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: 10315664
• 负责人: Maria Alexis Bent
• 金额: $ 3.96万
• 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/10315664
• 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; Structure; 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 在人类中，青少年是一个关键的发展时期，以增加冒险行为，大脑 成熟和认知发展。对于大多数未成年人来说，酒精被高度消耗为一种简单的药物 饮酒者要获得。饮酒的年龄增加了一个人滥用酗酒和依赖的风险 并可能导致蛋白质表达和行为的持久变化。青少年对 酒精可能是由于其持续发展所致，对负面影响的敏感性降低了 与成人相比，对奖励效应的敏感性提高了。这种发展差异 可能会进一步促进青少年饮酒，导致持久的变化更为严重 比成年人。饮酒导致蛋白质表达和记忆力障碍的变化 在成年人和青少年中都观察到。记忆中涉及的两个已知蛋白质是cAMP响应 元素结合（CREB）蛋白和CREB结合蛋白（CBP）。 CBP是一种组蛋白乙酰转移酶， 对于包括CREB在内的许多转录因子的共激活因子/辅助因子 术语内存。海马和额叶皮层是两个大脑区域，发生成熟 在青少年期间，并在记忆中发挥作用。性别也在记忆中发挥作用，研究有 建议的女性可能对酒精的影响更敏感。鉴于持久的影响酒精可能会有 关于行为和大脑，进一步了解性别和年龄引起的酒精的持续影响是 对于文献和进一步的治疗可能性重要。我们的实验室已显示乙醇对差异影响 最后剂量后3周记忆，在青少年的新对象识别任务中观察到了防御 治疗的小鼠，但没有成人治疗的小鼠。此外，我们发现了几个与CRE，CREB和CBP有关的基因 在微阵列分析后由于乙醇而改善。该建议将调查性的影响， 乙醇，以及使用行为和分子的记忆和CBP蛋白表达的发育年龄 DBA/2J小鼠的测定。 AIM 1将研究暴饮暴食对乙醇代谢，空间的影响 在青少年和成年期用乙醇治疗的雄性和雌性小鼠的记忆和认知灵活性 使用血液乙醇浓度和巴恩斯迷宫任务。在AIM 2中，我将评估蛋白质的水平 使用西方人的CBP和其他与CBP相互作用或与CRE/CREB相互作用的蛋白质的表达。我 还将使用共免疫沉淀和质谱法评估CBP蛋白相互作用。 最后，在AIM 3中，我将在青少年后使用小鼠中使用病毒载体测试CBP的充分性 评估对前面提到的内存任务的影响的乙醇程序。这些的结合 行为和分子研究将为解决有关差距的文献提供有用的知识 发育年龄，性别和乙醇在记忆和CBP途径中。