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.

本项目在目前资助期内的目标是采用基因工程小鼠品系。