Behavioral, molecular, and functional dissection of corticospinal neurons in motor performance deficits of physiological and pathological aging

项目摘要：运动功能，如精细运动技能，随着健康年龄的增长而逐渐下降 阿尔茨海默病的病理性衰老。这些损伤极大地影响了老年人的生活质量 老年人，被认为是AD患者认知症状的先兆。尽管有重叠的表型， 生理性(即健康)和病理性(如阿尔茨海默病)衰老中与年龄相关的运动障碍传统上是 分别进行了研究。因此，目前尚不清楚健康人群中是否存在运动表型和潜在机制 衰老不同于AD认知症状之前的那些。了解神经病理基础 健康老龄化和阿尔茨海默病中运动功能衰退的研究对于开发逆转运动功能衰退的治疗方法至关重要。 皮质脊髓神经元(CSN)，它控制着自主精细运动控制，是唯一直接的皮质输出到 脊髓，是年龄相关性运动缺陷的一个特别引人注目的候选因素。因为他们的 由于轴突极长，这些神经元可能特别容易受到生理和病理老化的影响。 事实上，几项关于人类衰老的研究已经描述了CSN的变化和精细运动的具体减少 技能，但没有一个人将这些变化与衰老中的运动能力下降联系起来。同样，尽管是金字塔形的 AD患者的症状是有报道的，而且研究将AD的病理与运动皮质联系起来，很少有 专门研究CSNS在AD运动症状中的作用。尽管如此，鼠标模型允许 细胞类型的特异性研究开始揭示CSNS在AD病理生理学中的作用。加在一起，这些 人类和小鼠的研究表明，CSN在与年龄相关的运动衰退中起着重要作用。然而，一个系统化的 尚未对CSN中与年龄相关的变化进行准确评估，以及在多大程度上 生理衰老和病理衰老的机制是相同的，但尚不清楚。这代表着一个重要的 如果解决了这一问题，可能会阐明治疗靶向的分子和细胞途径趋同。 我假设CSNS有助于在健康衰老和AD中观察到的精细运动下降。为了测试这一点， 我建议在三个方面使用行为、分子和细胞重新编程技术的组合 独立的目标。目标1将使用行为和细胞沉默技术来评估衰老的运动能力 以及有或没有CSNS的AD小鼠。目标2将使用转录组学来比较 成年、健康衰老和单细胞分辨率的阿尔茨海默病。Aim 3将利用新开发的蜂窝 来自何志刚和大卫·辛克莱实验室的重新编程方法，以评估CSN的治疗潜力- 针对衰老和AD的靶向治疗。这种治疗是一种驱动三个基因表达的病毒载体(Oct4， SOX2和KLF4)，最近被证明可以逆转小鼠神经退行性视力丧失。除了寻址 基本的科学问题，候选人的训练计划将包括磨练科学交流， 教学、指导和临床技能。何博士和辛克莱博士的联合指导将提供极好的培训 在装备精良的哈佛大学医学院的神经科学和老龄化领域。

PROJECT SUMMARY: Motor functions, such as fine motor skill, gradually decline with healthy aging as well as the pathological aging of Alzheimer’s disease (AD). These impairments considerably impact quality of life in the elderly and are thought to precede cognitive symptoms in patients with AD. Despite overlapping phenotypes, age-related motor deficits in physiological (i.e., healthy) and pathological (e.g., AD) aging have traditionally been studied separately. Thus, it is unknown if motor phenotypes and the underlying mechanisms present in healthy aging are distinct from those that precede AD cognitive symptoms. Understanding the neuropathological basis of motor decline in healthy aging and AD is crucial for the development of treatments to reverse motor decline. Corticospinal neurons (CSNs), which govern voluntary fine motor control as the only direct cortical outputs to the spinal cord, are a particularly compelling candidate underlying age-related motor deficits. Because of their extremely long axons, these neurons might be particularly vulnerable to physiological and pathological aging. Indeed, several studies of human aging have described changes in CSNs and a specific decrease in fine motor skills, but none have causally linked these changes with motor decline in aging. Likewise, though pyramidal symptoms are reported in AD patients and studies have linked AD pathology to the motor cortex, there are few studies specifically investigating the role of CSNs in AD motor symptoms. Nonetheless, mouse models that allow cell-type specific investigation are beginning to uncover a role of CSNs in AD pathophysiology. Together, these human and mouse studies nominate CSNs as important in age-related motor decline. However, a systematic assessment of precise age-related changes in CSNs has yet to be performed, and the extent to which mechanisms are shared between physiological and pathological aging is unknown. This represents a significant gap that, if addressed, could elucidate converging molecular and cellular pathways for therapeutic targeting. I hypothesize that CSNs contribute to fine motor decline observed in healthy aging and AD. To test this, I propose to use a combination of behavioral, molecular, and cellular reprogramming techniques in three independent aims. AIM 1 will use behavioral and cell silencing techniques to assess motor performance of aging and AD mice with or without CSNs. AIM 2 will use transcriptomics to compare molecular changes amongst adulthood, healthy aging, and AD at single-cell resolution. AIM 3 will leverage a newly developed cellular reprogramming method from the Zhigang He and David Sinclair labs to assess the therapeutic potential of CSN- targeted treatments in aging and AD. This treatment, a viral vector that drives expression of three genes (Oct4, Sox2, and Klf4), was recently shown to reverse neurodegenerative vision loss in mice. In addition to addressing fundamental scientific questions, the candidate’s training plan will include honing scientific communication, teaching, mentorship, and clinical skills. Joint mentorship from Drs. He and Sinclair will provide excellent training in neuroscience and aging within the well-equipped and collegial community of Harvard Medical School.