INIA: Stress, Anxiety of Alcohol Abuse

INIA：酗酒带来的压力和焦虑

• 批准号: 6623613
• 负责人: KATHLEEN A GRANT
• 金额: $ 62万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6623613
• 关键词: alcoholic beverage consumption; alcoholism /alcohol abuse; amygdala; anxiety; behavioral /social science research tag; behavioral genetics; biological models; biomedical facility; cooperative study; gene environment interaction; health science research analysis /evaluation; information dissemination; interdisciplinary collaboration; meeting /conference /symposium; neural plasticity; neural transmission; neurotransmitter receptor; neurotransmitters; organized financing; stress; training

DESCRIPTION (provided by applicant): The Administrative Core Component will make sure that all aspects of the INIA consortium work at an optimal level. The core will serve as an identifiable center for entire INIA consortium. This core will be responsible for decisions about research directions, including review of component progress and inclusion and exclusion of investigators. The core will also ensure the proper flow of information between the different consortium components, and flow of information to the larger research community in collaboration with the Bioinformatics Core. The duties of this core will also include organizing and financing all INIA committee meetings, retreats and research presentations. The administrative core will also track the INIA consortium finances and assist in budget planning for the different research components and cores. Stress contributes to excessive drinking and alcoholism, but the molecular and cellular mechanisms that underlie alcohol-stress interactions are not well understood. The brain circuitry involved in coordinating and producing responses to stress is known, and includes the extended amygdala (amygdala, bed nucleus of the stria terminalis and nucleus accumbens (NAc)], the hippocampus (HPC), the prefrontal cortex (PFC) and the hypothalamus. There is also considerable evidence implicating the neurotransmitters glutamate, GABA and serotonin (5-HT) in stress-induced neurophysiological responses in these brain regions. Alcohol effects on synaptic transmission in stress-related brain regions have not been characterized in much detail. Furthermore the role of the aforementioned neurotransmitters in these responses has not been examined. INIA component I will focus on examining synaptic transmission in amygdala, HPC, NAc and PFC in wild-type mice and mice with gene-targeted knockouts of the GABAAbeta3. Delta and gamma2 subunits, the NMDAR2A subunit, theGluRA subunit, the5-HTIA receptor and SERT. Similar experiments will be performed in selected randomly mutagenized mice identified in INIA component 3, and mice from selected BxD recombinant strains identified in INIA component 4. Brain slice preparations and isolated neurons will be examined from all of these groups of mice following chronic alcohol exposure and withdrawal. chronic alcohol self-administration and stress-induced reinstatement of alcohol drinking. Excitatory and inhibitory synaptic transmission will be measured using field potential and intracellular recording in brain slices containing the regions of interest. Synaptic plasticity will also be examined in brain slices. Acutely isolated neurons will be used to examine changes in neurotransmitter receptor function, and single-cell MRNA profiling will be used to identify neuronal subtypes. Serotonin release and reuptake will be examined in brain slices and synaptosomal preparations from the brain regions of interest. These studies will provide crucial information about neuroadaptive changes in synaptic transmission and plasticity induced by ETOH and stress in brain regions implicated in stress responses. We will also gather information about the role of particular neurotransmitter receptors and transporters in these neuroadaptive changes. Findings from this project " Ill be compared to data gathered in INIA components 2, 3 and 4 to generate more integrated information about the neuroadaptive changes related to alcohol-stress interactions. In future studies we will use mice developed by the Knockout Mouse Core and in component 7 in studies such as those proposed at present. Information gained in this component will be compared with that gained in the primate studies proposed in component 5, and will be shared with the larger research community on the INIA web page with the help of the Bioinformatics Core. It is predicted that information from this project will contribute to a better under- standing of the mechanisms underlying stress-alcohol interactions that may lead to better therapies for treating excessive drinking and alcoholism.

描述(由申请人提供)： 行政核心部分将确保INIA的所有方面 财团的工作处于最佳水平。核心将作为一个可识别的 整个INIA财团的中心。这个核心将负责决策 关于研究方向，包括审查组成部分的进展和 纳入和排除调查人员。核心还将确保适当的 不同联合体组件之间的信息流，以及 信息提供给更大的研究社区，与 生物信息学核心。该核心的职责还将包括组织和 资助INIA委员会的所有会议、务虚会和研究报告。 行政核心还将跟踪INIA财团的财务和 协助制定不同研究部分和核心的预算计划。 压力会导致过度饮酒和酗酒，但分子和 酒精应激相互作用的细胞机制并不是很好 明白了。参与协调和生产的大脑回路 对压力的反应是已知的，包括延伸的杏仁核(杏仁核， 终纹床核和伏隔核(NAC)]， 海马区(HPC)、前额叶皮质(PFC)和下丘脑。的确有 还有相当多的证据表明，神经递质谷氨酸、GABA 和5-羟色胺(5-羟色胺)在应激诱导的神经生理反应中的作用 大脑区域。酒精对应激相关突触传递的影响 大脑区域还没有得到太多细节的描述。此外，这一角色 在这些反应中，上述神经递质中的 检查过了。INIA组件I将重点检查突触传递 野生型小鼠和基因打靶小鼠杏仁核、HPC、NAC和PFC 加巴贝塔的淘汰赛3。Delta和Gamma2亚基，NMDAR2A亚基， GluRA亚单位、5-HTIA受体和SERT。类似的实验将会是 在INIA成分中确定的选定随机突变小鼠中执行 3，和INIA组分鉴定的BxD重组菌株中的小鼠 4.脑切片准备和分离的神经元将从所有 这些组小鼠在慢性酒精暴露和戒酒后。 慢性酒精自我给药和应激诱导的脑功能恢复 酗酒。兴奋性和抑制性突触传递将是 利用脑片的场电位和细胞内记录进行测量 包含感兴趣的区域。突触的可塑性也将被检查。 在脑片上。急性分离的神经元将被用来检查 神经递质受体功能，以及单细胞信使核糖核酸图谱 用于识别神经元亚型。5-羟色胺的释放和再摄取将 在脑片和大脑区域的突触小体准备中进行检查 感兴趣的人。这些研究将为以下方面提供关键信息 乙醇诱导突触传递和可塑性的神经适应性改变 以及大脑中与应激反应有关的区域的应激。我们还将 收集有关特定神经递质受体和 这些神经适应性变化中的转运蛋白。这个项目的发现是“生病” 与INIA组件2、3和4中收集的数据进行比较，以生成更多 有关神经适应性变化的综合信息与 酒精压力的相互作用。在未来的研究中，我们将使用由 在类似建议的研究中的基因敲除鼠标核心和组件7中 目前。在这个部分中获得的信息将与那个部分进行比较 在组成部分5中提议的灵长类研究中获得，并将与 在INIA网页上更大的研究社区在 生物信息学核心。据预测，来自该项目的信息将 有助于更好地了解潜在的机制 压力-酒精相互作用可能导致更好的治疗方法 酗酒和酗酒。