Functional, Structural and Epigenetic Modifications of Cerebellar Purkinje Neurons in Alcohol-Dependent Mice

酒精依赖小鼠小脑浦肯野神经元的功能、结构和表观遗传修饰

• 批准号: 10671092
• 负责人: Paula Andrea Zamudio-Bulcock
• 金额: $ 19.35万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-05 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10671092
• 关键词: Acute; Adult; Affect; Aging; Alcohol consumption; Alcohol dependence; Alcoholic Intoxication; Alcohols; Animal Model; Animals; Area; Behavioral; Brain; Brain region; Cell physiology; Cells; Cerebellar Cortex; Cerebellar Diseases; Cerebellum; Chemicals; Chronic; Confocal Microscopy; Consumption; Decision Making; Dendrites; Dendritic Spines; Dependence; Development; Diet; Electrophysiology (science); Enzymes; Epigenetic Process; Ethanol; Ethanol dependence; Exposure to; Female; Fiber; Foundations; Functional disorder; Gene Expression; Genome; Histone Acetylation; Human; Impairment; Institution; Interneurons; Intoxication; Label; Laboratories; Lead; Learning; Lobular; Lobule; Manuscripts; Measures; Mentored Research Scientist Development Award; Mentors; Methodology; Midbrain structure; Modeling; Modification; Molecular; Morphology; Mus; Neonatal; Neurons; Output; Physiology; Preparation; Presynaptic Terminals; Process; Professional Competence; Proteins; Purkinje Cells; Reporting; Research; Research Methodology; Research Personnel; Rewards; Rodent; Slice; Solid; Structure; Synapses; Synaptic Transmission; Synaptic plasticity; System; Techniques; Testing; Time; Training; Training Activity; Vertebral column; addiction; alcohol effect; alcohol exposure; alcohol research; alcohol use disorder; binge drinking; career development; chronic alcohol ingestion; density; drinking; experience; experimental study; functional adaptation; histone methylation; histone modification; interest; male; motor control; motor impairment; mouse model; neuronal survival; neurotransmission; patch clamp; prenatal; prenatal exposure; problem drinker; skills; therapeutic target; ultra high resolution; vapor

This Mentored Research Scientist Development Award (K01) application supports the career development and additional advanced technical training of Dr. Paula Zamudio-Bulcock to facilitate her transition to an independent academic investigator in the alcohol research field. She has extensive experience in ex-vivo slice electrophysiology, and during the mentoring period will gain experience with animal models of alcohol consumption and dependence. In addition, during the course of the proposed studies she will learn highly relevant techniques in the addiction research field including super-resolution confocal microscopy and epigenetic research methods. Importantly, Dr. Zamudio-Bulcock will also use the K01 protected training time to sharpen her career skills with a strong focus on manuscript preparation and submission, grantsmanship training and development of mentoring skills. Dr. Zamudio-Bulcock’s training will be supported by a strong institutional commitment to her career development and an outstanding and multifaceted mentoring team of leaders in the alcohol research field, each providing expert guidance throughout the progress of the proposed studies. The research plan evolved from Dr. Zamudio-Bulcock’s long standing interest in alcohol effects on the cerebellum and her experience studying the effects of acute and developmental alcohol exposures on cerebellar physiology. Thus, it is clearly distinguishable from the research focus of her mentor’s laboratory. Studies from the mentor and co-mentors have characterized functional, structural and epigenetic alterations after chronic alcohol exposure in brain regions implicated in alcohol consumption and dependence. Dr. Zamudio-Bulcock’s proposal will apply the methodologies used by her mentors to evaluate chronic alcohol–induced alterations in the cerebellum which, despite being highly sensitive to alcohol, has been understudied in the context of chronic alcohol use and dependence. The aims in this proposal have been tailored to test the hypothesis that chronic alcohol exposure leads to functional, structural and epigenetic alterations in the sole output of the cerebellar cortex, the GABAergic Purkinje cell. Importantly, the cerebellar cortex has been recently found to be a heterogeneous brain region with marked molecular, functional and structural differences among cerebellar lobules. Such differences are postulated to support the ample diversity of behavioral functions the cerebellum provides neuronal computation for. Given the functional connectivity of the posterior cerebellum with higher- order brain regions known to be affected in alcohol-dependent mice, the effects of chronic alcohol exposure will be studied in a sub-lobular specific manner with a focus on posterior lobules that are inter-connected with midbrain and cortical areas involved in reward and decision making. The opportunity to carry out these studies and engage in comprehensive career development training activities will provide a solid foundation for the candidate’s path to independence in the alcohol research field.

这项指导的研究科学家发展奖（K01）应用程序支持职业发展 以及Paula Zamudio-Bulcock博士的其他高级技术培训，以方便她过渡到 酒精研究领域的独立学术研究员。她在前体内有丰富的经验 切片电生理学，在心理时期将获得饮酒动物模型的经验 消费和依赖性。此外，在拟议的研究过程中，她将学到很高的学历 成瘾研究领域的相关技术，包括超分辨率共聚焦显微镜和表观遗传学 研究方法。重要的是，Zamudio-Bulcock博士还将使用K01受保护的训练时间来提高她 职业技能强烈专注于手稿准备和提交，授予技巧培训和 发展心理技能。 Zamudio-Bulcock博士的培训将得到强大的机构的支持 致力于她的职业发展，以及一个杰出而多方面的心理团队 酒精研究领域，每个研究领域在拟议的研究的整个进度中都提供专家指导。 该研究计划源自Zamudio-Bulcock博士对酒精对酒精影响的长期兴趣 小脑和她研究急性和发育性酒精暴露对小脑的影响的经验 生理。这显然可以与她的精神实验室的研究重点区分开来。研究 精神和联合官员表征了慢性后的功能，结构和表观遗传改变 酒精消费和依赖性实施的大脑区域的酒精暴露。 Zamudio-Bulcock博士 提案将应用她的导师使用的方法来评估慢性酒精诱导的改变 渴望对酒精高度敏感的小脑在慢性的背景下已被理解 饮酒和依赖。该提案的目的是为了检验慢性的假设而定制的 酒精暴露会导致小脑唯一输出的功能，结构和表观遗传改变 皮质，Gabaergic Purkinje细胞。重要的是，最近发现小脑皮层是 在小脑之间具有明显分子，功能和结构差异的异质大脑区域 小叶。此类差异被发布以支持小脑的充分行为功能多样性 提供神经元计算。考虑到后小脑的功能连通性 秩序的大脑区域已知在酒精依赖性小鼠中受到影响，慢性酒精暴露的影响将 以亚叶片特异性进行研究，重点是与 中脑和皮质区域涉及奖励和决策。进行这些研究的机会 并从事全面的职业发展培训活动将为 候选人在酒精研究领域的独立之路。