Insula Circuitry and Compulsive Alcohol Drinking

 描述（由申请人提供）：该提案旨在研究驱动强迫性饮酒的机制。强迫性酒精摄入的特征是即使酒精伴随着不良的社会、法律的和身体后果也会持续饮酒，这种厌恶性摄入是治疗酒精使用障碍（AUD）的主要障碍。因此，我们率先使用大鼠模型来识别大脑回路，这些回路是强迫性摄入的基础，即使酒精与令人厌恶的刺激相结合，饮酒也会继续。然而，人们对促进强迫性成瘾的大脑回路知之甚少，特别是控制对厌恶做出反应的大脑区域的作用。人类和动物研究表明，前额叶（aINS）和相关脑区与药物和酒精滥用有关。在人类中，酒精线索激活aINS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的因果作用。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，aINS通过输入到丘脑核，促进强迫性饮酒。考虑到厌恶抵抗反应在强迫性摄入过程中的重要性，有趣的是，aINS也调节厌恶相关的行为，并投射到强大的压力和厌恶调节器，中央杏仁核（CeA）和蓝斑/臂旁区（LCPB）。CeA介导对厌恶刺激的条件和非条件反应，以及过量的酒精摄入。LCPB通过激活去甲肾上腺素受体（NAdrR）介导应激反应，NAdrR促进啮齿动物和人类过度饮酒。鉴于这些途径对厌恶反应的重要性，我们假设aINS激活CeA和LCPB，以及随后激活NAdRs，促进强迫性饮酒。此外，aINS谷氨酸受体可能是激活这些aINS投射所必需的，并且基于我们的初步结果，我们进一步假设aINS内的钙渗透性AMPA型谷氨酸受体（CP-AMPAR）介导强迫样饮酒。我们将使用强大的光遗传学和化学遗传学技术结合受体药理学、投射追踪方法和离体电生理学来测试这些假设，以在功能上分离和定义饮酒期间aINS-CeA和aINS-LCPB输入的作用。目标1和目标2A将确定aINS投射到CeA或LCPB是否促进强迫性酒精摄入，对饮用无奎宁酒精或糖精±奎宁的影响很小。目标2B和目标3将 研究可能促进强迫性饮酒的受体机制。目的3将确定在强迫性饮酒过程中皮质NAdrRs的作用。目的3将检查不同的aINS细胞是否投射到CeA与LCPB，以及CP-AMPAR如何影响这些aINS神经元的离体活性。我们的研究将提供重要而新颖的信息，说明与厌恶相关的大脑回路是如何被用来驱动强迫性饮酒的。

 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.