Circuit-specific actions of endocannabinoids in stress and mood disorders

内源性大麻素在压力和情绪障碍中的电路特异性作用

• 批准号: 10238098
• 负责人: Cecilia J Hillard
• 金额: $ 38.5万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-11 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10238098
• 关键词: 2-arachidonylglycerol; Affect; Anatomy; Animals; Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Anxiety Disorders; Attenuated; Behavior; Behavioral; Brain; Brain region; Buffers; CNR1 gene; Cannabinoids; Cannabis; Cell Count; Cells; Clinical; Clinical Research; Data; Deep Brain Stimulation; Depressive disorder; Diagonal Band Nucleus; Disease; Disease remission; Electrophysiology (science); Endocannabinoids; Epithalamic structure; Evolution; Exposure to; Fright; G-Protein-Coupled Receptors; Genes; Glutamates; Goals; Habenula; Hormonal; Human; Hyperactivity; In Situ Hybridization; Individual; Lateral; Link; Literature; Medial; Mediating; Messenger RNA; Modeling; Mood Disorders; Moods; Neurons; Output; Pathway interactions; Patients; Physiological; Physiology; Play; Population Heterogeneity; Prevalence; Regulation; Reverse Transcriptase Polymerase Chain Reaction; Rodent; Role; Signal Transduction; Slice; Stress; Synapses; Synaptic plasticity; Techniques; Testing; Transcription Factor AP-1; anatomical tracing; antidepressant effect; anxiety-like behavior; avoidance behavior; base; behavioral phenotyping; behavioral response; biological adaptation to stress; cell type; cholinergic; conditioned fear; endocannabinoid signaling; endogenous cannabinoid system; gamma-Aminobutyric Acid; genetic manipulation; knock-down; lipoprotein lipase; mood regulation; mouse model; neural circuit; nonhuman primate; novel; optogenetics; preclinical study; receptor; relating to nervous system; response; rimonabant; stress disorder; stress management; stress reactivity; traumatic stress; treatment-resistant depression; virus genetics

Project Summary/Abstract The brain endocannabinoid (eCB) system can dampen behavioral and physiological responses to stress via activation of cannabinoid receptor 1 (CB1), one of the most abundant G protein-coupled receptors in the brain. However, the distinct neural circuits which underlie eCB-mediated effects remain incompletely identified and understood. Recent studies have identified the habenula, an epithalamic structure conserved across vertebrate evolution, to play a central role in encoding stress reactivity, avoidance behavior, and aversion in rodents and non-human primates, and its hyperactivity has been linked to anxiety-like behavior and mood dysregulation. Human studies have shown that habenula volumes and cell numbers are reduced in patients with depressive disorders, and deep brain stimulation of the habenula led to remission in an individual with treatment-resistant depression. Thus, both human and animal studies point to a critical role for the habenula in regulating behaviors relevant to stress responsivity and mood. In this study, we provide first evidence that neurons of the medial habenula (MHb) synthesize and release eCBs to suppress synaptic input from the medial septum and nucleus of the diagonal band (MSDB). Further, we show that this eCB/CB1 signaling is blunted in association with stress-induced anxiety-like behavior, and that knockdown of CB1 receptors in the MSDB is sufficient to mimic the stress-induced behavioral phenotype. Thus, these results, together with previous literature linking the MHb and the MSDB to anxiety-like behavior, led us to hypothesize that eCB/CB1 signaling in the MSDB- MHb pathway is a novel mechanism whereby eCBs attenuate stress-induced anxiety-like behavior, and that dysregulation of this signaling can contribute to this behavioral state. Three Specific Aims are proposed to test these hypotheses. Our first goal in Aim I will be to carry out a detailed assessment of the cell type-specific connectivity of the MSDB-MHb pathway, as very little is known regarding its anatomy and physiology. In Aim II, we will determine how eCBs regulate this circuit and how this regulation is affected by stress exposure. In Aim III, we will test the hypothesis that eCB signaling in this pathway regulates behavioral responses to stress. Successful completion of the outlined studies will advance our long-term objectives to understand the neural circuits underlying anxiety-like behavior, the specific mechanisms whereby eCBs exert behavior effects, and how dysregulation of eCB signaling may contribute to anxiety and mood-related disorders.

项目概要/摘要 大脑内源性大麻素（eCB）系统可以通过以下方式抑制对压力的行为和生理反应： 激活大麻素受体 1 (CB1)，这是大脑中最丰富的 G 蛋白偶联受体之一。 然而，eCB 介导效应背后的独特神经回路仍未完全确定，并且 明白了。最近的研究发现了缰核，这是脊椎动物中保守的上丘脑结构 进化，在编码啮齿类动物的应激反应、回避行为和厌恶方面发挥核心作用 非人类灵长类动物，其过度活跃与焦虑样行为和情绪失调有关。 人体研究表明，抑郁症患者的缰核体积和细胞数量减少 缰核的深部脑刺激使患有治疗耐药的个体得到缓解 沮丧。因此，人类和动物研究都表明缰核在调节中发挥着关键作用。 与压力反应和情绪相关的行为。在这项研究中，我们提供了第一个证据表明 内侧缰核 (MHb) 合成并释放 eCB，以抑制来自内侧隔膜的突触输入， 对角带核（MSDB）。此外，我们表明这种 eCB/CB1 信号传导在关联中被削弱 与压力诱发的焦虑样行为有关，并且 MSDB 中 CB1 受体的敲低足以 模仿压力诱导的行为表型。因此，这些结果以及之前的文献链接 MHb 和 MSDB 导致焦虑样行为，使我们推测 MSDB 中的 eCB/CB1 信号传导- MHb 途径是一种新机制，eCB 可通过该机制减弱压力引起的焦虑样行为，并且 这种信号传导的失调可能会导致这种行为状态。建议测试三个具体目标 这些假设。我们的目标 I 的首要目标是对特定细胞类型进行详细评估 MSDB-MHb 通路的连接性，因为对其解剖学和生理学知之甚少。在目标二中， 我们将确定 ECB 如何调节该电路以及压力暴露如何影响该调节。瞄准 III，我们将检验这一假设：该通路中的 eCB 信号传导调节对压力的行为反应。 成功完成概述的研究将推进我们了解神经网络的长期目标 焦虑样行为背后的回路、eCB 发挥行为影响的具体机制，以及 eCB 信号传导失调如何导致焦虑和情绪相关疾病。