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

此指导研究科学家发展奖(K01)申请支持职业发展 和Paula Zamudio-Bulcock博士的额外高级技术培训，以促进她过渡到 酒精研究领域的独立学术研究员。她在体外培养方面有丰富的经验。 切片电生理学，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，她将学到很高的东西 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，扎穆迪奥-布尔科克博士还将利用K01保护训练时间来磨练她 职业技能，专注于手稿的准备和提交，资质培训和 发展辅导技能。扎穆迪奥-布尔科克博士的培训将得到一个强大的机构的支持 致力于她的职业发展和一个杰出的、多方面的领导指导团队 在酒精研究领域，每个人都在拟议的研究过程中提供专家指导。 这项研究计划源于扎穆迪奥-布尔科克博士长期以来对酒精对健康影响的兴趣 小脑及其研究急性和发育性酒精暴露对小脑影响的经验 生理学。因此，这与她导师实验室的研究重点是明显不同的。研究来自 导师和共同导师的特征是慢性疾病后的功能、结构和表观遗传学改变 大脑区域的酒精暴露与酒精消费和依赖有关。扎穆迪奥-布尔科克医生的 Proposal将应用她的导师使用的方法来评估慢性酒精诱导的改变 小脑尽管对酒精高度敏感，但在慢性精神分裂症的背景下研究不足。 酗酒和依赖。这项提议的目的是为了测试慢性 酒精暴露导致小脑唯一输出的功能、结构和表观遗传学改变 皮质，GABA能浦肯野细胞。重要的是，最近发现小脑皮质是一种 小脑在分子、功能和结构上存在显著差异的异质性脑区 小叶。这种差异被认为支持小脑行为功能的丰富多样性。 提供神经元计算。鉴于小脑后部的功能连通性较高- 对已知的酒精依赖小鼠大脑区域进行排序，慢性酒精暴露的影响将 以小叶下特有的方式进行研究，重点放在与 参与奖励和决策的中脑和大脑皮层区域。开展这些研究的机会 并参与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。

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.