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

• 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
• 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' s Disease; Alzheimer' s disease model; Alzheimer' 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

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.

摘要 作为阿尔茨海默病(AD)和其他痴呆的最显著的危险因素，衰老导致渐进性的fi fic认知能力下降，如空间记忆，降低独立性和生活质量。1-3 然而，衰老导致的认知功能下降的神经生物学机制仍不清楚，仅限于 延长大脑健康寿命的治疗方法的发展2以促进我们对机械的理解 关于健康和疾病大脑老化的空间记忆下降，这项拟议的研究将同时进行 描述内侧内嗅觉皮质的分子、细胞和回路水平的变化，并将其联系起来 (MEC)，一个对空间记忆至关重要的大脑区域，在临床前4，5年受到分子病理的影响。 幼年啮齿动物和灵长类动物的MEC神经元fi环图案代表位置、速度、头部方向和 环境地标，促进目标导向导航和空间记忆。6-12 MEC如何进行空间编码 老年动物空间记忆的变化和功能支持尚不清楚。为了解决这个问题，我建议 当幼年和老年小鼠在虚拟环境中导航时，使用神经像素探针以高密度记录MEC神经元- 现实(VR)环境。我将量化老化如何影响单个单位的MEC属性，如位置-和 速度编码fi的精确度和稳定性，反过来，空间记忆，衡量的是学习和 在奖励的VR地点之间交替(目标1)。在幼年动物中，theta节律组织MEC活动 并支持空间记忆，但其在老年动物中的功能状态尚不清楚。因此，我也会 分析衰老如何影响跨MEC神经元群体的theta节律性活动协调(目标2)。 记录后，我将利用单核rna-DefiNe基因在MEC神经元中的表达随年龄的变化而变化。 测序(SnRNAseq)(目标3)。最终，我将把改变的基因表达与MEC编码和 空间记忆障碍为未来治疗衰老的大脑和治疗寻找靶点 像阿尔茨海默病这样的年龄调节痴呆。考虑到我以前研究衰老分子变化的经验 以及损害海马体依赖的空间记忆的神经退行性变，我很有能力 执行这些实验。追求这些目标也将培养我出类拔萃所需的新技能 未来的独立调查者，包括强有力地收集和分析大规模的神经和 转录数据集。我将在全球专家丽莎·乔科莫博士的赞助下进行这项工作 在电生理学和支持导航和空间记忆的神经系统方面。作为合作者和 Saul Villeda博士和Tony Wyss-Coray博士分别是共同赞助人，他们将利用 大规模分子数据集，以产生对大脑老化的洞察。他们的集体支持和斯坦福大学的 严谨的培训环境将确保这个项目的完成和我的发展成为一个创新的 被授权开发改善大脑老化和神经退化的疗法的内科科学家。