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.

项目摘要 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， 非典型的空间行为，如“私奔”，或四处游荡和迷路。的当前治疗 FXS是有限的，不治疗可能与这些症状相关的潜在神经系统变化。 海马CA 1亚区的活动支持空间记忆和空间认知，使其成为一个重要的空间记忆系统。 在FXS的背景下研究的重要候选人;然而，研究是否存在差异， FXS中CA 1的神经生理活动导致空间行为受损和记忆缺乏。的 本项目的目的是检查支持空间记忆形成的CA 1活动是否受损 在FXS的大鼠模型中。这些研究将使用体内电生理学来记录空间调制的 在大鼠模型中引入新环境作为空间记忆形成模型后的CA 1神经元， FXS（Fmr 1敲除，下文称为“FXS大鼠”）和野生型（WT）对照大鼠。具体目标1将测试 细胞外6-10 Hz θ节律对单个神经元的调节在FXS大鼠中是正常的。这一目标将 评估FXS大鼠从暴露于新环境开始是否存在这种调节， 在WT大鼠中。具体目标2将测试空间路径编码是否通过空间 在WT大鼠中随着新环境的经验而发育的调制的CA 1神经元，在 在FXS大鼠中也是如此。具体目标3将检查先前活跃的CA 1神经元的再激活 在FXS和WT大鼠的清醒休息和睡眠期间的集合。这一目的将检验CA 1神经元 在FXS大鼠的休息和睡眠期间，代表新环境的集合体并没有优先被重新激活 与WT大鼠的结果相反。这些拟议实验的结果可能会揭示特定的损伤 海马机制支持FXS的空间记忆，并可能提出新的治疗靶点， FXS。 这个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， 首席研究员进行独立研究。我相信我选择的机构和赞助商是理想的， 完成我提出的项目，以及必要的培训，以追求我的长期职业目标。的 UT Austin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， 我能够定期展示我的工作并收到反馈，并有机会教授和指导学生。 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和可复制的科学，以及 与职业顾问单独会面。通过这个奖学金，我将发展必要的技能，继续 未来的学术职位，并继续研究认知障碍的网络损伤。