Endocannabinoid Modulation of the Habenular Stress Response

项目摘要 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 重度抑郁症在大脑中，慢性压力导致中脑边缘多巴胺系统的适应， 增加临床人群中发展抑郁症和抑郁症相关行为的脆弱性， 临床前动物模型。大脑的一个区域最近得到了关注，那就是外侧 缰核（LHb），部分原因是它的能力，严格限制多巴胺的活动。值得注意的是，LHb是 在患有重度抑郁症的个体中过度活跃，同时恢复该区域的正常活动， 作为一种可行的治疗策略出现在治疗抵抗的患者。虽然我们还不知道 慢性应激导致LHb功能障碍，一个有趣的可能性是通过应激诱导的LHb功能的改变。 内源性大麻素（ECB）系统。ECB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，这有助于维持突触稳态。我们的数据表明 慢性应激增强了LHb中的ECB信号，而该系统的局部激活则导致了一种被动的- 绝望般的应对策略，损害行为的灵活性，在注意力转移任务，并减少 位于腹侧被盖区的多巴胺神经元的放电率。然而，欧洲央行的确切作用 LHb中的系统以及该系统调节压力相关行为的机制还有待进一步研究。 正式评估。在本提案中，我们将通过系统地 研究ECB系统如何调节LHb功能，并确定慢性应激诱导的LHb功能是否正常。 这个系统的改变是产生多巴胺细胞放电和表达缺陷所必需的。 与抑郁症有关的行为。在目标1中，我们将进行特定部位的药理学操作， ECB系统与自由行为中多巴胺细胞活性的体内电生理学记录串联 揭示应激诱导的LHb ECB信号转导的改变如何导致行为缺陷。 灵活性.在目标2中，我们将使用离体电生理学结合LHb投射的逆行标记， 确定ECB系统在调节兴奋性和抑制性LHb输入中的作用，并研究如何 慢性应激改变了ECB对投射定义的LHb突触的突触强度的控制。在目标3中，我们 使用组合病毒方法来确定LHb神经元的急性回路特异性激活对 压力应对和行为灵活性，并测试是否慢性，长期LHb激活重演 行为的影响，慢性应激的ECB依赖的方式。概括地说，拟议的研究将 通过确定欧洲央行系统如何调节一个关键电路的活动， 与心理健康的各个领域以及神经生理和行为后果有关 压力引起的系统变化。此外，本文的工作将为今后的研究探索铺平道路 这个系统与大脑功能和疾病的关系。

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.