Ethanol Mechanisms in GABAAR Gene Targeted Mice

GABAAR 基因靶向小鼠的乙醇机制

• 批准号: 8839369
• 负责人: Gregg E. Homanics
• 金额: $ 46.37万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-04-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8839369
• 关键词: Acute; Adult; Affect; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholism; Amygdaloid structure; Award; Behavior; Behavioral; Boxing; Brain; Brain-Derived Neurotrophic Factor; Breeding; Cells; Chronic; DNA Methylation; Development; Diet; Dopamine; Epigenetic Process; Ethanol; Ethanol dependence; Fathers; Female; Fright; Funding; Gene Expression; Gene Targeting; Generations; Genetic; Genetically Engineered Mouse; Germ Cells; Goals; Grant; Hippocampus (Brain); Individual; Instruction; Life Stress; Light; Measures; Mediating; Medical; Methodology; Methods; MicroRNAs; Modeling; Molecular; Mus; N-Methyl-D-Aspartate Receptors; Neurobiology; Neurons; Noise; Nucleus Accumbens; Paternal Exposure; Phase; Phenotype; Physiologic pulse; Population; Procedures; Progress Reports; Rattus; Recording of previous events; Regulation; Rodent Model; Role; Signal Transduction; Societies; Sperm Maturation; Stress; Synaptic Transmission; Synaptic plasticity; addiction; alcohol behavior; alcohol effect; alcohol exposure; alcohol sensitivity; alcohol use disorder; anxiety-like behavior; conditioned fear; critical period; drinking; drinking behavior; effective therapy; histone modification; in vivo; male; neural correlate; neurobiological mechanism; neurophysiology; next generation; novel; offspring; optogenetics; preference; programs; receptor function; research study; resilience; response; socioeconomics; sperm cell; transgenerational epigenetic inheritance; treatment strategy; vapor

The aims of this project for the currently funded period employed genetically engineered mouse lines. The overarching goal of these studies was to elucidate neurobiological mechanisms that contribute to an increased vulnerability to alcohol use disorders, with a focus on both hippocampal/amygdala GABAergic synaptic transmission (Aims 1-2) and epigenetics (Aim 3). As noted in earlier progress reports, some methodological challenges were encountered in re-establishing the breeding colonies of global and conditional Kl mice. Because of the delays in establishing the needed mouse lines, Aims 1&2 will continue essentially as originally described into the extension phase. Studies of the epigenetic effects of ethanol (Aim 3) will continue to focus on characterizing the effects of ethanol on histone modifications in mice following acute and chronic ethanol exposure and following ethanol withdrawal. The provocative discovery by the PI of transgenerational alterations in ethanol-induced behaviors and drinking following paternal preconception ethanol exposure has provided a need to significantly expand the experimental focus of this grant in an exciting new direction. Our results suggest that an individual's ethanol phenotype is dictated in part by his father's history of ethanol exposure prior to conceiving that individual. Remarkably, these transgenerational effects of ethanol appear to only affect male offspring. These exciting observations suggest that ethanol is an epimutagen (i.e., it alters the epigenetic program) that impacts germ cells in an enduring fashion. To further investigate the hypothesis that an individual's drinking and neurobiological sensitivity to ethanol are due in part to parental preconception ethanol exposure, we will (1) characterize the model in greater detail, (2) undertake studies to reveal the mechanism(s) that mediate these effects, (3) examine if these effects represent true transgenerational epigenetic inheritance, (4) develop a rat model of paternal preconception ethanol exposure, and (5) conduct neurobiological studies to better understand the phenotype. RELEVANCE (See instructions): EtOH addiction remains an imposing medical and socio-economic concern for our society. Elucidating the molecular and neurophysiological substrates that underlie EtOH addiction and the consequences of paternal preconception ethanol exposure will facilitate the development of more effective treatment strategies for alcoholism.

该项目对于当前资助的时期的目的是采用基因工程的小鼠线。 这些研究的总体目标是阐明有助于有助于的神经生物学机制 增加了酒精使用障碍的脆弱性，重点是海马/杏仁核Gabaergic 突触传播（AIMS 1-2）和表观遗传学（AIM 3）。正如较早的进度报告中指出的那样，有些 在重新建立全球繁殖菌落和 有条件的KL小鼠。由于建立所需的鼠标线的延迟，目标1和2将继续 本质上是最初描述的扩展阶段。研究乙醇的表观遗传作用（目标 3）将继续专注于表征乙醇对随后小鼠组蛋白修饰的影响 急性和慢性乙醇暴露，并在退出乙醇后。 PI对乙醇引起的行为的转世变化的挑衅性发现和 父亲先入后的饮酒乙醇暴露已经提供了显着扩展的需求 这笔赠款的实验重点是令人兴奋的新方向。我们的结果表明一个人的乙醇 表型部分取决于他父亲的乙醇暴露史，然后才考虑该人。 值得注意的是，这些乙醇的转世代作用似乎仅影响男性后代。这些令人兴奋 观察结果表明，乙醇是影响细菌的表观遗传学计划（即它改变表观遗传程序） 细胞以持久的方式。进一步研究一个人的饮酒和 神经生物学对乙醇的敏感性部分归因于父母的乙醇暴露，我们将（1） 更详细地表征模型，（2）进行研究以揭示介导这些的机制 效果，（3）检查这些效果是否代表真正的转世表观遗传遗传，（4）发展大鼠 父亲先入乙醇暴露的模型，（5）进行神经生物学研究以更好 了解表型。 相关性（请参阅说明）： Etoh成瘾仍然是我们社会的医学和社会经济关注。阐明 基于EtOH成瘾的基础的分子和神经生理底物以及父亲的后果 先选的乙醇暴露将促进开发更有效的治疗策略 酗酒。