Endocannabinoid Modulation of the Habenular Stress Response

项目总结 压力是日常生活中普遍存在的一个方面，也是一系列精神疾病的重要风险因素，包括 严重的抑郁症。在大脑中，慢性应激导致中脑边缘多巴胺系统的适应 增加临床人群中患抑郁症和抑郁症相关行为的易感性 分别建立临床前动物模型。最近，大脑的一个区域引起了人们的注意，那就是侧脑区 缰核(LHb)，部分是因为它有能力严格限制多巴胺的活动。值得注意的是，LHB是 患有严重抑郁症的人过度活跃，同时恢复这一区域的正常活动 在耐药患者中成为一种可行的治疗策略。尽管我们仍然不知道如何 慢性应激导致LHb功能障碍，一种有趣的可能性是通过应激诱导的 内源性大麻素(ECB)系统。欧洲央行系统在大脑中的主要作用是提供活动- 依赖的、按需的负反馈，有助于维持突触的动态平衡。我们的数据显示 慢性应激增强了LHb中的ECB信号，而该系统的局部激活引发了被动的- 绝望样的应对策略，损害了注意定势转移任务中的行为灵活性，并降低了 腹侧被盖区多巴胺神经元的放电频率。然而，欧洲央行的确切角色是 LHb中的系统以及该系统调节应激相关行为的机制尚未得到证实 正式评估。在目前的提案中，我们将通过系统地填补这一重要的知识空白 研究欧洲央行系统如何调节LHb功能，并确定慢性应激是否导致 这个系统的改变是产生多巴胺细胞激活和表达的缺陷所必需的 与抑郁相关的行为。在目标1中，我们将执行特定部位的药理操作 ECB系统与多巴胺细胞自由活动的在体电生理记录 大鼠揭示应激诱导的LHb ECB信号变化可能导致行为缺陷 灵活性。在目标2中，我们将使用体外电生理学结合LHb投射的逆行标记 确定欧洲央行系统在调节兴奋性和抑制性LHb输入方面的作用，并研究如何 慢性应激改变欧洲央行对投射定义的LHb突触的突触强度的控制。在《目标3》中，我们将 使用组合病毒方法确定急性、电路特异性激活LHb神经元对 压力应对和行为灵活性，并测试慢性、长期的LHb激活是否重述了 以欧洲央行依赖的方式对慢性应激的行为影响。广义地说，拟议的研究将 通过确定欧洲央行系统如何监管关键电路的活动来填补该领域的重大空白 牵涉到精神健康的各个领域，以及神经生理和行为后果 在这个系统中由压力引起的改变。此外，本文的工作还将为以后的研究探索做好铺垫 这个系统在大脑功能和疾病中的作用。

PROJECT SUMMARY Stress is a pervasive aspect of daily life and a significant risk factor for a host of mental illnesses, including major depression. In the brain, chronic stress causes adaptations in the mesolimbic dopamine system that increase vulnerability for developing depression and depression-related behaviors in clinical populations and preclinical animal models, respectively. One area of the brain that has gained attention as of late is the lateral habenula (LHb), in part because of its ability to tightly constrain dopamine activity. Notably, the LHb is hyperactive in individuals suffering from major depression, while restoring normal activity in this area has emerged as a viable therapeutic strategy in treatment-resistant patients. Although we still do not know how chronic stress leads to LHb dysfunction, one intriguing possibility is through stress-induced alterations in the endogenous cannabinoid (ECB) system. The primary role of the ECB system in the brain is to provide activity- dependent, on-demand negative feedback, which helps to maintain synaptic homeostasis. Our data indicate that chronic stress augments ECB signaling in the LHb, while local activation of this system elicits a passive- despair-like coping strategy, impairs behavioral flexibility in an attentional set-shifting task, and decreases the firing rate of dopamine neurons located in the ventral tegmental area. However, the precise role of the ECB system in the LHb and the mechanisms by which this system modulates stress-related behaviors has yet to be formally evaluated. In the current proposal, we will fill this important gap in knowledge by systematically examining how the ECB system modulates LHb function and identifying whether chronic stress-induced alterations in this system are necessary to produce deficits in dopamine cell firing and the expression of depression-related behaviors. In Aim 1, we will perform site-specific pharmacological manipulations of the ECB system in tandem with in vivo electrophysiology recordings of dopamine cell activity in freely behaving rats to uncover how stress-induced alterations in LHb ECB signaling may contribute to deficits in behavioral flexibility. In Aim 2, we will use ex vivo electrophysiology combined with retrograde labeling of LHb projections to identify the role of the ECB system in modulating excitatory and inhibitory LHb inputs and examine how chronic stress alters ECB control of synaptic strength at projectionally defined LHb synapses. In Aim 3, we will use a combinatorial viral approach to determine effects of acute, circuit-specific activation of LHb neurons on stress coping and behavioral flexibility, and test whether chronic, long-term LHb activation recapitulates the behavioral effects of chronic stress in an ECB-dependent manner. Broadly stated, the proposed research will fill a significant gap in the field by identifying how the ECB system regulates the activity of a key circuit that has been implicated in various domains of mental health, and the neurophysiological and behavioral consequences of stress-induced alterations in this system. Moreover, this work will pave the way for future studies exploring the involvement of this system in brain function and disease.