Circuit-specific actions of endocannabinoids in stress and mood disorders

项目总结/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： 大麻素受体1（CB 1）的激活，是大脑中最丰富的G蛋白偶联受体之一。 然而，作为eCB介导效应基础的不同神经回路仍然没有完全确定， 明白最近的研究已经确定了缰，一种在脊椎动物中保守的上丘脑结构 进化，在编码啮齿动物的应激反应、回避行为和厌恶中发挥核心作用， 非人类灵长类动物，它的多动症已被链接到焦虑样行为和情绪失调。 人类研究表明，抑郁症患者的缰核体积和细胞数量减少， 疾病，并且缰核的深部脑刺激导致患有治疗抵抗性疾病的个体的缓解。 萧条因此，人类和动物的研究都指出了缰核在调节 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，表明神经元的 内侧缰核（MHb）合成并释放eCB以抑制来自内侧隔的突触输入， 对角带核（MSDB）。此外，我们表明，这种eCB/CB 1信号是钝化的协会， 压力诱导的焦虑样行为，并且MSDB中CB 1受体的敲低足以 模仿应激诱导的行为表型。因此，这些结果，连同以前的文献链接 MHb和MSDB与焦虑样行为的关系，使我们假设MSDB中的eCB/CB 1信号传导- MHb通路是eCB减轻应激诱导的焦虑样行为的新机制， 这种信号传导的失调可促成这种行为状态。提出了三个具体目标来测试 这些假设。我们在目标I中的第一个目标将是对细胞类型特异性进行详细评估。 MSDB-MHb途径的连接性，因为关于其解剖学和生理学知之甚少。在Aim II中， 我们将确定eCB如何调节这个回路，以及这种调节如何受到压力暴露的影响。在Aim中 第三，我们将测试的假设，eCB信号在这条途径调节行为反应的压力。 成功完成概述的研究将推进我们的长期目标，以了解神经 焦虑样行为的潜在回路，eCB发挥行为效应的具体机制，以及 eCB信号传导失调如何导致焦虑和情绪相关疾病。

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.