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: 10013295
• 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/10013295
• 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; Hyperactive behavior; 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.

项目摘要/摘要 大脑内源性大麻素（ECB）系统可以通过 大麻素受体1（CB1）的激活，这是大脑中最丰富的G蛋白偶联受体之一。 但是，欧洲央行介导的作用构成的不同神经回路仍未得到完全识别，并且 理解。最近的研究确定了Habenula，这是跨脊椎动物的上皮结构 进化，在编码压力反应性，回避行为和啮齿动物的厌恶和厌恶中发挥核心作用 非人类灵长类动物及其多动症与焦虑样行为和情绪失调有关。 人类研究表明，抑郁症患者的habenula量和细胞数量减少 疾病和对Habenula的深脑刺激导致耐药的人缓解 沮丧。因此，人类和动物研究都指出了Habenula在调节中的关键作用 与压力反应性和情绪有关的行为。在这项研究中，我们提供了第一个证据，表明 内侧Habenula（MHB）合成并释放ECB，以抑制内侧隔膜的突触输入和 对角线带（MSDB）的核。此外，我们表明这种欧洲央行/CB1信号在关联中被钝化 具有压力引起的焦虑样行为，而MSDB中CB1受体的敲低足以使 模仿应力诱导的行为表型。因此，这些结果以及以前的文献链接 MHB和MSDB达到焦虑症行为，使我们假设MSDB-中的欧洲央行/CB1信号传导 MHB途径是一种新型机制，ECB会减轻压力引起的类似焦虑的行为，并且 该信号的失调可能导致这种行为状态。提出了三个特定目标来测试 这些假设。我们目标的第一个目标是对细胞类型特定的详细评估进行详细评估 MSDB-MHB途径的连通性，关于其解剖学和生理学知之甚少。在AIM II中， 我们将确定ECB如何调节该电路以及该调节如何受到压力暴露的影响。目标 iii，我们将检验以下假设：该途径中的欧洲央行信号传导调节对压力的行为反应。 成功完成概述的研究将促进我们的长期目标以了解神经 类似焦虑行为的电路，ECB施加行为影响的特定机制和 欧洲央行信号传导的失调可能导致焦虑和情绪相关的疾病。