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.

总结