Endocannabinoid Modulation of the Habenular Stress Response

内源性大麻素对缰核应激反应的调节

基本信息

批准号：
10305687
负责人：
Ryan Joseph McLaughlin
金额：
$ 38.25万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2025-10-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10305687
关键词：
2-arachidonylglycerol 2-arachidonylglycerol signaling Acute Address Animal Model Area Attention Behavior Behavioral Brain CNR1 gene Cell Nucleus Cells Chronic Chronic stress Clinical Cognitive deficits Coping Skills Data Deep Brain Stimulation Disease Disease susceptibility Dopamine Economic Burden Electrophysiology (science)Endocannabinoids Exhibits Exposure to Feedback Female Frequencies Functional disorder Future Goals Habenula Homeostasis Hyperactivity Impairment Individual Knowledge Label Lateral Life Major Depressive Disorder Mediating Mental Depression Mental Health Mental disorders Midbrain structure Modeling Neurons Outcome Pathologic Pathway interactions Patients Pharmacology Phenotype Population Positioning Attribute Rattus Research Resistance Risk Factors Rodent Rodent Model Role Signal Transduction Site Stress Stress and Coping Synapses Synaptic Transmission Synaptic plasticity System Testing Therapeutic Time Ventral Tegmental Area Viral Work behavioral impairment biological adaptation to stress combinatorial depressed patient dopaminergic neuron endogenous cannabinoid system flexibility in vivo innovation interdisciplinary approach male mesolimbic system neurophysiology postsynaptic pre-clinical recruit tool transmission process

项目摘要

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.

项目摘要压力是日常生活的普遍方面，也是许多精神疾病的重要危险因素，包括重度抑郁症。在大脑中，慢性应激会导致中脱脂胺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。最近引起注意的大脑的一个区域是横向 Habenula（LHB），部分原因是它具有严格限制多巴胺活性的能力。值得注意的是，LHB是患有严重抑郁症患者的人多动，而恢复该领域的正常活动有在耐治疗患者中成为一种可行的治疗策略。虽然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压力诱导的改变内源性大麻素（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，按需负面反馈，有助于维持突触稳态。我们的数据表明长期的应力增加了LHB中的欧洲央行信号传导，而该系统的局部激活引起了被动的类似于绝望的应对策略，会损害注意力转移任务中的行为灵活性，并减少多巴胺神经元的发射速率位于腹侧对段区域。但是，欧洲央行的确切作用 LHB中的系统以及该系统调节与压力相关行为的机制正式评估。在当前的建议中，我们将通过系统地填补这一重要差距检查欧洲央行系统如何调节LHB功能并识别慢性应激诱导的该系统中的改变对于产生多巴胺细胞发射和表达不足是必要的与抑郁有关的行为。在AIM 1中，我们将对特定地点的药理学操纵欧洲央行系统与自由行为的多巴胺细胞活性的体内电生理记录大鼠发现LHB ECB信号传导中应力诱导的改变如何导致行为缺陷灵活性。在AIM 2中，我们将使用离体电生理学与LHB投影的逆行标签相结合确定欧洲央行系统在调节兴奋性和抑制性LHB输入中的作用，并研究如何慢性应力改变了欧洲央行在投影定义的LHB突触时对突触强度的控制。在AIM 3中，我们将使用组合病毒方法来确定LHB神经元对急性电路特异性激活的影响压力应对和行为灵活性，并测试慢性的长期LHB激活是否概括了慢性应激的行为影响以欧洲央行依赖性方式。广泛地指出，拟议的研究将通过确定欧洲央行系统如何调节具有的关键电路的活动，以填补现场的显着空白与心理健康的各个领域有关，以及神经生理和行为后果该系统中应力诱导的改变。此外，这项工作将为将来的研究铺平道路该系统参与大脑功能和疾病。