Genetic Regulation of the Ethanol/Anxiety Interaction: Neurobiological Mechanisms

描述（由申请人提供）：压力与酒精的相互作用明显会导致酒精滥用的后果，包括慢性酒精暴露后戒断过程中焦虑的增加。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对这些问题的理解做出重大贡献。例如，比较遗传定义的近交小鼠品系将提供一个独特的机会来了解调节对慢性乙醇和戒断的适应的相关遗传机制。同样，将这些菌株置于定义的环境压力源下，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”机制产生重要见解。虽然已知有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”回路的核心组成部分。由于杏仁核GABAA受体调节焦虑行为，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很重要。我们的初步结果表明，C57BL/6 （B6）和DBA/2J （D2）近交系小鼠的基础焦虑以及表达于外侧/基底外侧杏仁核（BLA）的GABAA受体的功能和分子表达存在显著差异。初步研究结果还表明，慢性乙醇暴露会不同程度地改变B6和D2神经元表达的BLA - GABAA受体的功能。因此，本应用程序将专门测试核心假设，即外侧/基底外侧杏仁核GABAA受体表达/功能是BLA - GABAA的表型标记物，即压力-酒精相互作用的相对焦虑相关倾向。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，以研究环境应激源，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学实验方法，以更好地理解与焦虑样行为相关的应激-乙醇相互作用。最终，我们希望我们的方法将使我们最终能够描述与这些关系相关的调节分子和神经生理适应的特定遗传机制。

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.