Exercise Preconditioning and Compensatory Oligodendrogenesis in Subcortical Ischemic Vascular Dementia

/ABSTRACT White matter damage plays an important role in the pathophysiology of cerebrovascular disease, including vascular contributions to cognitive impairment and dementia (VCID). Oligodendrocytes, the primary cells in the white matter, do not proliferate on their own; instead, their progenitor cells, known as oligodendrocyte precursor cells (OPCs), are essential for the generation of new oligodendrocytes during the remyelination process following white matter injury. Although OPCs are essential for white matter recovery and repair, the mechanisms regulating their proliferation and differentiation, key processes in compensatory oligodendrogenesis, still remain poorly understood. Subcortical ischemic vascular dementia (SIVD) is the most common subtype of VCID and is often associated with aging. It is clinically manifested by cognitive decline due to subcortical infarcts and persistent cerebral hypoperfusion leading to progressive white matter deterioration. As the global population ages, the incidence of SIVD is expected to increase, underscoring the urgency of developing effective treatments. Understanding the cellular and molecular basis of white matter damage and repair, with a focus on the role of OPCs in compensatory oligodendrogenesis, is critical. While the regulatory mechanisms behind OPC proliferation and differentiation during development are relatively well understood, the processes in the adult brain under pathological conditions remain elusive and represent a significant gap in our current knowledge. Notably, polypharmacy among elderly patients has become a serious societal problem worldwide, and it is important to pursue the therapeutic option of exercise as a non-pharmacological approach to mitigate cognitive decline in patients with SIVD or other dementias. We and others have shown that daily exercise is effective in promoting compensatory responses in mouse models of cerebrovascular disease, including stroke and VCID. Given the link between exercise, circadian/diurnal rhythms, and OPC function, our study proposes two specific aims to test the overarching hypothesis that exercise preconditioning promotes compensatory oligodendrogenesis by regulating the time-dependent expression changes of Bmal1, a key clock gene, in SIVD. In Aim 1, we will evaluate the effects of exercise preconditioning on OPC function and Bmal1 circadian/diurnal changes in mouse models of SIVD. Aim 2 will demonstrate that Bmal1 deficiency in OPCs reduces the efficacy of exercise preconditioning on compensatory oligodendrogenesis and cognitive function in SIVD mice. Our study is expected to pave the way for new non-pharmacological therapeutic strategies for SIVD and other types of dementia. Project Number: 1R21NS145499-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Ken Arai | Institution: MASSACHUSETTS GENERAL HOSPITAL, BOSTON, MA | Award Amount: $439,150 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 CN-E (02)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11243073