Mechanisms underlying impaired hippocampal physiology in Fragile X Syndrome

项目总结 脆性X综合征(FXS)是一种神经发育障碍，可导致空间记忆和 非典型的空间行为，如“私奔”，或四处游荡并迷路。目前的治疗方法 FXS是有限的，不治疗可能与这些症状相关的潜在神经变化。 海马区CA1区的活动支持空间记忆和空间认知，使其成为 在FXS背景下研究的重要候选对象；然而，研究是否存在差异 FXS中CA1区的神经生理活动与空间行为受损和记忆缺乏有关。这个 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的大鼠模型中。这项研究将使用体内电生理学来记录空间调制的活动 引入新环境作为大鼠空间记忆形成模型后的CA1神经元 FXS(Fmr1基因敲除，以下简称FXS大鼠)和野生型(WT)对照组。《特定目标1》将测试 在FXS大鼠中，细胞外6-10 Hztheta节律对单个神经元的调制是正常的。这一目标将 从FXS大鼠暴露于新环境开始，评估这种调制是否存在 是在WT大鼠身上。具体目标2将测试是否通过协调的空间集合对空间路径进行编码 在WT大鼠中，在新环境中经历发育的调制CA1神经元在 在FXS大鼠中也是如此。特殊目标3将检查先前激活的CA1神经元的重新激活 FXS和WT大鼠清醒休息和睡眠时的集合。这一目标将检验CA1神经元 代表新环境的集合在FXS大鼠的休息和睡眠中不优先被重新激活 与WT大鼠的结果相反。这些拟议实验的结果可能揭示出特定的损伤。 在支持FXS空间记忆的海马区机制中，可能会提出新的治疗靶点 FXS。 这一奖学金将使我能够发展必要的技术和专业技能，以追求职业生涯 执行独立研究的首席调查员。我相信我选择的机构和赞助商是理想的 完成我提议的项目以及追求我长期职业目标所需的培训。这个 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，一个协作的工作环境， 我经常能够展示我的工作，并收到反馈，以及教授和指导学生的机会。 通过学院为研究生提供的就业服务，我还能够参加以下科目的课程 作为科学传播、数据管理和规划严谨和可重现的科学，以及 单独与职业顾问会面。通过这笔奖学金，我将发展继续下去所需的技能 并继续研究认知障碍中的网络障碍。

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.