Extended amygdala mGlu8 receptor signaling in stress-reward interactions

压力-奖励相互作用中杏仁核 mGlu8 受体信号传导的扩展

• 批准号: 10440273
• 负责人: Bretton Nabit
• 金额: $ 3.15万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10440273
• 关键词: ADRA2A gene; Abate; Address; Adrenergic Agents; Agonist; Alleles; Amygdaloid structure; Anatomy; Animals; Anxiety; Automobile Driving; Behavior; Behavioral; Behavioral Model; Biological Assay; Brain; Brain region; Calcium; Cell Nucleus; Cells; Characteristics; Chronic stress; Cocaine; Coupled; Data; Development; Drug Interactions; Exposure to; Extinction (Psychology); Fiber; Fright; G Protein-Coupled Receptor Signaling; Genes; Genetic; Genetic Recombination; Glutamates; Goals; Guanfacine; Image; Immunohistochemistry; Label; Lead; Measures; Mediating; Mental Depression; Mental disorders; Metabotropic Glutamate Receptors; Monitor; Mus; Mutation; Neurons; Neurosciences; Pathologic; Pathway interactions; Patient-Focused Outcomes; Pharmaceutical Preparations; Pharmacology; Photometry; Population; Post-Traumatic Stress Disorders; Process; Property; Public Health; Publishing; Receptor Activation; Receptor Signaling; Relapse; Reporting; Rewards; Rodent; Role; Series; Signal Transduction; Slice; Stress; Stressful Event; Structure; Structure of terminal stria nuclei of preoptic region; Substance Use Disorder; Synapses; Synaptic Receptors; Technology; Testing; Training; Transcript; Treatment outcome; Work; addiction; base; biological adaptation to stress; brain dysfunction; conditioned place preference; designer receptors exclusively activated by designer drugs; drug relapse; experimental study; genetic approach; improved; in vivo; innovation; insight; new therapeutic target; novel; optogenetics; prevent; rational design; receptor; recruit; relating to nervous system; response; stressor; substance use treatment; therapeutic target; tool

Project Summary Exposure to chronic stress has been implicated in numerous psychiatric conditions such as PTSD, depression, addiction and anxiety, and exposure to stressful experiences are one of the most common causes of drug relapse. The Bed Nucleus of the Stria Terminalis (BNST) mediates many anxiety- and stress-responses that drives relapse and the addictive cycle characteristic of substance use disorders. Post-synaptic Gi-coupled GPCR signaling in the BNST (via Gi-DREADDs and α2A adrenoreceptors on non-noradrenergic Adra2a+ neurons) is sufficient to increase neuronal activity and drive drug-dependent behaviors, while pharmacological blockade or avoidance of post-synaptic receptor activation decreased neuron activity and cocaine-dependent behavior. The Gi-coupled metabotropic glutamate (mGlu) receptor subtype 8, implicated in numerous psychiatric conditions such as substance use disorders, is co-expressed on this population of Adra2a+ BNST cells. Efforts targeting adrenergic signaling to prevent relapse have been largely unsuccessful, highlighting the need for innovative therapeutic targets. Interestingly, systemic mGlu8 activation induces cfos expression, a marker of neuron activity, in stress-sensitive brain regions, suggesting that mGlu8 modulation may be a means by which to alter BNST activity to prevent stress-induced relapse. In Specific Aim 1, I will begin to investigate the effects of mGlu8 signaling on measures of BNST activity using convergent anatomical and pharmacological mapping strategies. In Specific Aim 2, I will assess the effect of BNST mGlu8 KO on gross anxiety measures as well as in our cocaine conditioned place preference and reinstatement assays to test the sufficiency of this receptor in driving stress-sensitive behaviors. Furthermore, I will analyze the stress-induced activity of DCPG-sensitive neurons through the use of fiber photometry and in vivo optogenetics. Together, these aims will examine our hypothesis that mGlu8 positively modulates the activity of a pro-reinstatement population of BNST neurons and that mGlu8 signaling is functionally necessary for cocaine reinstatement. In doing so, we hope to identify novel therapeutic targets that will serve to decrease the instance of stress- induced relapse and improve the treatment outcomes of the patients currently struggling with substance use disorders.

项目摘要 暴露于慢性压力与许多精神疾病有关，如创伤后应激障碍，抑郁症， 成瘾和焦虑，以及暴露于压力的经验是最常见的原因之一，药物 复发终纹床核（BNST）介导许多焦虑和压力反应， 导致药物使用障碍的复发和成瘾循环。突触后Gi-偶联 BNST中的GPCR信号传导（通过Gi-DREADD和非去甲肾上腺素能Adra 2a+上的α2A肾上腺素受体） 神经元）足以增加神经元活性并驱动药物依赖性行为，而药理学上 阻断或避免突触后受体激活会降低神经元活动和可卡因依赖性 行为GI偶联代谢型谷氨酸（mGlu）受体亚型8涉及许多 精神疾病，如物质使用障碍，在Adra 2a + BNST的这一群体上共表达 细胞针对肾上腺素能信号传导以防止复发的努力在很大程度上是不成功的，这突出了 需要创新的治疗靶点。有趣的是，系统性mGlu 8激活诱导cfos表达， 神经元活动的标记，在压力敏感的大脑区域，这表明mGlu 8调节可能是一种手段， 从而改变BNST活性以防止应激诱导的复发。在具体目标1中，我将开始调查 mGlu 8信号传导对使用会聚解剖学方法测量BNST活性的影响， 药理学绘图策略。在具体目标2中，我将评估BNST mGlu 8 KO对大体 焦虑的措施，以及在我们的可卡因条件位置偏好和恢复测定，以测试 这种受体在驱动压力敏感行为中的充分性。此外，我将分析压力引起的 DCPG敏感神经元的活性，通过使用纤维光度法和体内光遗传学。我们一起努力， 这些目标将检验我们的假设，即mGlu 8积极调节促恢复的活性， 的BNST神经元的群体和mGlu 8信号传导是可卡因恢复功能所必需的。在 通过这样做，我们希望找到新的治疗靶点，以减少压力的发生- 诱导复发，并改善目前正在与物质使用作斗争的患者的治疗结果 紊乱