From Molecules to Behavior: Understanding How Aging Impacts Entorhinal-based Navigation

从分子到行为：了解衰老如何影响基于内嗅的导航

基本信息

批准号：
10535298
负责人：
Charlotte Sophia Herber
金额：
$ 3.94万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10535298
关键词：
Address Adult Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease risk Animals Behavior Behavioral Brain Brain Diseases Brain region Cell Nucleus Cells Code Cognition Computer Models Coupling Data Analyses Data Collection Data Set Dementia Deposition Development Disease Doctor of Philosophy Dorsal Electrophysiology (science)Ensure Environment Frequencies Functional disorder Future Gene Expression Genes Goals Head Hippocampus (Brain)Human Immunohistochemistry Impaired cognition Impairment Individual Interneurons Learning Linear Models Link Liquid substance Location Maps Measures Medial Mediating Memory Memory Loss Memory impairment Molecular Mus Nerve Degeneration Neurologic Neurons Pathologic Pattern Performance Periodicity Phase Physicians Population Positioning Attribute Primates Property Quality of life RNA Recording of previous events Research Personnel Rewards Risk Factors Rodent Rodent Model Scientist Speed Support System Surface System Therapeutic Theta Rhythm Time Training Transgenic Organisms Wild Type Mouse Work age effect age related aged aging brain base cognitive ability density empowered entorhinal cortex experience experimental study extracellular flexibility functional status healthspan healthy aging innovation insight juvenile animal mild cognitive impairment molecular pathology molecular scale neural circuit neural correlate neurobiological mechanism neuromechanism novel pre-clinical predictive modeling prevent relating to nervous system skills spatial memory therapy development transcriptome sequencing transcriptomics virtual reality virtual reality environment water environment

项目摘要

SUMMARY As the most signiﬁcant risk factor for Alzheimer's disease (AD) and other dementias, aging causes the gradual decline of speciﬁc cognitive abilities, like spatial memory, reducing independence and quality of life.1-3 However, the neurobiological mechanisms underlying aging-mediated cognitive decline remain unclear, limiting the development of therapies that extend the brain's healthspan.2 To advance our mechanistic understanding of spatial memory decline in healthy and diseased brain aging, the proposed study will simultaneously characterize and then correlate molecular, cellular, and circuit-level changes in the medial entorhinal cortex (MEC), a brain region critical for spatial memory and impacted by molecular pathology in pre-clinical AD.4,5 In young rodents and primates, MEC neuron ﬁring patterns represent position, speed, head direction, and environmental landmarks, facilitating goal-directed navigation and spatial memory.6-12 How MEC spatial coding changes and functionally supports spatial memory in aged animals is unknown. To address this, I propose to record from MEC neurons at high density using Neuropixels probes as young and aged mice navigate virtual- reality (VR) environments. I will quantify how aging impacts single-unit MEC properties, such as position- and speed-coding ﬁdelity and stability, and, in turn, spatial memory, measured as the rate of learning and alternating between rewarded VR locations (Aim 1). In young animals, theta rhythm organizes MEC activity and supports spatial memory, but its functional status in aged animals is not understood. Thus, I will also analyze how aging impacts theta-rhythmic coordination of activity across populations of MEC neurons (Aim 2). After recording, I will deﬁne gene expression changes with age in MEC neurons using single nucleus RNA- sequencing (snRNAseq) (Aim 3). Ultimately, I will correlate altered gene expression with MEC coding and spatial memory dysfunction to identify targets for future therapies to rejuvenate the aging brain and to treat age-modulated dementias like AD. Given my previous experience investigating molecular changes in aging and neurodegeneration that compromise hippocampus-dependent spatial memory, I am well-equipped to execute these experiments. Pursuing these aims will also cultivate new skills necessary for me to excel as future independent investigator, including robustly collecting and analyzing large-scale neural and transcriptomic datasets. I will conduct this work under the sponsorship of Lisa Giocomo, PhD: a global expert in electrophysiology and the neural systems that support navigation and spatial memory. As a collaborator and a co-sponsor, respectively, Saul Villeda, PhD and Tony Wyss-Coray, PhD will contribute expertise leveraging large-scale molecular datasets to generate insights about brain aging. Their collective support and Stanford's rigorous training environment will ensure this project's completion and my development into an innovative physician scientist empowered to develop therapies that ameliorate brain aging and neurodegeneration.

概括作为阿尔茨海默氏病（AD）和其他痴呆症的最显着危险因素，衰老会导致等级特定认知能力的下降，例如空间记忆，降低独立性和生活质量。1-3 然而，衰老介导的认知下降的神经生物学机制尚不清楚，限制扩展大脑健康状况的疗法的开发。2促进我们的机械理解拟议的研究将随着健康和解散的大脑衰老的空间记忆力下降而减少表征，然后将介质内嗅皮层中的分子，细胞和电路级变化相关联（MEC），一个对空间记忆至关重要的大脑区域，受到临床前AD的分子病理影响4,5 年轻的啮齿动物和素数，MEC神经元模式代表位置，速度，头部方向和环境地标，支持目标导航和空间内存。6-12MEC空间编码变化并在功能上支持老年动物的空间记忆是未知的。为了解决这个问题，我建议使用神经质素问题从高密度的MEC神经元记录，因为年轻小鼠和老年小鼠可导航虚拟现实（VR）环境。我将量化衰老如何影响单单元MEC的特性，例如位置和位置 - 速度编码的有限和稳定性，进而将空间记忆衡量为学习率和在奖励的VR位置之间更改（AIM 1）。在年轻动物中，theta节奏组织MEC活动并支持空间记忆，但尚不理解其在老年动物中的功能状态。那我也会分析衰老如何影响MEC神经元种群活动活动的theta-Rhimthmic协调（AIM 2）。记录后，我将使用单核RNA-将基因表达随着MEC神经元的年龄而变化。测序（SNRNASEQ）（AIM 3）。最终，我将将改变的基因表达与MEC编码和空间记忆功能障碍以识别未来疗法的靶标，以使大脑衰老并治疗年龄调节的痴呆症如AD。鉴于我以前研究了衰老分子变化的经验和损害海马依赖性空间内存的神经变性，我有足够的能力执行这些实验。追求这些目标还将培养我擅长的新技能未来的独立研究者，包括强大的收集和分析大型神经和转录组数据集。我将根据丽莎·乔科莫（Lisa Giocomo）博士的赞助：全球专家在电生理学和支持导航和空间记忆的神经系统中。作为合作者和共同发起人，分别是索尔·维雷达（Saul Villeda），博士和托尼·韦斯（Tony Wyss-Coray），博士将贡献专业知识大规模分子数据集，以产生有关大脑衰老的见解。他们的集体支持和斯坦福严格的培训环境将确保该项目的完成和我的发展成创新医师科学家有权开发缓解脑老化和神经退行性的疗法。