Extended amygdala mGlu8 receptor signaling in stress-reward interactions

项目摘要 暴露在慢性压力下与许多精神疾病有关，如创伤后应激障碍、抑郁症、 上瘾和焦虑，以及暴露在紧张的经历中，是导致吸毒的最常见原因之一 旧病复发。终纹床核(BNST)介导许多焦虑和应激反应， 驱动复发和物质使用障碍的成瘾循环特征。突触后Gi偶联 非去甲肾上腺素能ADRA2a+上GI-DREADD和α-2A型肾上腺素受体的GPCR型信号转导 神经元)足以增加神经元活性并驱动药物依赖行为，而药理学上 阻断或避免突触后受体激活可降低神经元活性和可卡因依赖 行为。Gi偶联的代谢性谷氨酸(MGlu)受体亚型8，与许多 精神疾病，如物质使用障碍，在ADRA2A+BNST人群中共同表达 细胞。针对肾上腺素能信号以防止复发的努力在很大程度上并不成功，突显出 需要创新的治疗靶点。有趣的是，系统激活mGlu8诱导CFOS表达，a 应激敏感脑区神经元活动的标志，提示mGlu8调节可能是一种手段 通过它来改变BNST的活性，以防止应激诱导的复发。在具体目标1中，我将开始调查 MGlu8信号对利用融合的解剖学和统计学方法测量BNST活性的影响 药理测绘策略。在具体目标2中，我将评估BNST mGlu8 KO对毛利率的影响 焦虑测量以及我们的可卡因条件性位置偏爱和恢复试验，以测试 该受体在驱动应激敏感行为方面的充分性。此外，我将分析由压力引起的 通过使用纤维光度法和活体光遗传学研究DCPG敏感神经元的活性。一起， 这些目的将检验我们的假设，即mGlu8积极调节支持恢复的活动 BNST神经元的数量和mGlu8信号在功能上是可卡因恢复所必需的。在……里面 这样做，我们希望找到新的治疗目标，将有助于减少压力的情况- 诱导复发并改善目前正在与药物使用作斗争的患者的治疗结果 精神错乱。

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.