Insula Circuitry and Compulsive Alcohol Drinking

 描述(申请人提供)：这项提案旨在研究像饮酒一样的强迫症的驱动机制。强迫性酒精摄入的特点是即使在酒精伴随着不良的社会、法律和身体后果的情况下仍持续饮酒，这种抵抗厌恶的摄入是治疗酒精使用障碍(AUD)的主要障碍。因此，我们率先使用老鼠模型来识别大脑回路，这些回路构成了强迫性摄入的基础，在这种情况下，即使酒精与令人厌恶的刺激相结合，饮酒仍会继续。然而，关于促进强迫性成瘾的大脑回路，特别是控制对厌恶反应的大脑区域的作用，人们知之甚少。人类和动物的研究表明，前脑岛(ANS)和相互连接的大脑区域与滥用药物和酒精有关。在人类中，酒精线索激活了An回路，活动水平可以预测未来的摄入量，这表明在驱动成瘾行为中起到了因果作用。为数不多的动物研究支持这些人类数据，我们最近的工作发现，通过伏隔核的输入，ANS促进了类似强迫症的饮酒。考虑到在强迫性摄取过程中抗厌恶反应的重要性，有趣的是，ANS还调节与厌恶相关的行为，并投射到压力和厌恶的强大调节器-杏仁中央核(CEA)和蓝斑/臂旁区(LCPB)。CEA调节对厌恶刺激的条件性和非条件性反应，以及过量饮酒。LCPB通过激活去甲肾上腺素受体(NAdrRs)来调节应激反应，NAdrRs促进啮齿动物和人类的过量饮酒。鉴于这些反应厌恶的途径的重要性，我们假设CEA和LCPB的激活以及随后的NAdr的激活促进了类似强迫的饮酒。此外，AINS谷氨酸受体可能是激活这些ANS投射的关键，根据我们的初步结果，我们进一步假设，AINS内的钙通透性AMPA型谷氨酸受体(CP-AMPAR)介导了强迫性饮酒。我们将使用强大的光遗传学和化学遗传学技术测试这些假说，结合受体药理学、投射追踪方法和体外电生理学，从功能上分离和确定饮酒过程中INS-CEA和ANS-LCPB输入的作用。目标1和目标2A将确定AIN对CEA或LCPB的投射是否促进强迫样酒精摄入，而对不含奎宁的酒精或糖精±奎宁的饮用几乎没有影响。目标2B和目标3将 研究可以促进强迫性饮酒的受体机制。目标3将确定皮质NAdrRs在类似强迫症饮酒过程中的作用。目的3将研究不同的ANS细胞是否投射到CEA和LCPB，以及CP-AMPAR如何在体外影响这些ANS神经元的活动。我们的研究将提供重要而新颖的信息，说明厌恶相关的大脑回路是如何被用来驱动像饮酒一样的强迫性行为的。

 DESCRIPTION (provided by applicant): This proposal is aimed at studying mechanisms that drive compulsion-like alcohol drinking. Compulsive alcohol intake is characterized by drinking that persists even when alcohol is paired with adverse social, legal and physical consequences, and this aversion-resistant intake is a major obstacle to treating alcohol use disorders (AUDs). Thus, we have pioneered the use of rat models to identify brain circuits that underlie compulsion-like intake, where drinking continues even when alcohol is paired with aversive stimuli. However, little is known about brain circuits that promote compulsive addiction, especially the role of brain areas that control responding to aversion. Human and animal studies implicate anterior insula (aINS) and connected brain regions in abuse of drugs and alcohol. In humans, alcohol-cues activate aINS circuitry, and the level of activity can predict future intake, suggesting a causal role in driving addictive behaviors. The few animal studies support these human data, and our recent work found that the aINS, through inputs to nucleus accumbens, promotes compulsion-like drinking. Given the importance of aversion-resistant responding during compulsion-like intake, it is interesting that the aINS also regulates aversion-related behavior, and projects to powerful regulators of stress and aversion, the central amygdala (CeA) and locus coeruleus/parabrachial areas (LCPB). The CeA mediates conditioned and unconditioned responses to aversive stimuli, as well as excessive alcohol intake. The LCPB mediates stress responses through activation of noradrenaline receptors (NAdrRs), and NAdrRs promote excessive drinking in rodents and humans. Given the importance of these pathways for responding to aversion, we hypothesize that aINS activation of CeA and LCPB, and subsequent activation of NAdRs, promote compulsion-like drinking. In addition, aINS glutamate receptors are likely to be essential for activating these aINS projections, and, based on our preliminary results, we further hypothesize that calcium-permeable AMPA-type glutamate receptors (CP- AMPARs) within the aINS mediate compulsion-like drinking. We will test these hypotheses using powerful opto- and chemo-genetics techniques to functionally isolate and define the role of aINS-CeA and aINS- LCPB inputs during alcohol drinking, in combination with receptor pharmacology, projection tracing methods and ex vivo electrophysiology. Aim 1 and Aim 2A will determine whether aINS projections to CeA or LCPB promote compulsion-like alcohol intake, with little effect on drinking of quinine-free alcohol or saccharin±quinine. Aim 2B and Aim 3 will examine receptor mechanisms that could promote compulsion-like drinking. Aim 3 will determine the role of cortical NAdrRs during compulsion-like drinking. Aim 3 will examine whether different aINS cells project to CeA versus LCPB, and how CP-AMPARs impact the activity of these aINS neurons ex vivo. Our studies will provide important and novel information about how aversion-related brain circuits become coopted to drive compulsion-like alcohol drinking.