Voluntary wheel running behavior is reduced by SARS-CoV-2 S1 administration and mitigates hypothalamic...

Post-acute sequelae of SARS-CoV-2 infection (PASC) is a major public health consequence of COVID-19. Persistent PASC symptoms affect multiple physiological systems, including the nervous system. The etiology of PASC is unknown; however, brain-mediated symptoms may arise from dysregulated neuroinflammatory processes. We have reported that intra-cisterna magna (ICM) administration of the SARS-CoV-2 spike (S)1 antigen in rats induces behavioral alterations, prolonged neuroinflammation, and reduced brain corticosterone. Inappropriate neuroinflammation triggered by immune challenge suppresses motivated behaviors, including voluntary wheel running (VWR), and disrupts diurnal rhythms. Accordingly, this study tested the hypothesis that S1 reduces VWR distance and changes diurnal activity patterns. Given evidence that regular physical activity reduces inflammation, we also determined whether VWR attenuates the neuroinflammatory effects of S1. Male Sprague-Dawley rats were housed with either locked (sedentary) or unlocked (VWR) running wheels. After 12 days, rats received ICM S1 or vehicle and remained undisturbed while VWR was recorded for 17 days. S1-treated rats ran less and showed disrupted diurnal VWR patterns compared with vehicle controls. Eighteen days post-ICM injections, sedentary S1-treated rats, but not VWR rats, exhibited persistent elevation of hypothalamic gene expression of IL1β, MhcII, Tlr2, and Tlr4. In contrast, VWR S1-treated rats, but not sedentary S1-treated rats, had elevated hypothalamic corticosterone 18 days post-injection. Taken together, S1 in the brain produces behavioral symptoms of PASC and prolonged neuroinflammation. Despite reductions in total running distance after S1, VWR was sufficient to block the persistent upregulation of neuroinflammatory genes. Brain corticosterone may contribute to the impacts of S1 and VWR.