Neural circuit mechanisms of stress-induced alcohol seeking behavior

项目总结 酒精使用障碍(AUD)是在寻求治疗的人中最常见的疾病之一 创伤后应激障碍(PTSD)的治疗，这是一种神经精神应激和焦虑相关障碍 这通常发生在经历了创伤性或有压力的生活事件之后。许多创伤后应激障碍患者倾向于使用 饮酒，试图改善虚弱的症状。然而，反复过量饮酒 消费往往会导致AUD的发展，似乎会加剧PTSD症状。因此， 迫切需要对相互作用的神经生物学基础进行系统研究。 这些障碍旨在制定有效的治疗策略，以减少创伤后应激障碍患者的酒精滥用和依赖 病人。 杏仁核是厌恶和食欲行为的关键神经底物。近期 对小鼠的研究表明，杏仁核内不同的神经元亚群是不同的 负责激活和抑制恐惧记忆。此外，不同的合奏活动来自 这些亚群似乎调节了正价或负价编码。杏仁核也直接 受到各种急性和慢性应激源以及成瘾物质的影响，这可能导致 对其反应性的敏化。特别是，已有研究表明，患有AUD和PTSD的患者 杏仁核在出现厌恶/痛苦刺激和酒精时表现出高反应性 暗示。这些有趣的发现表明，杏仁核是调节相互作用的关键结构。 在AUD和PTSD之间；然而，杏仁核背后的分子、细胞和神经回路机制 AUD和创伤后应激障碍共病的功能障碍尚不清楚。 我们将采用CRE驱动的小鼠品系、光遗传神经电路操作和 在体电生理记录技术检测：1)是否经历创伤性应激 改变特定恐惧(Dkk3/Ntsr2/Thy1)神经元亚群中的神经元集合编码 在酒精背景联系形成过程中的杏仁基底外侧核，以及2)如果压力增强的酒精- 上下文关联是由杏仁核Thy1之间功能相互作用的变化所介导的 神经元投射和伏隔核(NAcc)-物质成瘾的中心结构- 可能因此导致酒精使用的升级。 这些研究的结果将提供对DISTINCT的关键作用的第一次洞察 应激诱导的酒精寻求行为中杏仁核神经元的亚群。结果也将是 阐明了杏仁核如何与NAcc相互作用导致酒精成瘾的发展。 最终，这些研究的发现可能会为开发诊断学和新奇的 对AUD和PTSD患者的治疗干预。

PROJECT SUMMARY Alcohol use disorder (AUD) is one of the most co-occurring disorders among people seeking treatment for post-traumatic stress disorder (PTSD), a neuropsychiatric stress and anxiety-related disorder that often develops after experiencing traumatic or stressful life events. Many PTSD patients tend to use alcohol in an attempt to ameliorate the debilitating symptoms. However, repeated excessive alcohol consumption often leads to the development of an AUD that appears to worsen PTSD symptoms. Therefore, there is a critical need for systemic studies on the neurobiological underpinnings of the interactions between these disorders to tailor effective therapeutic strategies to reduce alcohol abuse and dependence in PTSD patients. The amygdala is a critical neural substrate of both aversive and appetitive behaviors. Recent studies in mice have indicated that distinct subpopulations of neurons within the amygdala are differentially responsible for the activation and inhibition of fear memory. In addition, divergent ensemble activity from these subpopulations seems to mediate positive or negative valence coding. The amygdala is also directly affected by a variety of acute and chronic stressors as well as addictive substances, which can lead to sensitization of its reactivity. Particularly, it has been shown that patients with comorbid AUD and PTSD exhibit hyper-reactivity of the amygdala upon presentations of both aversive/distressful stimuli and alcohol cues. These intriguing findings suggest that the amygdala is a key structure mediating the interactions between AUD and PTSD; however, molecular, cellular and neural circuit mechanisms underlying amygdala dysfunction in AUD and PTSD comorbidity are not well understood. We will employ a combination of a Cre-driver mouse line, optogenetic neural circuit manipulation, and in vivo electrophysiological recording techniques to examine: 1) whether the experience of traumatic stress alter the neuronal ensemble code in a specific Fear-Off (Dkk3/Ntsr2/Thy1+) neuronal subpopulation in the basolateral amygdala during the formation of alcohol-context associations, and 2) if stress-enhanced alcohol- context associations are mediated by changes in functional interactions between the amygdala Thy1+ neuronal projections and the nucleus accumbens (NAcc) - a central structure of substance addiction - which can consequently lead to the escalated alcohol use. The findings of these studies will provide the first insight into the crucial roles of distinct subpopulations of amygdala neurons in stress-induced alcohol seeking behavior. The results will also shed light on how the amygdala interacts with the NAcc to lead to the development of alcohol addiction. Ultimately, the findings of these studies may provide new ways for developing diagnostics and novel therapeutic interventions for AUD and PTSD patients.