Effects of exercise on behavior and hippocampal neuroinflammation in rat model of autism spectrum disorder

Background: Running exercise has been shown to relieve symptoms of autism spectrum disorder (ASD), but the mechanisms underlying the positive effects of exercise are unclear. Neuroinflammation, involving dysregulated microglial activation and cytokine release, is implicated in ASD pathophysiology. The hippocampus is a key region for social and cognitive functions impaired in ASD and is susceptible to neuroinflammatory changes. However, the effects of running exercise on hippocampal neuroinflammation in ASD have not been studied. Methods: An ASD rat model was induced by prenatal valproic acid (VPA) exposure, followed by a 6-week voluntary running wheel intervention starting from postnatal day 28. The behavioral performance before and after the intervention was evaluated using the three-chamber social interaction test, the open field test, and the Morris water maze test to assess social, exploratory, and cognitive functions. After the intervention, hippocampal tissues were collected, and Iba1+ microglial activation subregions were analyzed by immunofluorescence, and cytokine levels were quantified based on luminex. Results: The results showed that 6-week of voluntary running exercise could improve the social ability and social novelty preference of ASD rats, increase their exploration behavior and spontaneous activities, and improve the ability of learning and memory. In addition, 6-week of voluntary running exercise attenuated the VPA-induced microglial activation in the CA1 and CA3 region of the hippocampus. Furthermore, exercise could reduce the level of IL- 2, IL-4 and increase the level of IL-7 and IL-10. Conclusions: These findings suggest that the antidepressant effects of exercise may be mediated by reducing the number of microglia and inhibiting microglial activation and neuroinflammation in the hippocampus.