Mechanisms and relevance of the ethanol-induced suppression of inhibitory signaling in the basolateral amygdala

乙醇诱导的基底外侧杏仁核抑制信号传导抑制的机制和相关性

• 批准号: 9370487
• 负责人: Megan E. Tipps
• 金额: $ 12.28万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2018-05-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9370487
• 关键词: Ablation; Abstinence; Adaptive Behaviors; Addictive Behavior; Advisory Committees; Agreement; Alcohol dependence; Alcohols; Amygdaloid structure; Behavior; Behavioral; Brain; Brain region; Cell Nucleus; Characteristics; Cognitive; Complex; Consensus; Consumption; Cues; Data; Development; Diagnosis; Disease; Dopamine; Drug usage; Electrophysiology (science); Ethanol; Exposure to; Future; G-substrate; GIRK3 subunit, G protein-coupled inwardly-rectifying potassium channel; GTP-Binding Proteins; Gene Expression; Glutamates; Goals; Lead; Learning; Longevity; Maintenance; Measures; Mediating; Memory; Mentorship; Modeling; Molecular; Molecular Target; Mus; Neurons; Nucleus Accumbens; Periodicity; Pharmaceutical Preparations; Physiological; Physiology; Play; Positioning Attribute; Process; Relapse; Research; Research Personnel; Research Training; Rewards; Role; Scanning; Signal Transduction; Slice; Stimulus; Structure; Substance abuse problem; Synaptic plasticity; Testing; Therapeutic; Therapeutic Intervention; Training; Viral; Work; addiction; alcohol abstinence; alcohol abuse therapy; alcohol exposure; alcoholism therapy; behavior measurement; classical conditioning; design; drug of abuse; hippocampal pyramidal neuron; improved; in vivo; insight; interdisciplinary approach; inward rectifier potassium channel; learned behavior; memory process; mouse model; neuroadaptation; neuronal excitability; neurotransmission; novel; preference; programs; response; reward processing

Project Summary There is an emerging consensus that addiction is a form of maladaptive learning, wherein exposure to drugs such as ethanol (EtOH) promotes continued drug use by altering the structure and/or function of learning- related brain regions. The premise of this proposal is that the identification of molecular and cellular mechanisms by which EtOH alters associative learning will clarify critical aspects of EtOH addiction and may lead to improved therapeutic approaches for the treatment of alcoholism. Recent work, including studies from the candidate, has suggested that EtOH may modulate associative learning via its effect on G protein-gated inwardly rectifying K+ (GIRK) channels. Preliminary data show that GIRK channels are expressed in the basolateral nucleus of the amygdala (BLA), a critical structure for associative learning, and that repeated in vivo EtOH exposure suppresses GIRK-dependent signaling in pyramidal/projection neurons in this region. This proposal will combine an array of interdisciplinary approaches to test the hypothesis that the EtOH-induced suppression of GIRK channel activity in BLA pyramidal neurons contributes to the complex effects of repeated EtOH exposure, including changes in reward signaling and behavior. In AIM 1, the candidate will utilize slice electrophysiology to probe the salient characteristics and underlying mechanisms of the EtOH-induced suppression of GIRK signaling. In AIM 2, the candidate will combine viral-mediated GIRK suppression with behavioral measures of preference and reward, as well as slice electrophysiology and fast scan cyclic voltammetry (FSCV), to assess the impact of GIRK suppression in the BLA on reward-related neurotransmission and behavior. This project will offer the opportunity for advanced research training that will assist the candidate in her future endeavors, including approaches to measuring excitatory neurotransmission and plasticity in brain slices, neuron-specific manipulation of gene expression, measuring dopamine release by fast-scan cyclic voltammetry (FSCV), and the use of voluntary EtOH consumption models in mice. Mentorship and training will be provided by Dr. Kevin Wickman and Dr. Anna Lee. Additional support for the project and the professional development of the candidate will come from Dr. Jeffery Weiner (Consultant), an expert in the effects of EtOH on amygdala physiology, and a local Advisory Committee composed of experts in addiction research with a strong track record of training independent investigators (Drs. Marilyn Carroll, Stan Thayer, and Robert Meisel). All facets of this proposal are designed to assist the candidate in achieving her goal of transitioning to an independent research position, where she intends to develop a research program that investigates the impact of EtOH across an interconnected network of regions involved in the learning processes that support addiction.

项目摘要 有一个新兴的共识，即成瘾是一种适应不良的学习形式，其中暴露于药物 例如乙醇（ETOH）通过改变学习的结构和/或功能来促进持续的药物使用 - 相关的大脑区域。该提议的前提是鉴定分子和细胞 ETOH改变关联学习将阐明EtoH成瘾的关键方面的机制，可能 导致改进的治疗酗酒方法。最近的工作，包括来自 候选人表明，ETOH可以通过其对G蛋白门控的影响来调节关联学习 向内纠正K+（GIRK）通道。初步数据表明，GIRK通道在 杏仁核（BLA）的基底核，这是一种关联学习的临界结构，并在 Vivo EtOH暴露抑制了该区域的锥体/投影神经元中的GIRK依赖性信号传导。这 提案将结合一系列跨学科方法，以检验EtOH诱导的假设 BLA锥体神经元中GIRK通道活性的抑制作用有助于重复的复杂作用 ETOH暴露，包括奖励信号和行为的变化。在AIM 1中，候选人将使用切片 电生理学以探测EtOH诱导的显着特征和潜在机制 抑制Girk信号。在AIM 2中，候选人将结合病毒介导的Girk抑制作用 偏好和奖励的行为度量，以及切片电生理学和快速扫描环状 伏安法（FSCV），以评估BLA中GIRK抑制对奖励相关的影响 神经传递和行为。该项目将为高级研究培训提供机会 协助候选人将来的努力，包括测量兴奋性神经传递的方法 和脑切片中的可塑性，神经元特异性的基因表达操作，测量多巴胺释放 快速扫描的循环伏安法（FSCV），以及在小鼠中使用自愿ETOH消耗模型。指导 培训将由Kevin Wickman博士和Anna Lee博士提供。对该项目的额外支持， 候选人的专业发展将来自Jeffery Weiner博士（顾问），专家 ETOH对杏仁核生理学的影响，以及由成瘾专家组成的当地咨询委员会 与培训独立研究人员的良好记录进行研究（玛丽莲·卡罗尔（Marilyn Carroll），斯坦·泰耶（Stan Thayer）， 还有罗伯特·迈塞尔（Robert Meisel））。该提案的所有方面旨在帮助候选人实现她的目标 过渡到独立的研究职位，她打算制定一个研究计划 研究ETOH对学习中涉及区域的互连网络的影响 支持成瘾的过程。