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

内源性大麻素对腹侧海马-伏隔核回路的调节及其对应激介导行为的影响

• 批准号: 10551206
• 负责人: Veronika Kondev
• 金额: $ 1.12万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2023-05-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10551206
• 关键词: 2-arachidonylglycerol; Affect; Affective; American; Anxiety; Anxiety Disorders; Automobile Driving; Behavior; Behavioral Paradigm; Biosensor; Brain; CNR1 gene; Cells; Characteristics; Chronic; Clinical Research; Complex; Corticotropin-Releasing Hormone; Data; Development; Disease; Electrophysiology (science); Emotional; Endocannabinoids; Equilibrium; Event; Exposure to; Fiber; Fright; Future; G-Protein-Coupled Receptors; Generalized Anxiety Disorder; Glutamates; Hippocampus; Interneurons; Investments; Knockout Mice; Learning; Life; Mediating; Mental disorders; Modeling; Molecular; Motivation; Mus; Neurons; Nucleus Accumbens; Odors; Optics; Output; Parvalbumins; Patients; Pharmaceutical Preparations; Pharmacotherapy; Photometry; Physiological; Play; Population; Post-Traumatic Stress Disorders; Predisposition; Process; Prosencephalon; Protocols documentation; Psychopathology; Public Health; Regulation; Reporter Genes; Research; Rodent; Role; Slice; Somatostatin; Sorting; Specificity; Stimulus; Stress; Symptoms; Synapses; Testing; Therapeutic; Therapeutic Effect; Time; Training; Transgenic Organisms; Translations; United States; Ventral Striatum; Viral; analog; anxiety-like behavior; arm; avoidance behavior; biological adaptation to stress; cell type; conditional knockout; drug development; endocannabinoid signaling; endogenous cannabinoid system; experimental study; fear memory; genetic approach; improved; in vivo; insight; neural; neural circuit; neuromechanism; novel; optogenetics; patch clamp; prevent; response; restraint stress; sensor; stress reactivity; stress reduction; stress related disorder; stress resilience; stressor; sustained recovery; targeted treatment; therapeutic target; tool

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.

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人生的某个阶段受到影响。然而，这种不断增长的 尽管投入了数十亿美元，但有效的药物疗法却有限地解决了公共卫生问题 药物开发。研究已经开始关注介导压力敏感性的神经过程 潜在的治疗靶标；因此，内源性大麻素系统最近已成为一个中心 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，它是未来药物开发的一个引人注目的候选者。内源性大麻素信号传导的增强 已被证明可以减少压力引起的回避并提高压力恢复能力。在这里，我们的目的是了解 哪些神经回路驱动内源性大麻素介导的有害压力效应的保护。最近的证据 表明腹侧海马（vHIPP）-伏隔核（NAc）回路参与调节压力 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 在这个提案中，我们将结合接近/回避行为范例，与用于记录的光学工具（光纤） 光度测定）和操纵（INTERSECT 病毒方法）内源性大麻素信号传导以阐明 介导应激适应的电路特异性内源性大麻素信号传导。总之，这个提案将给我带来 回答有关行为及其神经基础的复杂问题的技术和理论培训 压力引起的疾病的失调。在目标 1 中，我将描述什么样的刺激会引起 使用新型内源性大麻素传感器结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 与光纤光度测定。这些研究允许时间动态和活动依赖机制介导 首次在体内应激诱导的内源性大麻素释放。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对 vHIPP-NAc 电路进行内源性大麻素调节 转基因报告小鼠识别离散的神经元群体；这将提供细胞类型特异性评估 内源性大麻素如何介导 NAc 中的神经活动。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。这将使我们能够定义充分性和必要性 内源性大麻素信号传导在压力反应性回避行为的各个方面的研究。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如何 内源性大麻素系统可能成为开发更特异性药物来治疗精神疾病的治疗靶点 失调。