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: 10656228
• 负责人: Bretton Nabit
• 金额: $ 3.25万
• 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/10656228
• 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; Fiber; Fright; G Protein-Coupled Receptor Signaling; Genes; Genetic; Genetic Recombination; Glutamates; Goals; Guanfacine; Image; Immunohistochemistry; Label; Maps; Measures; Mediating; Mental Depression; Mental disorders; Metabotropic Glutamate Receptors; Monitor; Mus; Mutation; Neurons; Neurosciences; Pathologic; Pathway interactions; Patient-Focused Outcomes; Pharmaceutical Preparations; 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; Technology; Testing; Training; Transcript; Treatment outcome; Work; addiction; biological adaptation to stress; brain dysfunction; cocaine related behaviors; conditioned place preference; designer receptors exclusively activated by designer drugs; drug relapse; experimental study; genetic approach; improved; in vivo; innovation; insight; neural; new therapeutic target; novel; optogenetics; pharmacologic; postsynaptic; prevent; rational design; receptor; recruit; relapse prevention; 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 在诸如PTSD，抑郁症， 成瘾和焦虑以及对压力体验的暴露是毒品最常见的原因之一 复发。脊柱末端（BNST）的床核介导了许多焦虑和应力反应，这些反应是 驱动继电器和物质使用障碍的附加周期特征。突触后的GI耦合 BNST中的GPCR信号传导（通过gi-dreadds和α2a肾上腺受体在非甲状腺素能ADRA2A+上 神经元足以增加神经元活性并驱动药物依赖性行为，而药物 封锁或避免突触后受体激活降低神经元活性和可卡因依赖性 行为。 GI偶联的代谢型谷氨酸（MGLU）受体亚型8，与许多 诸如药物使用障碍之类的精神病疾病在ADRA2A+ BNST的这一人群中共同表达 细胞。针对肾上腺信号的努力以防止继电器的努力在很大程度上没有成功，突显了 需要创新的治疗靶标。有趣的是，全身MGLU8激活诱导CFOS表达，A 神经元活性的标记，在压力敏感的大脑区域中，表明MGLU8调制可能是一种手段 通过这些改变双方活性以防止压力引起的缓解。在特定目标1中，我将开始调查 使用收敛解剖学和 药理映射策略。在特定目标2中，我将评估BNST MGLU8 KO对总的影响 焦虑措施以及在我们可卡因条件的地方偏好和恢复测定法 该受体在驱动压力敏感行为方面的足够。此外，我将分析应力诱导的 通过使用纤维光度法和体内光遗传学，对DCPG敏感的神经元的活性。一起， 这些目的将研究我们的假设，即MGLU8积极调节了亲临时的活动 BNST神经元的种群和MGLU8信号在可卡因恢复功能上是必需的。在 这样做，我们希望确定新型的治疗靶标，以减少压力的实例 - 诱导继电器并改善目前正在使用药物苦苦挣扎的患者的治疗结果 疾病。