A novel hippocampal GABAergic projection and its potential role in spatial recognition

一种新型海马 GABA 能投射及其在空间识别中的潜在作用

• 批准号: 10462880
• 负责人: Lauren Glassburn
• 金额: $ 3.39万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-21 至 2025-06-20
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10462880
• 关键词: Acute; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Animal Model; Area; Behavior; Behavioral; Brain; Brain region; Calcium Signaling; Cells; Coupled; Data; Development; Discrimination; Electrophysiology (science); Elements; Endoscopes; Environment; Exposure to; Familiarity; Fiber; Fiber Optics; Head; Hippocampus (Brain); Impairment; Implant; Injections; Knowledge; Label; Light; Location; Maps; Memory; Microscope; Minnesota; Mus; Neurons; Neurosciences; Process; Research; Research Personnel; Rodent; Rodent Model; Role; Shapes; Signal Transduction; Slice; Statistical Data Interpretation; Sum; Synapses; Technical Expertise; Techniques; Temporal Lobe; Temporal Lobe Epilepsy; Testing; Training; University resources; Update; Viral; Work; calcium indicator; career; dentate gyrus; experimental study; fluorescence imaging; in vivo; in vivo calcium imaging; insight; memory encoding; memory recognition; novel; object recognition; optogenetics; patient population; programs; response; skills; spatial memory; way finding

Project Summary Identifying novelty or familiarity of the environment is required for spatial navigation and influences forming and maintaining internal spatial maps. This process of identifying an environment as novel or familiar and forming the appropriate spatial map is impaired in aging rodents and in rodent models of Alzheimer’s disease and temporal lobe epilepsy, possibly reflecting spatial processing deficits in patient populations. Recently identified spatial novelty signals from the supramammillary area to the hippocampal dentate gyrus (SuM→DG) shape spatial processing in the hippocampus; however, what signals influence SuM spatial novelty signals is unknown. This proposal investigates a novel hippocampal CA1 GABAergic projection to the SuM and its potential role in signaling spatial recognition and suppressing SuM spatial novelty signals. I term these cells HIPS (hippocampal inhibitory cells projecting to the supramammillary area), and my preliminary data indicates their fibers are near SuM→DG neurons. This proposal tests the hypothesis that HIPS signal spatial recognition, inhibit SuM→DG neurons, and influence spatial processing. I am proposing three aims to analyze the functional connectivity, behavioral impact, and in vivo activity of HIPS. I will utilize slice electrophysiology combined with optogenetic stimulation of HIPS to analyze HIPS connections to SuM→DG neurons and other neurons of the SuM (Aim 1) to test if HIPS have functional, inhibitory connections to the SuM and to test if HIPS preferentially inhibit SuM→DG neurons. To test HIPS impact on behavior and memory, I will apply in vivo optogenetics to stimulate HIPS in behavioral tasks which vary spatial and non-spatial familiarity and novelty (Aim 2). I will additionally use head-mounted miniature microscopes to perform in vivo calcium imaging of HIPS in freely behaving mice to test if HIPS’ activity reflects spatial recognition (Aim 3). This proposal provides insight into a novel hippocampal GABAergic projection and potential circuits involved in spatial recognition. This work also gives me the excellent opportunity to train in analysis of cells, circuits, and behavior using techniques which have all been successfully applied in the lab of my sponsor, Dr. Esther Krook- Magnuson. My sponsor and co-sponsor, Dr. David Redish, will fully support me in the knowledge and technical skills required for the proposal, and they are each committed to my development of professional skills needed for an academic research career. Their support combined with the resources of the University of Minnesota Graduate Program in Neuroscience will fully prepare me to pursue a career as an independent researcher.

项目摘要 识别环境的新奇或熟悉性是空间导航和影响形成所必需的， 维护内部空间地图。这一过程确定一个环境是新的或熟悉的， 适当的空间映射在老年啮齿动物和阿尔茨海默病的啮齿动物模型中受损， 颞叶癫痫，可能反映了患者人群的空间处理缺陷。最近发现 从乳头体上区到海马齿状回（SuM→DG）形状的空间新奇信号 然而，影响SuM空间新奇信号的信号是 未知 本研究旨在探讨海马CA1区GABA能神经元向SuM的投射及其在海马CA1区的作用。 信令空间识别和抑制SuM空间新奇信号。我将这些细胞称为HIPS （海马抑制细胞投射到乳头体上区），我的初步数据表明， 纤维位于SuM→DG神经元附近。该提议测试了HIPS信号空间识别的假设， 抑制SuM→DG神经元，影响空间加工。我提出了三个目标来分析 功能连接性、行为影响和HIPS的体内活性。我会利用切片电生理学 结合HIPS的光遗传学刺激来分析HIPS与SuM→DG神经元和其他神经元的连接。 SuM的神经元（目的1），以测试HIPS是否具有与SuM的功能性抑制性连接，并测试是否 HIPS优先抑制SuM→DG神经元。为了测试HIPS对行为和记忆的影响，我将在体内应用 光遗传学在不同空间和非空间熟悉性和新奇的行为任务中刺激HIPS (Aim 2）。我还将使用头戴式微型显微镜进行体内钙成像的高抗冲聚苯乙烯 在自由行为的小鼠中测试HIPS的活性是否反映了空间识别（目的3）。 这项提议提供了一个新的海马GABA能投射和潜在的电路参与的见解， 空间识别这项工作也给了我一个极好的机会，在细胞，电路分析， 行为使用的技术都已经成功地应用在我的赞助商，埃斯特·克鲁克博士的实验室， 马格努森我的赞助商和共同赞助商，大卫Redish博士，将全力支持我的知识和技术 建议所需的技能，他们每个人都致力于我所需要的专业技能的发展 从事学术研究他们的支持与明尼苏达大学的资源相结合 神经科学研究生课程将为我从事独立研究人员的职业做好充分准备。