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:
    10786033
  • 负责人:
  • 金额:
    $ 4.04万
  • 依托单位:
  • 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

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.
总结 作为阿尔茨海默病(AD)和其他痴呆症的最重要的风险因素,衰老导致逐渐的 特定认知能力下降,如空间记忆,降低独立性和生活质量。 然而,衰老介导的认知能力下降的神经生物学机制仍不清楚, 发展延长大脑健康寿命的疗法。2为了推进我们对大脑机制的理解, 在健康和患病的大脑衰老中,空间记忆力下降,这项研究将同时 表征内侧内嗅皮质的分子、细胞和回路水平变化,然后将其关联起来 (MEC)这是一个对空间记忆至关重要的大脑区域,并受到临床前AD分子病理学的影响。 在年轻的啮齿动物和灵长类动物中,MEC神经元放电模式代表位置,速度,头部方向, 环境地标,促进目标导向导航和空间记忆。6 -12 MEC空间编码 老年动物的空间记忆的变化和功能支持是未知的。为了解决这个问题,我建议 记录MEC神经元在高密度使用Neuropixels探针作为年轻和老年小鼠导航虚拟, 现实(VR)环境。我将量化老化如何影响单单元MEC属性,如位置和 速度编码的灵活性和稳定性,以及,反过来,空间记忆,衡量学习和 在奖励的VR位置之间交替(目标1)。在幼年动物中,θ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,我也将 分析衰老如何影响MEC神经元群体之间的θ节律协调活动(目标2)。 记录后,我将使用单核RNA定义MEC神经元中基因表达随年龄的变化- 测序(snRNAseq)(目的3)。最终,我将把改变的基因表达与MEC编码联系起来, 空间记忆功能障碍,以确定未来治疗的目标,以恢复衰老的大脑和治疗 像AD这样的老年痴呆症鉴于我之前研究衰老过程中分子变化的经验 和神经变性,损害了依赖于校园的空间记忆,我有充分的准备, 做这些实验。追求这些目标也将培养新的技能,使我成为优秀的人。 未来的独立调查员,包括强大的收集和分析大规模的神经和 转录组数据集。我将在全球专家丽莎乔科莫博士的赞助下开展这项工作 在电生理学和支持导航和空间记忆的神经系统中。成为合作者和 共同赞助商,分别为扫罗Villeda,博士和托尼Wyss-Coray,博士将贡献专业知识,利用 大规模的分子数据集,以产生关于大脑衰老的见解。他们的集体支持和斯坦福大学的 严格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 医生科学家有权开发改善大脑衰老和神经退行性疾病的疗法。

项目成果

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Charlotte Sophia Herber其他文献

Charlotte Sophia Herber的其他文献

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{{ truncateString('Charlotte Sophia Herber', 18)}}的其他基金

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
  • 财政年份:
    2022
  • 资助金额:
    $ 4.04万
  • 项目类别:

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