Mechanisms underlying impaired hippocampal physiology in Fragile X Syndrome

脆性 X 综合征海马生理学受损的机制

• 批准号: 10582539
• 负责人: Margaret McNeil Donahue
• 金额: $ 4.44万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10582539
• 关键词: Address; Algorithms; Behavior; Brain region; Cells; Code; Cognition; Cognition Disorders; Communication; Complex; Cues; Data; Data Set; Doctor of Philosophy; Educational process of instructing; Electrophysiology (science); Environment; Event; Exposure to; FMR1; Feedback; Fellowship; Fire - disasters; Fragile X Syndrome; Future; Goals; Hippocampus; Impairment; Individual; Institution; Knock-out; Location; Maps; Measures; Mediating; Memory; Memory impairment; Modeling; Neurodevelopmental Disorder; Neurologic; Neurons; Neurosciences; Phase; Physiology; Play; Population; Positioning Attribute; Principal Investigator; Rattus; Reproducibility; Research; Rest; Running; Science; Sensory; Services; Sleep; Spatial Behavior; Symptoms; Testing; Theta Rhythm; Time; Training; Vocational Guidance; Work; austin; career; college; data management; experience; experimental study; extracellular; graduate student; in vivo; memory consolidation; memory retrieval; mouse model; multimodality; neurophysiology; non rapid eye movement; novel; place fields; professional atmosphere; programs; receptive field; skills; spatial memory; student mentoring; way finding

PROJECT SUMMARY Fragile X Syndrome (FXS) is a neurodevelopmental disorder that can cause impaired spatial memory and atypical spatial behaviors such as “elopement,” or wandering around and becoming lost. Current treatments for FXS are limited and do not treat underlying neurological changes that may be associated with these symptoms. Activity in the CA1 subregion of the hippocampus supports spatial memory and spatial cognition, making it an important candidate to study in the context of FXS; however, research into whether differences in neurophysiological activity in CA1 in FXS contribute to impaired spatial behaviors and memory is lacking. The goal of this project is to examine whether the activity in CA1 that supports spatial memory formation is impaired in a rat model of FXS. The studies will use in vivo electrophysiology to record the activity of spatially modulated CA1 neurons after introduction to a novel environment as a model of spatial memory formation in a rat model of FXS (Fmr1 knockout, hereafter “FXS rats”) and wildtype (WT) control rats. Specific Aim 1 will test whether the modulation of individual neurons by the extracellular 6-10 Hz theta rhythm is normal in FXS rats. This Aim will assess whether this modulation is present from the onset of exposure to a novel environment in FXS rats as it is in WT rats. Specific Aim 2 will test whether coding of spatial paths by coordinated ensembles of spatially modulated CA1 neurons, which develops with experience in novel environments in WT rats, fails to develop at the same rate in FXS rats. Specific Aim 3 will examine the reactivation of previously active CA1 neuron ensembles during waking rest and sleep in FXS and WT rats. This Aim will test the hypothesis that CA1 neuronal ensembles representing novel environments are not preferentially reactivated during rest and sleep in FXS rats in contrast to results from WT rats. The results from these proposed experiments may reveal specific impairments in hippocampal mechanisms that support spatial memory in FXS and may suggest novel treatment targets for FXS. This fellowship will allow me to develop the necessary technical and professional skills to pursue a career as a principal investigator performing independent research. I believe my choice of institution and sponsor is ideal for completing my proposed project as well as the training necessary to pursue my long-term career goals. The Institute for Neuroscience at UT Austin offers a rigorous PhD program, a collaborative work environment where I am regularly able to present my work and receive feedback, and opportunities to teach and mentor students. Through the college’s career services for graduate students, I am also able to attend courses in subjects such as science communication, data management, and planning rigorous and reproducible science, as well as to meet individually with a career counselor. Through this fellowship, I will develop the skills necessary to continue onto future academic positions and continue to research network impairments in cognitive disorders.

项目概要 脆性 X 综合征 (FXS) 是一种神经发育障碍，可导致空间记忆受损和 非典型的空间行为，例如“私奔”或四处游荡并迷路。 FXS 的作用有限，并且不能治疗可能与这些症状相关的潜在神经系统变化。 海马 CA1 亚区的活动支持空间记忆和空间认知，使其成为 然而，研究 FXS 是否存在差异； FXS 中 CA1 的神经生理活动会导致空间行为受损和记忆力缺乏。 该项目的目标是检查 CA1 中支持空间记忆形成的活动是否受损 在 FXS 大鼠模型中，研究将使用体内电生理学来记录空间调制的活动。 CA1神经元在引入新环境后作为大鼠模型空间记忆形成的模型 FXS（Fmr1 敲除，以下简称“FXS 大鼠”）和野生型 (WT) 对照大鼠将测试是否 在 FXS 大鼠中，细胞外 6-10 Hz theta 节律对单个神经元的调节是正常的。 评估这种调节是否从 FXS 大鼠暴露于新环境开始就存在，因为它 具体目标 2 将测试空间路径是否通过空间协调整体进行编码。 调节的 CA1 神经元在 WT 大鼠的新环境中随着经验而发育，但在 FXS 大鼠中的特定目标 3 将检查先前活跃的 CA1 神经元的重新激活。 FXS 和 WT 大鼠在清醒休息和睡眠期间的整体测试将检验 CA1 神经元的假设。 FXS 大鼠在休息和睡眠期间不会优先重新激活代表新环境的整体 与 WT 大鼠的结果相反，这些实验的结果可能揭示了特定的损伤。 在支持 FXS 空间记忆的海马机制中，可能会提出新的治疗目标 FXS。 这项奖学金将使我能够发展必要的技术和专业技能，以从事职业生涯 我相信我选择的机构和赞助商是进行独立研究的理想选择。 完成我提议的项目以及实现我的长期职业目标所需的培训。 德克萨斯大学奥斯汀分校神经科学研究所提供严格的博士课程和协作的工作环境， 我能够定期展示我的作品并获得反馈，以及教导和指导学生的机会。 通过学院为研究生提供的就业服务，我还能够参加诸如 作为科学传播、数据管理和规划严格且可重复的科学，以及 通过这次奖学金，我将与职业顾问单独会面，培养继续下去所需的技能。 未来的学术职位并继续研究认知障碍中的网络障碍。