Physiology and function of amygdalo-cortical endocannabinoid signaling

杏仁核皮质内源性大麻素信号传导的生理学和功能

• 批准号: 9395056
• 负责人: David J. Marcus
• 金额: $ 2.87万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9395056
• 关键词: 2-arachidonylglycerol; Agonist; Amygdaloid structure; Animal Behavior; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Behavioral; Behavioral Model; Behavioral Paradigm; Brain region; Buffers; CNR1 gene; CNR2 gene; Cannabinoids; Cells; Chemosensitization; Clinical; Cognitive; Complex; Corticosterone; Coupling; Data; Development; Dissection; Down-Regulation; Electrophysiology (science); Endocannabinoids; Enzymes; Etiology; Functional disorder; Gene Transfer; Generalized Anxiety Disorder; Genetic; Glutamates; Human; Hyperactive behavior; Immunohistochemistry; Impairment; Investigation; Knockout Mice; Label; Laboratories; Learning; Ligand Binding; Ligands; Link; Measures; Medial; Mediating; Mental Depression; Mental disorders; Mood Disorders; Morphology; Mus; Neural Pathways; Neurons; Neurotransmitters; Nodal; Operative Surgical Procedures; Output; Pathologic; Pathology; Pathway interactions; Patients; Pharmacology; Phenotype; Physiological; Physiology; Play; Post-Traumatic Stress Disorders; Predisposition; Prefrontal Cortex; Presynaptic Terminals; Probability; Production; Psychopathology; Recruitment Activity; Regulation; Risk Factors; Rodent Model; Role; Signal Transduction; Slice; Specificity; Stress; Structure; Synapses; System; Techniques; Technology; Testing; Training; Translating; Viral; anxiety-like behavior; cell cortex; conditioned fear; coping; depressive symptoms; emotional behavior; endocannabinoid signaling; endogenous cannabinoid system; experimental study; generalized anxiety; in vivo; intersectionality; knockout animal; knockout gene; lipoprotein lipase; negative emotional state; neural circuit; neuroadaptation; neurochemistry; neuropathology; neuropsychiatric disorder; neuroregulation; neurotransmission; neurotransmitter release; novel; optogenetics; pre-clinical; presynaptic; relating to nervous system; resilience; response; skills; stress resilience; therapeutic target

PROJECT SUMMARY Stress exposure is ubiquitous risk factor for the development of negative emotional states and neuropsychiatric disorders such as anxiety, depression, and post-traumatic stress disorder (PTSD). However, a causal link between stress-induced neuropathologies and resultant pathological behavioral states remains elusive. There is significant evidence to suggest that stress induces a wide variety of morphological and neurochemical adaptions in the prelimbic component of the medial prefrontal cortex (plPFC), a key nodal structure that is highly implicated in the top down regulation of emotional behavior. Indeed, susceptibility to the depressive effects of traumatic stress exposure is correlated with synaptic potentiation within this region. Interestingly, the anxiolytic effects of cannabinoid compounds are primarily mediated by activation of CB1 receptors on glutamatergic axon terminals within the mPFC. Stress itself dynamically alters endocannabinoid (eCB) signaling within the mPFC, as stress exposure induces a dramatic increase in levels of the EC ligand 2- AG in the mPFC, which is purported to represent an adaptive coping response that buffers against the negative physiological effects induced by stress exposure. However, it is completely unknown what neural pathways are modulated by eCBs to elicit this buffering effect on stress-induced behavioral pathologies. In our studies, we are looking at the projections to the plPFC from the Basolateral Amygdala (BLA), a brain region that has been highly implicated in the pathophysiology of affective disorders and PTSD. The BLA sends glutamatergic projections to the plPFC, and also receives reciprocal glutamatergic input from the plPFC. Using optogenetic projection targeting techniques combined with retrograde labeling of plPFC cells, we gain both specificity of input to the plPFC but also specificity of output of plPFC cells projecting to the BLA. In order to understand the role that eCB signaling plays in buffering against stress induced psychopathologies in the BLA- plPFC circuit, we have developed a behavioral model that separates mice into stress-susceptible and stress- resilient groups. The current proposal will aim to answer two critical open questions: Does eCB signaling in the BLA-plPFC circuit represent a resiliency factor that blunts stress-induced behavioral pathology? Can we experimentally induce stress susceptibility by impairing eCB signaling within BLA-plPFC reciprocal circuits? Using state of the art viral mediated gene transfer approaches and conditional gene knockout animals, we aim to understand the role of eCB signaling within the BLA-plPFC circuits in conferring resiliency to stress. These experiments represent the first investigation of eCB signaling in a reciprocal glutamatergic circuit. This will enhance are understanding of the pathophysiology of anxiety and mood disorders, as well as reveal a putative target for the anxiolytic effects of cannabinoid agonists. This proposal also constitutes a rigorous technical training plan, in which I will learn and refine skills related to stereotaxic surgery, whole-cell electrophysiology, immunohistochemistry, and animal behavior.

项目摘要 压力暴露是发展消极情绪状态的普遍危险因素， 神经精神障碍，如焦虑、抑郁和创伤后应激障碍（PTSD）。然而，在这方面， 压力诱发的神经病理学和由此产生的病理行为状态之间的因果关系仍然存在 难以捉摸。有显著的证据表明，胁迫诱导了多种形态和 内侧前额叶皮层（plPFC）的前边缘成分中的神经化学适应，这是一个关键的节点。 这种结构与情绪行为的自上而下调节密切相关。事实上， 创伤应激暴露的抑郁效应与该区域内的突触增强相关。 有趣的是，大麻素化合物的抗焦虑作用主要通过激活CB 1介导。 mPFC内神经元轴突终末上的受体。压力本身会动态地改变内源性大麻素 (eCB)mPFC内的信号传导，因为应激暴露诱导EC配体2- AG在mPFC中，这是一种自适应应对反应， 压力暴露引起的负面生理效应。然而，我们完全不知道什么神经系统 通过eCB调节这些通路以引起对应激诱导的行为病理学的这种缓冲作用。在我们 研究中，我们正在研究从基底外侧杏仁核（BLA）到前额叶皮层的投射， 与情感障碍和创伤后应激障碍的病理生理学密切相关。BLA发送 在前额叶皮层，神经元向前额叶皮层投射，并且还从前额叶皮层接收相互的神经元输入。使用 光遗传学投射靶向技术结合pIPFC细胞的逆行标记，我们获得了 这不仅是对plPFC的输入的特异性，而且是投射到BLA的plPFC细胞的输出的特异性。为了 了解eCB信号传导在缓冲BLA中压力诱导的精神病理学中的作用， plPFC电路，我们已经开发了一种行为模型，将小鼠分为应激敏感和应激敏感， 弹性群体。目前的提案旨在回答两个关键的开放问题： BLA-plPFC回路代表了一种弹性因素，它能减弱压力引起行为病理学？我们能 通过在BLA-plPFC互易电路中损害eCB信号传导来实验诱导应激易感性？ 使用最先进的病毒介导的基因转移方法和条件性基因敲除动物，我们的目标是 了解BLA-plPFC回路中eCB信号传导在赋予压力弹性中的作用。这些 这些实验代表了在相互的放热回路中eCB信号传导的第一次研究。这将 增强了对焦虑和情绪障碍的病理生理学的理解，并揭示了一个假定的 大麻素激动剂抗焦虑作用的靶点。该提案还构成了一项严格的技术 培训计划，我将学习和完善与立体定位手术，全细胞电生理学， 免疫组织化学和动物行为。