Endocannabinoid regulation of ventral hippocampus-nucleus accumbens circuit and consequences for stress-mediated behaviors

摘要：创伤后应激障碍和其他焦虑症是最常见的精神疾病 在美国，近三分之一的美国人在生活中的某个时候受到影响。然而，这一增长 尽管投入了数十亿美元，但对公共卫生的关注遇到的有效药物疗法有限 药物开发。研究已经开始集中在调节应激敏感性的神经过程作为一种 潜在的治疗靶点；因此，内源性大麻素系统最近已成为 压力反应、回避行为、恐惧概括和厌恶学习过程的调节因子，以及 因此，它是未来药物开发的一个引人注目的候选者。内源性大麻素信号的增强 已被证明可以减少压力诱导的回避，并提高压力恢复能力。在这里，我们的目标是了解 神经回路驱动内源性大麻素介导的有害应激效应的保护。最近的证据 已证实腹侧海马区(VHIPP)-伏隔核(NAC)回路参与了应激的调节 易感性，我们已经收集数据证实，内源性大麻素调节vHIPP-NAC突触。在……里面 在这项提议中，我们将结合接近/回避行为范例和用于记录的光学工具(光纤 光度法)和操纵(交叉病毒方法)内源性大麻素信号来阐明 调节压力适应的电路特异性内源性大麻素信号。总之，这项提议将给我带来 训练回答有关行为的神经基础及其复杂问题的技术和理论训练 应激性精神障碍中的调节失调。在目标1中，我将描述什么类型的刺激会引起 联合使用新型内源性大麻素传感器在vHIPP-NAC突触体内释放内源性大麻素 用纤维光度法。这些研究允许时间动力学和依赖于活动的机制调节 应激诱导的内源性大麻素释放，这是第一次在体内。在目标2中，我将定义特定单元格类型 用全细胞膜片钳电生理和电生理方法研究内源性大麻素对vHIPP-NAC通路的调节作用 转基因报告鼠识别离散神经元群体；这将提供细胞类型特异性评估 内源性大麻素如何调节NAC的神经活动。最后，在目标3中，我将有选择地删除组件 来自vHIPP-NAC回路的内源性大麻素系统。这将使我们能够界定充分性和必要性 内源性大麻素信号在应激反应回避行为的各个方面。通过这些小说 发现，我们将了解调节功能障碍应激反应的机制，以及如何 内源性大麻素系统可能提供一个治疗靶点，以开发更特异的药物来治疗精神病 精神错乱。

Summary: Post-traumatic stress disorder and other anxiety disorders are the most common mental illnesses in the United States, affecting nearly one third of Americans at some point in their life. However, this growing public health concern is met with limited efficacious pharmacotherapies despite billions of dollars invested in drug development. Research has begun to focus on the neural processes mediating stress susceptibility as a potential target for therapeutics; as such, the endocannabinoid system has recently emerged as a central regulator of stress responsivity, avoidance behaviors, fear generalization, and aversive learning processes, and is thus a compelling candidate for future drug development. Augmentation of endocannabinoid signaling has been shown to reduce stress-induced avoidance and promote stress resilience. Here, we aim to understand which neural circuits drive endocannabinoid-mediated protection of deleterious stress effects. Recent evidence has implicated the ventral hippocampus (vHIPP)-nucleus accumbens (NAc) circuit in mediating stress susceptibility, and we have collected data confirming that endocannabinoids regulate vHIPP-NAc synapses. In this proposal, we will combine approach/avoidance behavioral paradigms, with optical tools for recording (fiber photometry) and manipulating (INTERSECT viral approach) endocannabinoid signaling to elucidate the role of circuit-specific endocannabinoid signaling in mediating stress adaptations. Together, this proposal will give me the technical and theoretical training to answer complex questions about the neural basis of behavior and its dysregulation in stress-induced disorders. In Aim 1, I will characterize what sort of stimuli induce endocannabinoid release in vivo at vHIPP-NAc synapses using a novel endocannabinoid sensor in conjunction with fiber photometry. These studies allow for temporal dynamics and activity-dependent mechanism mediating stress-induced endocannabinoid release, in vivo, for the first time. In Aim 2, I will define cell-type specific endocannabinoid regulation of vHIPP-NAc circuitry using whole cell patch clamp electrophysiology and transgenic reporter mice to identify discrete neuronal populations; this will provide cell-type specific assessment of how endocannabinoids mediate neural activity in the NAc. Finally, in Aim 3, I will selectively delete components of the endocannabinoid system from vHIPP-NAc circuit. This will allow us to define the sufficiency and necessity of endocannabinoid signaling in various aspects of stress-responsive avoidance behaviors. Through these novel findings, we will learn about the mechanisms that mediate dysfunctional stress responding and how the endocannabinoid system may present a therapeutic target to develop more specific drugs to treat psychiatric disorders.