Insula-amygdala circuits in alcohol abuse

酒精滥用中的岛杏仁核回路

• 批准号: 10735851
• 负责人: Junghyup Suh
• 金额: $ 51.63万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735851
• 关键词: Abstinence; Affect; Affective; Alcohol abuse; Alcohol consumption; Alcohols; Amygdaloid structure; Animal Model; Animals; Anterior; Anxiety; Area; Behavior; Behavioral; Behavioral Assay; Brain; Clinical; Code; Consummatory Behavior; Darkness; Data; Desire for food; Development; Disease model; Electrophysiology (science); Etiology; Functional disorder; Goals; Insula of Reil; Interoception; Knowledge; Lead; Measurement; Mediating; Mental Depression; Modeling; Molecular; Motivation; Mus; Negative Valence; Neuronal Plasticity; Neurons; Outcome; Pathologic; Patients; Population; Positive Valence; Procedures; Recording of previous events; Research; Research Proposals; Risk Factors; Role; Self Administration; Stimulus; Structure; Symptoms; Synapses; Synaptic plasticity; Transgenic Mice; Translational Research; Work; alcohol behavior; alcohol seeking behavior; alcohol use disorder; anxiety-like behavior; approach behavior; associated symptom; behavioral plasticity; binge drinking; cell type; drinking; effective therapy; experience; experimental study; in vivo calcium imaging; neural; neural circuit; neural correlate; neuroimaging; novel; optogenetics; preclinical study

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.

项目摘要 饮酒障碍（AUD）可能是由于情感价值的严重失调而引起的 在脑电路中处理。暴饮暴食的重复发作会改变正价和负面价 加工并导致食欲增强以寻求和喝酒以及出现 厌恶症状。该研究建议旨在了解如何反复饮酒 改变神经编码和可塑性与基底外侧杏仁核（BLA）的行为变化相关，A 众所周知的价值编码的大脑区域及其来自前岛皮层（AIC）的传入，一个核心区域 互认为。这些目标将通过酒精操作者自我迫切地追求 管理范式，动画测量的行为分析和“黑暗中饮酒” 程序。在这里，实验将在功能和分子上识别AIC-内的神经元种群 参加饮酒并确定重复饮酒的bla圈子如何影响这些 神经元并导致不良适应性情感行为，例如寻求酒精和焦虑症 行为。 在初步数据的支持下，我们的中心假设是重复饮酒不同 通过合成可塑性的合成可塑性，改变了杏仁核神经元（THY1+）的活性 AIC-Amygdala项目导致与酒精有关的增强的食欲和厌恶行为。瞄准一个 将使用体内钙成像和光遗传学方法来确定BLA价编码在 反复的暴饮暴食引起的行为可塑性。在第二个目标中，我们计划调查突触 AIC的可塑性在BLA价值编码神经元中有助于持续动机 在饮酒之后，饮酒次数是在饮酒后饮酒。这项工作将发现变化 AIC-BLA电路中的重叠，相交或平行价编码系统对 通过反复饮酒来发展不良适应性情感行为。提议 实验工作描绘了一个面向神经电路的和高度翻译的AUD相关研究 症状。