The role of intermittent binge ethanol, sex, and age on memory and CREB binding protein (CBP) expression

间歇性酗酒、性别和年龄对记忆和 CREB ​​结合蛋白 (CBP) 表达的影响

• 批准号: 10429943
• 负责人: Maria Alexis Bent
• 金额: $ 4.04万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-09 至 2024-06-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10429943
• 关键词: Abstinence; Address; Adolescence; Adolescent; Adult; Affect; Age; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohols; Behavior; Behavioral; Binding; Binding Proteins; Biological Assay; Blood; Brain; Brain region; CREBBP gene; Categories; Co-Immunoprecipitations; Cognition; Cognitive; Consumption; Coupled; Cyclic AMP Response Element; Cyclic AMP-Responsive DNA-Binding Protein; Development; Dose; Ethanol; Ethanol Metabolism; Female; Genes; Hippocampus (Brain); Hour; Human; Impairment; Knowledge; Lead; Life; Literature; Mass Spectrum Analysis; Mediating; Memory; Memory impairment; Methods; Microarray Analysis; Modification; Molecular; Molecular Target; Mus; Ontology; Pathway interactions; Pharmaceutical Preparations; Play; Prefrontal Cortex; Procedures; Proteins; Recovery; Research; Rewards; Risk-Taking; Rodent; Role; Sex Differences; Sexual Development; Short-Term Memory; Techniques; Testing; Therapeutic; Tissues; United States; Viral Vector; Virus; Western Blotting; Woman; adolescent brain development; adolescent drug abuse; age difference; alcohol effect; alcohol exposure; alcohol response; alcohol risk; alcohol sensitivity; cofactor; cognitive development; cohort; critical developmental period; drinking; drug of abuse; early drinking; epidemiology study; flexibility; histone acetyltransferase; long term memory; male; memory recognition; novel; object recognition; overexpression; protein expression; protein protein interaction; sex; spatial memory; therapeutic target; transcription factor; underage drinker; underage drinking

Summary In humans, adolescence is a critical developmental period marked by increased risk-taking behaviors, brain maturation, and cognitive development. Alcohol is highly consumed as an easy drug for most underage drinkers to obtain. The early age of drinking increases one’s risk of alcohol abuse and dependence later in life and can lead to lasting changes in protein expression and behavior. Adolescents have an altered sensitivity to alcohol likely due to their ongoing development, showing decreased sensitivity to the negative effects while having increased sensitivity to the rewarding effects as compared to adults. This difference in development may further promote alcohol drinking in adolescents, resulting in long-lasting changes that are more severe than in adults. Alcohol consumption has resulted in changes in protein expression and memory impairments observed in both adults and adolescents. Two known proteins involved in memory are cAMP-response element binding (CREB) protein and CREB binding protein (CBP). CBP is a histone acetyltransferase, coactivator/cofactor for many transcription factors including CREB, and necessary for both short term and long- term memory. The hippocampus and prefrontal cortex are two brain regions that undergo maturation changes during adolescence and play a role in memory. Sex is also known to play a role in memory and studies have suggested women may be more sensitive to the effects of alcohol. Given the lasting impact alcohol can have on behavior and the brain, further understanding the persistent effects of alcohol due to sex and age is important for the literature and further treatment possibilities. Our lab has shown ethanol to differentially impact memory 3 weeks after the last dose, with an observed deficit in the novel object recognition task in adolescent treated mice but not adult treated mice. Furthermore, we found several genes related to CRE, CREB, and CBP were decreased due to ethanol following microarray analysis. This proposal will investigate the effects of sex, ethanol, and developmental age on memory and CBP protein expression using behavioral and molecular assays in DBA/2J mice. Aim 1 will investigate the impact of binge ethanol on ethanol metabolism, spatial memory, and cognitive flexibility in male and female mice treated with ethanol in adolescence and adulthood using blood ethanol concentration and the Barnes Maze task. In Aim 2, I will assess the level of protein expression of CBP and other proteins that interact with CBP or are involved with CRE/CREB using westerns. I will also assess CBP protein interactions using co-immunoprecipitation coupled with mass spectrometry. Finally, in Aim 3 I will test the sufficiency of CBP using viral vectors in mice following the adolescent binge ethanol procedure to assess the impact on the previously mentioned memory tasks. The combination of these behavioral and molecular studies will provide useful knowledge to the literature addressing the gap regarding developmental age, sex, and ethanol in memory and the CBP pathway.

概括 对于人类来说，青春期是一个关键的发育时期，其特点是冒险行为、大脑 对于大多数未成年人来说，酒精作为一种简单的药物而被高度消费。 饮酒者早期饮酒会增加晚年酗酒和依赖酒精的风险。 并可能导致蛋白质表达和行为的持久变化，青少年对这些物质的敏感性发生改变。 酒精可能是由于它们的持续发育，显示出对负面影响的敏感性降低，而 与成年人相比，他们对奖励效果的敏感性更高。 可能会进一步促进青少年饮酒，导致更严重的长期持续变化 与成人相比，饮酒会导致蛋白质表达的变化和记忆障碍。 在成人和青少年中都观察到了与记忆有关的两种已知蛋白质：cAMP 反应。 元件结合蛋白（CREB）和CREB结合蛋白（CBP）是一种组蛋白乙酰转移酶， 许多转录因子（包括 CREB）的辅激活因子/辅因子，对于短期和长期转录都是必需的。 海马体和前额叶皮层是经历成熟变化的两个大脑区域。 青春期时性对记忆也有影响，研究表明性也对记忆有影响。 鉴于酒精可能产生的持久影响，建议女性可能对酒精的影响更敏感。 对行为和大脑的影响，进一步了解酒精对性别和年龄的持续影响是 对于文献和进一步治疗的可能性很重要，我们的实验室已经证明乙醇会产生不同的影响。 最后一次给药后 3 周的记忆力，在青少年的新物体识别任务中观察到缺陷 此外，我们发现了一些与 CRE、CREB ​​和 CBP 相关的基因。 微阵列分析后由于乙醇而减少。该提案将调查性别的影响， 使用行为和分子方法研究乙醇和发育年龄对记忆和 CBP 蛋白表达的影响 DBA/2J 小鼠实验的目的 1 将研究暴食乙醇对乙醇代谢、空间的影响。 在青春期和成年期接受乙醇处理的雄性和雌性小鼠的记忆力和认知灵活性 在目标 2 中，我将使用血液乙醇浓度和巴恩斯迷宫任务来评估蛋白质水平。 使用 Westerns I 表达 CBP 以及与 CBP 相互作用或与 CRE/CREB ​​相关的其他蛋白质。 还将使用免疫共沉淀结合质谱法评估 CBP 蛋白质相互作用。 最后，在目标 3 中，我将在青少年暴饮暴食后使用病毒载体在小鼠中测试 CBP 的充分性 乙醇程序来评估对前面提到的记忆任务的影响。 行为和分子研究将为文献提供有用的知识，解决以下方面的差距 发育年龄、性别和记忆中的乙醇以及 CBP 途径。