Insula-amygdala circuits in alcohol abuse

项目总结 酒精使用障碍(AUD)可能是由情感价态的严重失调引起的 在大脑回路中进行处理。反复酗酒可以改变正价和负价 加工并导致寻求和饮酒的食欲增强，并出现 令人厌恶的症状。这项研究建议旨在了解反复酗酒是如何 改变与杏仁基底外侧核(BLA)行为变化相关的神经编码和可塑性 已知的价编码脑区及其核心区--前岛叶皮质的传入 用来进行内部感知。这些目标将使用酒精操作者自身的组合来经验性地实现 管理范式，焦虑测量的行为分析，以及“在黑暗中喝酒” 程序。在这里，实验将从功能和分子上识别AIC内的神经元群体- 参与饮酒的BLA回路，并确定反复酗酒如何影响这些 并导致不适应的情感行为，如酗酒和类焦虑 行为。 在初步数据的支持下，我们的中心假设是反复酗酒不同于 改变杏仁核价编码神经元(Thy1+)的活性，部分通过突触的可塑性 AIC-杏仁核投射，导致酒精相关的食欲和厌恶行为增强。目标一 将使用体内钙成像和光遗传学方法来确定BLA价码在 反复酗酒导致的行为可塑性。在第二个目标中，我们计划研究突触 AIC传入BLA价编码神经元的可塑性与持续性动机 在反复酗酒后的酒精摄入量。这项工作将揭示 AIC-BLA电路中的重叠、交叉或并行价编码系统 反复过量饮酒导致的不良适应情感行为的发展。建议数 实验工作描绘了一项面向神经回路和高度翻译的AUD相关研究 症状。

PROJECT SUMMARY Alcohol use disorder (AUD) may result from profound dysregulations of affective valence processing in brain circuits. Repeated episodes of binge drinking can alter positive and negative valence processing and result in enhanced appetitive drives to seek and drink alcohol and the emergence of aversive symptoms, respectively. This research proposal aims to understand how repeated binge drinking alters neural coding and plasticity correlated with behavioral changes in the basolateral amygdala (BLA), a well-known brain area for valence coding, and its afferents from the anterior insular cortex (aIC), a core area for interoception. These aims will be empirically pursued using a combination of an alcohol operant self- administration paradigm, behavioral assays for anxiety measurement, and a “drinking-in-the-dark” procedure. Here, experiments will functionally and molecularly identify neuronal populations within the aIC- BLA circuits that participate in alcohol drinking and determine how repeated binge drinking affects these neurons and leads to maladaptive affective behavior, such as enhanced alcohol seeking and anxiety-like behavior. Supported by preliminary data, our central hypothesis is that repeated binge drinking differentially alters the activity of valence coding amygdala neurons (Thy1+), in part, through the synaptic plasticity of aIC-amygdala projections, resulting in alcohol-related enhanced appetitive and aversive behavior. Aim one will use in vivo calcium imaging and optogenetic approaches to determine the role of BLA valence coding in repeated binge drinking-induced behavioral plasticity. In the second aim, we plan to investigate synaptic plasticity in the aIC afferents to the BLA valance coding neurons that contribute to the persistent motivation for alcohol intake after repeated episodes of binge alcohol drinking. This work will uncover changes in overlapping, intersecting or parallel valence coding systems in the aIC-BLA circuits that are critical for the development of maladaptive affective behaviors by repeated excessive alcohol drinking. The proposed experimental work portrays a neural circuit-oriented and highly translational investigation of AUD-associated symptoms.