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 酒精使用障碍（AUD）可能是由情感效价严重失调引起的 大脑回路中的处理过程。反复发作的酗酒可以改变积极和消极的效价 加工，并导致增强的食欲驱动力，以寻求和饮酒，并出现 症状，分别。这项研究计划旨在了解反复酗酒 改变与基底外侧杏仁核（BLA）行为变化相关的神经编码和可塑性， 一个著名的价编码脑区，它的传入来自前岛皮层（aIC），一个核心区 用于内感受这些目标将通过酒精操作性自我- 管理范式，焦虑测量的行为测定，以及“在黑暗中饮酒” procedure.在这里，实验将在功能上和分子上识别aIC内的神经元群体， BLA回路参与饮酒，并确定反复酗酒如何影响这些 神经元和导致适应不良的情感行为，如增强酒精寻求和焦虑样 行为 在初步数据的支持下，我们的中心假设是，反复酗酒的差异 改变杏仁核神经元（Thy 1+）的活性，部分是通过突触可塑性， aIC-杏仁核投射，导致酒精相关的增强食欲和厌恶行为。瞄准一号 将使用体内钙成像和光遗传学方法来确定BLA价编码在 反复狂饮导致的行为可塑性在第二个目标中，我们计划研究突触 对持续性动机有贡献的BLA效价编码神经元的aIC传入的可塑性 反复酗酒后的酒精摄入量。这项工作将揭示 在aIC-BLA电路中的重叠、交叉或平行的价编码系统， 反复过量饮酒导致适应不良的情感行为。拟议 实验工作描绘了一个神经回路为导向的和高度翻译的调查audd相关的 症状