurons Intervention Investigation Knowledge Learning Life Life Experience LoxP-flanked allele Membrane Memory Memory impairment Mental Depression Mental Health Metabolism Modeling Molecular Monoacylglycerol Lipases Mood Disorders Mus Neurons Norepinephrine Odors Pain Pharmaceutical Preparations Pharmacology Post-Traumatic Stress Disorders Potassium Channel Production Psychological Stress Purkinje Cells Receptor Signaling Regulation Research Rodent Role Signal Pathway Stress Synaptic Transmission Testing Urine Veterans anxiety-like behavior behavioral phenotyping biological adaptation to stress conditioned fear designer receptors exclusively activated by designer drugs endocannabinoid signaling experience experimental study fear memory gamma-Aminobutyric Acid in vivo lipoprotein lipase locus ceruleus structure memory consolidation memory retention neural circuit neuronal excitability new therapeutic target novel novel strategies novel therapeutic intervention presynaptic prevent psychological trauma reduce symptoms response stressor synthetic enzyme transmission process traumatic event traumatic stress treatment strategy

项目摘要

One debilitating mental health problem among veterans is post-traumatic stress disorder (PTSD), which is an anxiety disorder (PTSD) and develops following the experience of life- threatening psychological trauma. Individuals with PTSD have reduced circulating levels of endocannabinoids (eCB) including 2-AG. Since disruption of 2-AG signaling leads to mood disorders, impaired memory extinction and enhanced pain, the ability to reverse the stress- induced change in 2-AG production/degradation holds great potential for the treatment of PTSD. Given the importance of 2-AG signaling in the stress response and associative fear learning, an understanding of how stress produces a lasting decrease in 2-AG levels is needed to bridge the knowledge gap that exists between traumatic stress and the associated reduction in 2-AG content. Exposure of rodents to natural predator odors causes psychological stress, leading to enhanced associative fear learning and thus has been used to model several aspects of PTSD. We have previously shown that fox urine exposure produced a lasting increase in excitatory synaptic transmission via the activation of adrenergic receptors in the mouse cerebellum. This brain region is required for the innate response to predator odor and for the consolidation of fear memory. Our pilot data show that predator odor exposure reduced 2-AG signaling in the cerebellum and this stressor abolished A-type K currents in inhibitory interneurons. Therefore our central hypothesis is that predator odor stress enhances excitability of GABAergic interneurons and thereby reduces 2-AG signaling, thus pharmacological interventions that inhibit 2-AG degradation and reduce neuronal excitability would reverse the stress-induced decrease in 2-AG levels. In Aim 1, we will determine whether a psychological stress reduces 2- AG tone by increasing 2-AG degradation or by reducing 2-AG production. Aim 2 will test the hypothesis that emotional stress reduces 2-AG signaling by increasing inhibitory interneuron activity. We will test whether several FDA approved drugs that reduce neuronal activity can reverse the stress-induced change. Because the proposed study investigates a new mechanism underlying the regulation of 2-AG metabolism by psychological stress, it could suggest novel treatment strategies for PTSD and new therapeutic targets.

退伍军人中的一个使人衰弱的心理健康问题是创伤后应激障碍（PTSD），这是一种焦虑症（PTSD），并遵循生命的经验 - 威胁心理创伤。具有PTSD的个体循环水平降低内源性大麻素（欧洲央行），包括2-AG。由于2-AG信令的破坏会导致情绪疾病，记忆灭绝和增强的疼痛，扭转应力的能力 - 诱导的2AG生产/降解变化具有PTSD治疗的巨大潜力。鉴于2 ag信号在压力反应和联想恐惧学习中的重要性，需要了解压力如何产生持久的2-AG水平以桥接创伤应力与2 AG的相关减少之间存在的知识差距内容。啮齿动物暴露于天然捕食者气味会引起心理压力，导致增强的关联恐惧学习，因此已被用来模拟PTSD的多个方面。我们以前已经表明，Fox尿液暴露导致兴奋性持久通过小脑小脑中肾上腺素受体的激活的激活突触传播。这天生对捕食者气味和恐惧的巩固需要大脑区域记忆。我们的飞行员数据表明，捕食气味暴露减少了2 ag信号传导小脑和该压力源消除了抑制性中间神经元中的A型K电流。所以我们的中心假设是捕食者气味应力增强了GABA能的兴奋性中间神经元，从而减少2 ag信号传导，从而进行药理学干预措施抑制2-AG降解并降低神经元兴奋性会逆转应力诱导的减少2-AG水平。在AIM 1中，我们将确定心理压力是否减少了2- 通过增加2-AG降解或减少2AG产生来增加Ag音调。 AIM 2将测试假设情绪压力通过增加抑制性中间神经元来降低2-ag信号传导活动。我们将测试几种FDA批准的减少神经元活性的药物是否可以扭转应力诱导的变化。因为拟议的研究调查了一种新机制通过心理压力来调节2-ag代谢的基础，它可能建议新颖 PTSD和新的治疗靶标的治疗策略。