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: 10228091
• 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/10228091
• 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; 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; Resolution; Rewards; Rodent; Slice; Solid; Structure; Structure of molecular layer of cerebellar cortex; 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; 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.

这个指导研究科学家发展奖（K 01）应用程序支持职业发展 以及Paula Zamudio-Bulcock博士的额外高级技术培训，以帮助她过渡到 酒精研究领域的独立学术调查员。她在体外实验方面有丰富的经验， 切片电生理学，并在指导期间将获得酒精动物模型的经验 消费和依赖。此外，在拟议的研究过程中，她将学到很高的 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博士还将利用K 01保护的训练时间来提高她的能力。 职业技能，重点是手稿准备和提交，granitary培训和 发展辅导技能。Zamudio-Bulcock博士的培训将得到强大的机构支持 致力于她的职业发展和一个杰出的和多方面的指导团队的领导者， 酒精研究领域，每一个提供专家指导整个拟议的研究进展。 这项研究计划是从Zamudio-Bulcock博士长期以来对酒精对人体的影响的兴趣发展而来的。 小脑和她的经验，研究急性和发育中的酒精暴露对小脑的影响， physiology.因此，它与她导师实验室的研究重点有着明显的区别。研究从 导师和共同导师的特点功能，结构和表观遗传改变后，慢性 酒精暴露在与酒精消费和依赖有关的大脑区域。Zamudio-Bulcock博士 建议将采用她的导师使用的方法来评估慢性酒精引起的改变， 小脑尽管对酒精高度敏感，但在慢性酒精中毒的背景下研究不足。 酒精使用和依赖。这项提案的目的是为了检验慢性病的假设， 酒精暴露导致小脑唯一输出的功能，结构和表观遗传改变 皮质，GABA能浦肯野细胞。重要的是，最近发现小脑皮层是一个 小脑间分子、功能和结构差异显著异质性脑区 小叶这种差异被假定为支持小脑行为功能的丰富多样性 提供神经元计算。考虑到小脑后部的功能连接， 在酒精依赖的小鼠中，已知大脑区域受到影响，慢性酒精暴露的影响将 以小叶下特异性方式进行研究，重点关注与 中脑和皮质区域参与奖励和决策。开展这些研究的机会 和从事全面的职业发展培训活动将提供坚实的基础， 候选人在酒精研究领域走向独立的道路。