Circuit-specific actions of endocannabinoids in stress and mood disorders

项目摘要/摘要 脑内大麻素(Ecb)系统可通过以下途径抑制对应激的行为和生理反应 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，欧洲央行介导的效应背后的不同神经回路仍未完全确定和 明白了。最近的研究已经确定缰核，一种在脊椎动物中保存的上皮性结构 进化，在编码啮齿动物的应激反应、回避行为和厌恶行为中发挥核心作用 非人类灵长类动物，其多动与焦虑样行为和情绪失调有关。 人类研究表明，抑郁症患者缰核体积和细胞数量减少 精神障碍和缰核深部脑刺激导致耐药个体缓解 抑郁症。因此，人类和动物研究都指出缰核在调节 与压力、反应能力和情绪有关的行为。在这项研究中，我们提供了第一个证据，即 内侧缰核(MHB)合成和释放ECB以抑制来自内侧隔核的突触输入 斜角带核(MSDB)。此外，我们还证明了这种ECB/CB1信号是钝化的 与应激诱导的焦虑样行为有关，MSDB中CB1受体的敲除足以 模仿应激诱导的行为表型。因此，这些结果与以前的文献联系在一起 MHB和MSDB的焦虑样行为，导致我们假设MSDB-ECB/CB1信号- MHB途径是ECB减轻应激诱导的焦虑样行为的一种新机制 这种信号的失调可能会导致这种行为状态。提出了三个具体的测试目标 这些假设。我们在AIM I的第一个目标是对特定类型的细胞进行详细的评估 MSDB-MHB途径的连通性，因为对其解剖学和生理学知之甚少。在AIM II中， 我们将确定ECB如何调节这一回路，以及这种调节如何受到压力暴露的影响。在AIM 第三，我们将检验ECB在这一途径中的信号调节应激行为反应的假设。 成功完成概述的研究将推进我们理解神经的长期目标。 焦虑类行为背后的回路，ECB施加行为影响的具体机制，以及 欧洲央行信号的失调可能会导致焦虑和情绪相关的障碍。

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.