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 脆弱的X综合征（FXS）是一种神经发育障碍，可能导致空间记忆和 非典型的空间行为，例如“私奔”或四处徘徊并迷失。当前治疗 FX是有限的，并且不处理可能与这些符号相关的潜在神经系统变化。 海马的CA1子区域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人；但是，研究是否有差异 FX中CA1中的神经生理活性导致空间行为受损，并且缺乏记忆。 该项目的目标是检查CA1中支持空间内存形成的活动是否受损 在FXS的大鼠模型中。研究将使用体内电生理学记录空间调节的活性 引入新环境后，CA1神经元作为大鼠模型中的空间记忆形成模型 FXS（FMR1淘汰赛，以下是“ FXS大鼠”）和WildType（WT）控制大鼠。具体目标1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。这个目标 评估该调制是否从FXS大鼠的新型环境的接触开始是否存在 是在WT大鼠中。特定的目标2将测试是否通过空间的合奏编码空间路径 调制CA1神经元，该神经元具有在WT大鼠新颖环境中经验的发展，无法在 FXS大鼠的速率相同。特定的目标3将检查先前活性CA1神经元的重新激活 在醒着休息和睡觉时，合奏在FXS和WT大鼠中。这个目标将检验CA1神经元的假设 代表新环境的合奏在休息期间没有优先重新激活，在FXS大鼠中睡觉 与WT大鼠的结果相反。这些提出的实验的结果可能揭示了特定的损害 在支持FXS空间记忆的海马机制中，可能提出了新的治疗目标 FXS。 该奖学金将使我能够发展必要的技术和专业技能，从而从事职业 进行独立研究的主要研究人员。我相信我对机构和赞助商的选择是理想的选择 完成我的拟议项目以及追求我长期职业目标所需的培训。 UT Austin的神经科学研究所提供严格的博士学位计划，这是一个协作工作环境 我经常能够介绍自己的作品并获得反馈，以及教学和精神学生的机会。 通过大学为研究生提供的职业服务，我还可以参加此类学科的课程 作为科学沟通，数据管理以及计划严格且可重复的科学，以及 与职业顾问单独见面。通过这项奖学金，我将发展继续进行的技能 进入未来的学术职位，并继续研究认知障碍的网络障碍。