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

总结：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他们生命中的某个时刻受到影响。然而，这种增长 尽管投入了数十亿美元， 药物开发研究已经开始集中在神经过程介导的压力易感性作为一个 潜在的治疗目标;因此，内源性大麻素系统最近已成为一个中心的 压力反应、回避行为、恐惧泛化和厌恶学习过程的调节器，以及 因此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引起的回避，促进压力恢复力。在这里，我们的目标是了解 该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 暗示腹侧海马（vHIPP）-丘脑核（NAc）回路介导应激 易感性，我们收集的数据证实内源性大麻素调节vHIPP-NAc突触。在 在这个建议中，我们将把联合收割机接近/回避行为范例与光学记录工具（光纤）结合起来 光度法）和操纵（INTERSECT病毒方法）内源性大麻素信号传导，以阐明 回路特异性内源性大麻素信号在介导压力适应中的作用。总之，这个提议会给我 技术和理论培训，以回答有关行为的神经基础及其 压力引起的失调。在目标1中，我将描述什么样的刺激诱导 结合使用新型内源性大麻素传感器在vHIPP-NAc突触处的体内内源性大麻素释放 用纤维光度法这些研究允许时间动态和活动依赖机制介导 压力诱导的内源性大麻素释放，在体内，第一次。在目标2中，我将定义特定于细胞类型的 使用全细胞膜片钳电生理学的vHIPP-NAc回路的内源性大麻素调节和 转基因报告小鼠，以识别离散的神经元群体;这将提供细胞类型特异性评估 内源性大麻素是如何调节NAc的神经活动的。最后，在目标3中，我将有选择地删除组件 vHIPP-NAc回路的内源性大麻素系统。这将使我们能够确定充分性和必要性， 内源性大麻素信号在压力反应回避行为的各个方面。通过这些小说 研究结果，我们将了解介导功能失调的压力反应的机制，以及 内源性大麻素系统可能是开发更特异性药物治疗精神疾病的治疗靶点。 紊乱

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.