Genetic Regulation of the Ethanol/Anxiety Interaction: Neurobiological Mechanisms

乙醇/焦虑相互作用的基因调控：神经生物学机制

基本信息

批准号：
7688881
负责人：
BRIAN A MCCOOL
金额：
$ 1.8万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-05 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7688881
关键词：
Acute Adaptive Behaviors Address Adolescent Adult Alcohol abuse Alcohol withdrawal syndrome Alcohols Allopregnanolone Amygdaloid structure Animal Model Anti-Anxiety Agents Anxiety Architecture Behavior Behavioral Bioinformatics Biological Blood Boutos Brain region Breathing Chronic Chronic stress Complex Computer Simulation Data Databases Dopamine End Point Environment Ethanol Exhibits Foundations Fright Funding Future GABA Receptor Gene Expression Gene Expression Profile Generations Genes Genetic Housing Hydrocortisone Inbred Mouse Inbred Strain Inbred Strains Mice Individual Knockout Mice Laboratories Lateral Macaca Measures Messenger RNA Metabolism Modeling Molecular Monkeys Mouse Strains Mus Neurobiology Neurons Neurotransmitters Not Defined Numbers Pattern Pharmacology Phenotype Physiological Play Principal Investigator Procedures Rattus Recording of previous events Regulation Relative (related person)Research Research Personnel Resources Rest Rewards Role Self Administration Sentinel Severities Social Hierarchy Social isolation Standards of Weights and Measures Steroids Stress Structure of terminal stria nuclei of preoptic region Synapses Synaptic Transmission System Testing Time Tissue Sample Transgenic Organisms Withdrawal Work alcohol behavior alcohol effect alcohol exposure alcohol research alcohol response base behavior influence drinking environmental stressor experience gene environment interaction genetic trans acting element innovation insight interest juvenile animal neurobiological mechanism neurophysiology preference presynaptic programs receptor receptor expression receptor function research study response synaptic function

项目摘要

DESCRIPTION (provided by applicant): Stress-alcohol interactions clearly contribute to consequences of alcohol abuse, including increased anxiety during withdrawal from chronic exposure. However, little is known about the biological basis for these complex relationships. Animal models are likely to make significant contributions to our understanding of these issues. For example, comparisons between genetically-defined inbred mouse strains would provide a unique opportunity to understand the relevant genetic mechanisms regulating adaptations to chronic ethanol and withdrawal. Likewise, subjecting these strains to defined environmental stressors would yield important insight into the 'experience-dependent' mechanisms that influence the behavioral consequences (e.g. anxiety) related to this alcohol exposure. Although numerous brain regions are known to govern fear/anxiety behaviors, the lateral/basolateral amygdala is a central component of 'anxiety' circuitry. Because amygdale GABAA receptors regulate anxiety behavior, ethanol- and stress-dependent adaptations in this system may be important for the behavioral consequences related to their interactions. Our preliminary results suggest that the C57BL/6 (B6) and DBA/2J (D2) inbred mouse lines differ markedly in their basal anxiety as well as the functional and molecular expression of GABAA receptors expressed in lateral/basolateral amygdale (BLA). Preliminary findings also indicate that chronic ethanol exposure differentially alters the function of BLA GABAA receptors expressed by B6 and D2 neurons. Therefore, this application will specifically test the central hypothesis that lateral/basolateral amygdala GABAA receptor expression/function is a phenotypic marker for BLA GABAA the relative anxiety-related liability of stress-alcohol interactions. We will test our central hypothesis using housing manipulations and chronic ethanol inhalation to investigate the interactions between environmental stressors, amygdala GABAergic expression/function, and the neurobiological consequences of withdrawal. We will specifically integrate behavioral, molecular biological, and electrophysiological experimental approaches to better understand the stress-ethanol interactions related to anxiety-like behaviors. Ultimately, we hope our approach will allow us to eventually characterize the specific genetic mechanisms regulating the molecular and neurophysiological adaptations associated with these relationships.

描述（由申请人提供）：压力 - 酒精相互作用显然会导致酗酒的后果，包括在长期暴露期间戒断期间增加焦虑症。但是，对于这些复杂关系的生物学基础知之甚少。动物模型可能会为我们对这些问题的理解做出重大贡献。例如，遗传定义的近交小鼠菌株之间的比较将提供一个独特的机会，以了解调节对慢性乙醇和戒断适应的相关遗传机制。同样，将这些菌株承受定义的环境压力源将产生对影响与这种酒精暴露有关的行为后果（例如焦虑）的“经验依赖性”机制的重要见解。尽管已知许多大脑区域来控制恐惧/焦虑行为，但侧/基底外侧杏仁核是“焦虑”电路的核心组成部分。由于杏仁核GABAA受体调节焦虑行为，因此该系统中的乙醇和压力依赖性适应可能对与其相互作用相关的行为后果可能很重要。我们的初步结果表明，C57BL/6（B6）和DBA/2J（D2）近交小鼠系的基础焦虑以及在侧面/基底外侧杏仁核（BLA）中表达的GABAA受体的功能和分子表达明显不同。初步发现还表明，慢性乙醇暴露差异改变了B6和D2神经元表达的BLA GABAA受体的功能。因此，该应用将特别检验中心假设：侧/基底外侧杏仁核受体表达/功能是BLA GABAA的表型标记物是应激 - 酒精相互作用的相对焦虑相关责任。我们将使用住房操作和慢性乙醇吸入来检验我们的中心假设，以研究环境压力源，杏仁核GABA能表达/功能以及戒断的神经生物学后果之间的相互作用。我们将特别整合行为，分子生物学和电生理实验方法，以更好地了解与焦虑样行为相关的压力 - 乙醇相互作用。最终，我们希望我们的方法最终能够最终表征调节与这些关系相关的分子和神经生理适应的特定遗传机制。