INIA: Stress, Anxiety of Alcohol Abuse

INIA：酗酒带来的压力和焦虑

• 批准号: 6841159
• 负责人: KATHLEEN A GRANT
• 金额: $ 48.67万
• 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 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6841159
• 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 的各个方面 联合体工作处于最佳水平。核心将作为一个可识别的 整个 INIA 联盟的中心。该核心将负责决策 关于研究方向，包括组件进展回顾和 纳入和排除调查人员。核心还将确保适当的 不同联盟成员之间的信息流以及 与更大的研究界合作提供信息 生物信息学核心。该核心的职责还包括组织和 资助所有 INIA 委员会会议、务虚会和研究报告。 行政核心还将跟踪 INIA 财团的财务状况和 协助不同研究部分和核心的预算规划。 压力会导致过度饮酒和酗酒，但分子和 酒精与应激相互作用的细胞机制尚不完善 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，包括扩展的杏仁核（amygdala， 终纹床核和伏隔核 (NAc)]， 海马体 (HPC)、前额皮质 (PFC) 和下丘脑。有 还有大量证据表明神经递质谷氨酸、GABA 和血清素（5-HT）在应激诱导的神经生理反应中的作用 大脑区域。酒精对压力相关突触传递的影响 大脑区域尚未得到详细描述。此外角色 上述神经递质在这些反应中的作用尚未被证实 检查了。 INIA 部分我将重点检查突触传递 野生型小鼠和基因靶向小鼠的杏仁核、HPC、NAc 和 PFC GABAAbeta3 的敲除。 Delta 和 gamma2 亚基、NMDAR2A 亚基、 GluRA 亚基、5-HTIA 受体和 SERT。类似的实验将会 在 INIA 组件中确定的选定随机诱变小鼠中进行 3、INIA成分中鉴定出的选定BxD重组品系的小鼠 4. 将从所有部位检查脑切片制剂和分离的神经元。 这些小鼠长期接触酒精并戒断后。 慢性酒精自我管理和压力诱导的恢复 饮酒。兴奋性和抑制性突触传递将 使用脑切片中的场电位和细胞内记录进行测量 包含感兴趣的区域。还将检查突触可塑性 在脑切片中。急性分离的神经元将用于检查 神经递质受体功能和单细胞 mRNA 分析将 用于识别神经元亚型。血清素的释放和再摄取将 在大脑区域的脑切片和突触体制剂中进行检查 的兴趣。这些研究将提供有关以下方面的重要信息： 乙醇诱导的突触传递和可塑性的神经适应性变化 以及与压力反应有关的大脑区域的压力。我们还将 收集有关特定神经递质受体作用的信息以及 这些神经适应性变化中的转运蛋白。该项目的调查结果“Ill 与 INIA 组件 2、3 和 4 中收集的数据进行比较，以生成更多信息 有关神经适应性变化的综合信息 酒精与压力的相互作用。在未来的研究中，我们将使用由 敲除小鼠核心和在研究中的第 7 部分，例如那些提出的研究 现在。在此组件中获得的信息将与该组件中获得的信息进行比较 在第 5 部分中提出的灵长类动物研究中获得的结果，并将与 在 INIA 网页上的更大的研究社区的帮助下 生物信息学核心。预计该项目的信息将 有助于更好地理解其背后的机制 压力与酒精的相互作用可能会带来更好的治疗方法 过度饮酒和酗酒。