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 有一个正在形成的共识，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- 相关脑区这一建议的前提是，分子和细胞的鉴定 EtOH改变联想学习的机制将阐明EtOH成瘾的关键方面， 从而改进治疗酒精中毒的方法。最近的工作，包括来自 研究人员认为，乙醇可能通过影响G蛋白门控的神经元， 内向整流钾通道（GIRK）。初步数据显示，GIRK通道表达于 杏仁核的基底外侧核（BLA），一个关键的结构，为联想学习，并重复在 体内EtOH暴露抑制该区域锥体/投射神经元中的GIRK依赖性信号传导。这 一项提案将联合收割机结合一系列跨学科的方法来测试这一假设，即乙醇诱导的 BLA锥体神经元GIRK通道活性的抑制有助于重复的GIRK通道的复杂效应。 EtOH暴露，包括奖励信号和行为的变化。在AIM 1中，候选人将利用切片 电生理学，以探索EtOH诱导的 抑制GIRK信号传导。在AIM 2中，候选药物将结合联合收割机病毒介导的GIRK抑制和 偏好和奖励的行为测量，以及切片电生理和快速扫描循环 伏安法（FSCV），以评估BLA中GIRK抑制对奖励相关的 神经传递和行为。该项目将提供高级研究培训的机会， 协助候选人在她未来的努力，包括方法来测量兴奋性神经传递 脑切片的可塑性，基因表达的神经元特异性操作， 快速扫描循环伏安法（FSCV），以及在小鼠中使用自愿EtOH消耗模型。指导 培训将由凯文·威克曼博士和安娜·李博士提供。为项目提供更多支持， 候选人的专业发展将来自Jeffery Weiner博士（顾问），他是 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 具有良好的培训独立调查人员记录的研究（Marilyn卡罗尔博士，Stan Thayer， Robert Meisel）。本建议书的所有方面都旨在帮助候选人实现其目标， 过渡到一个独立的研究职位，在那里她打算开发一个研究项目， 研究EtOH对参与学习的区域的互联网络的影响 支持成瘾的过程。