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

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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.