Neural circuit mechanisms of stress-induced alcohol seeking behavior

项目摘要 酒精使用障碍（AUD）是寻求酒精治疗的人群中最常见的疾病之一。 治疗创伤后应激障碍（PTSD），一种神经精神应激和焦虑相关障碍 这通常是在经历创伤或压力性生活事件后发生的。许多PTSD患者倾向于使用 酒精以试图改善衰弱的症状。然而，反复过量饮酒 消费往往导致AUD的发展，似乎恶化PTSD症状。因此，我们认为， 迫切需要系统地研究神经生物学基础的相互作用， 这些疾病，以定制有效的治疗策略，以减少酒精滥用和依赖的创伤后应激障碍 患者 杏仁核是厌恶和食欲行为的关键神经基质。最近 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， 这些亚群似乎介导正或负效价编码。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 其反应性的敏感化。特别是，已经表明患有AUD和PTSD共病的患者 在出现厌恶/痛苦刺激和酒精时表现出杏仁核的高反应性 线索这些有趣的发现表明，杏仁核是一个关键的结构介导的相互作用 AUD和PTSD之间的关系;然而，杏仁核的分子，细胞和神经回路机制 AUD和PTSD合并症的功能障碍尚不清楚。 我们将采用Cre-driver小鼠线、光遗传神经回路操纵和 在体电生理记录技术检查：1）是否经历创伤性应激 改变神经元中特定Fear-Off（Dkk 3/Ntsr 2/Thy 1+）神经元亚群的神经元系综编码， 基底外侧杏仁核在酒精背景协会的形成过程中，和2）如果压力增强酒精- 情境关联是由杏仁核Thy 1 + 神经元投射和物质成瘾的中心结构-神经核（NAcc）， 可能导致酒精使用量的增加。 这些研究的结果将首次深入了解不同基因的关键作用。 杏仁核神经元亚群在应激诱导的酒精寻求行为中的作用结果也将 揭示了杏仁核如何与NAcc相互作用，导致酒精成瘾的发展。 最终，这些研究的结果可能为开发诊断和新的治疗方法提供新的方法。 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.