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

基本信息

批准号：
10386602
负责人：
Veronika Kondev
金额：
$ 3.2万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10386602
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 (Brain)Interneurons Knockout Mice Learning Life Light 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 Recovery Regulation Reporter Research Rodent Role Slice Somatostatin Specificity Stimulus Stress Symptoms Synapses Testing Therapeutic Therapeutic Effect Time Training Transgenic Organisms Translations Triad Acrylic Resin United States Ventral Striatum Viral analog anxiety-like behavior arm avoidance behavior base 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 circuit neuromechanism novel optogenetics patch clamp prevent relating to nervous system response restraint stress sensor stress reactivity stress related disorder stress resilience stressor targeted treatment therapeutic target tool

项目摘要

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，一生中某个时候影响了近三分之一的美国人。但是，这个成长尽管投资了数十亿美元，但有限的有效药物治疗遇到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治疗剂的潜在靶标；因此，内源性大麻素系统最近成为中央压力反应性，回避行为，恐惧概括和厌恶学习过程的调节者因此，是未来药物开发的引人注目的候选人。内源性大麻素信号的增强具有被证明可以减少压力引起的回避并促进压力弹性。在这里，我们旨在了解神经回路驱动内源性大麻素介导的有害压力效应的保护。最近的证据已牵涉到腹侧海马（VHIPP）-Nucleus ac伏犬（NAC）电路中的介导应力敏感性，我们收集了数据证实内源性大麻素可以调节VHIPP-NAC突触。在该建议，我们将结合方法/避免行为范例，并将其录制的光学工具（光纤）结合起来（光纤光度法）和操纵（相交病毒方法）内源性大麻素信号传导，以阐明介导应力适应中的电路特异性内源性大麻素信号传导。在一起，这个建议会给我技术和理论培训，以回答有关行为神经及其神经基础的复杂问题压力引起的疾病失调。在AIM 1中，我将表征什么样的刺激内源性大麻素在Vhipp-NAC突触中使用新型内源性大麻素传感器在Vhipp-NAC突触中释放纤维光度法。这些研究允许介导时间动力学和活动依赖性机制应力诱导的内源性大麻素释放，在体内首次释放。在AIM 2中，我将定义特定于细胞类型内源性大麻素对VHIPP-NAC电路的调节，使用全细胞贴片夹电生理学和转基因记者小鼠识别离散的神经元群体；这将提供细胞类型的特定评估内源性大麻素如何介导NAC中的神经活性。最后，在AIM 3中，我将有选择地删除组件来自Vhipp-NAC电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应力反应避免行为的各个方面。通过这些小说调查结果，我们将了解介导功能失调的压力响应的机制以及如何内源性大麻素系统可能会提出一个治疗靶标，以开发更特定的药物来治疗精神病学疾病。