Sex differences in the effects of prior social isolation stress on stroke outcomes

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Project Summary Social isolation increases risk of all-cause mortality and chronic diseases such as obesity, cardiovascular disease, dementia, and stroke.12,13 A lack of social connectedness, or isolation, is exacerbated with age due to partner loss, family disconnect, and a narrowing of social networks. However, with the ongoing COVID-19 pandemic and long periods of social distancing, social isolation has become a widespread phenomenon. As such, it is urgent to elucidate the physiological effects of social isolation (SI) and subsequent vulnerability to injury or disease. Stroke is a leading cause of death worldwide and is the cause of 1 in 6 cardiovascular related deaths. Ischemic stroke accounts for over 80% of overall incidence.14,15 Social isolation after stroke is of clinical relevance due to the recovery process requiring patients to spend many hours in physical and occupational therapies away from family members, loss of mobility, and language impairment. Thus while social isolation in stroke patients has often been studied during the recovery period,16,17 a recent study showed that the risk of death due to stroke was higher when comparing the most isolated patients to the least isolated patients prior to stroke.18 In the following proposed studies the overarching hypothesis that prior-social isolation (SI) mediates worsened stroke outcomes will be tested. The immediate goal is to identify, if any, sex differences in prior-SI and stroke severity. The long-term goal is to understand the mechanism by which prior-SI affects stroke severity and propose a potential therapy for mitigating harmful effects of prior-SI. This will be studied in the following 3 aims: Aim 1: To investigate the effect of pre-stroke social isolation on stroke severity and outcome. -Sub-Aim 1a: To investigate the hypothesis that prior-SIS worsens acute post-stroke outcomes. -Sub-Aim 1b: To investigate the hypothesis that prior SIS worsens post-stroke cognitive impairment. Aim 2: To test the hypothesis that stroke outcomes are exacerbated by prior social isolation stress (SIS) due to maladaptive cellular changes and inflammation in the central nervous system. -Sub Aim 2a: To test the hypothesis that prior-SIS increases stroke-induced blood brain barrier permeability. -Sub Aim 2b: To test the hypothesis that prior-SIS will induce a neuroinflammatory state in which microglia and astrocytes become activated, leading to worsened stroke outcomes. Considering the extensive isolation undergone by the majority of the population throughout the COVID-19 pandemic, it is critical to consider the long-term effects of prior-SIS on stroke. These findings advance our understanding and awareness of the future implications of COVID-19. This training plan's focus on elucidating the effects of stressors on brain health and vulnerability to disease fit well with my goal of becoming a physician scientist in the field of neurology. The procedures described in this application are well established in the sponsor's lab, and the pilot data was acquired by me while learning these techniques.