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

• 批准号: 7215942
• 负责人: BRIAN A MCCOOL
• 金额: $ 19.92万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 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/7215942
• 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

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酒精滥用的后果，包括在从慢性暴露中戒断时增加焦虑。然而，人们对这些复杂关系的生物学基础知之甚少。动物模型可能会对我们理解这些问题做出重大贡献。例如，遗传定义的近交系小鼠品系之间的比较将提供一个独特的机会，以了解相关的遗传机制调节适应慢性乙醇和戒断。同样，将这些菌株置于定义的环境压力下，将对影响与酒精暴露相关的行为后果（例如焦虑）的“经验依赖”机制产生重要的见解。虽然已知许多大脑区域控制恐惧/焦虑行为，但外侧/基底外侧杏仁核是“焦虑”回路的中心组成部分。由于杏仁核GABAA受体调节焦虑行为，乙醇和压力依赖性适应在这个系统中可能是重要的行为后果相关的相互作用。我们的初步研究结果表明，C57 BL/6（B6）和DBA/2 J（D2）近交系小鼠的基础焦虑，以及在外侧/基底外侧杏仁核（BLA）中表达的GABAA受体的功能和分子表达显着不同。初步研究结果还表明，慢性乙醇暴露差异改变B6和D2神经元表达的BLA GABAA受体的功能。因此，本申请将专门检验中心假设，即外侧/基底外侧杏仁核GABAA受体表达/功能是BLA GABAA的表型标志物，即压力-酒精相互作用的相对焦虑相关倾向。我们将使用房屋操作和慢性乙醇吸入来检验我们的中心假设，以研究环境应激源、杏仁核GABA能表达/功能和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将使我们能够最终表征调节与这些关系相关的分子和神经生理学适应的特定遗传机制。