Effects Of Exercise On Behavior And Hippocampal Neuroinflammation In Autistic Rats

Objective: Autism spectrum disorder(ASD)is a pervasive neurodevelopmental disorder with persistent impairments in social interaction and social interactions,as well as a range of behaviors,interests,and activities that exhibit restriction,repetition,and stereotypy.At present,the etiology of ASD is unknown,and neuroinflammation may be an important pathogenic factor of ASD.Exercise therapy is an effective way to improve symptoms of ASD,but its biological mechanism is unknown.We speculate that exercise may improve ASD symptoms by reducing neuroinflammation(such as regulating microglia and cytokines).This study explored the effects of 6-week voluntary running wheel exercise on the behavior and hippocampal neuroinflammation of ASD rats induced by valproic acid(VPA),so as to provide a reference for the neurobiological mechanism of exercise improving ASD symptoms.Methods: In this study,SD rats were injected with 400 mg/kg weight of VPA solution on the 12.5th day of pregnancy,and the obtained offspring were used as the autism model group.Normal control group(Control,n=14).The offspring rats were subjected to behavioral tests(three-chamber social,open field,water maze test)on the23 rd day after birth,and qualified ASD group rats(n=24)were screened out through behavioral tests.Afterwards,rats(ASD,n=8,CON,n=7)were randomly selected from the two groups,and the hippocampal tissue of the rat brain was dissected out,and the levels of cytokines in the hippocampus were detected by Luminex liquid suspension chip,and the activated microglia were detected by Western blotting.The relative expression of cell-specific binding protein(Iba1)and immunofluorescence technique were used to detect the expression level of Iba1 in each subregion of hippocampus.ASD rats were randomly divided into an exercise group(E+ASD,n=8)and a nonexercise group(NE+ASD,n=8),and the E+ASD group was given 6 weeks of voluntary running wheel exercise intervention,the behavior after the intervention The clinical test and other index detection were the same as before the intervention,and compared with the normal control group(n=7).Results: 1.Behavioral changes before and after exercise intervention: Before exercise intervention,the social ability and social novelty preference of rats in the ASD group were impaired(reduced head contact time with unfamiliar rats,p<0.05),voluntary movement ability was impaired,and the desire to explore novel environments decreased(open field corner time increased,p<0.05);learning,memory,and navigation were impaired(swimming distance in the quadrant of the platform and times of crossing the platform decreased p<0.05).After 6 weeks of voluntary running wheel exercise intervention,compared with the NE+ASD group,the rats in the E+ASD group had improved social ability and social novelty preference(p<0.05),increased spontaneous activity and exploratory behavior(p<0.05),learning Improved memory capacity(p<0.05).2.Cytokine changes before and after exercise intervention: Compared with the CON group,the levels of cytokines IL-6(p=0.032)and IFN-γ(p=0.028)in the hippocampus of rats in the ASD group before intervention were significantly increased High;the protein levels of IL-4(p=0.037),IL-7(p=0.033),and IL-10(p=0.038)were significantly decreased in the ASD group.After 6-week of voluntary running exercise intervention,the protein levels of cytokine IL-2(p=0.044)、IL-4(p=0.034)protein levels in the NE+ASD group were significantly higher than those in the E+ASD group,and IL-10(p=0.040)protein levels were significantly lower than those in the E+ASD group.3.Changes in the relative expression levels of microglial activation proteins before and after exercise intervention: Before the intervention,there was no significant difference in the relative expression of Iba1 protein between the ASD group and the CON group(p>0.05);the Iba1 fluorescence intensity of the hippocampal CA1(p=0.043)and CA3(p=0.031)subregions in the ASD group was significantly increased compared with that in the CON group.After 6 weeks of voluntary running wheel exercise intervention,the relative expression of Iba1 protein in the E+ASD group was significantly lower than that in the NE+ASD group(p=0.045),and there was no statistically significant difference between the E+ASD group and the CON group;the Iba1 fluorescence intensity of the hippocampal CA1(p=0.030)and CA3(p=0.011)subregions in the E+ASD group was significantly lower than that of the NE+ASD group in,and there was no significant difference with the CON group(p>0.05).4.Correlation analysis between behavior and neuroinflammation: Iba1 and IL-2levels were negatively correlated with the exploration behavior and spontaneous activity of ASD rats(r=-0.499,p=0.030;r=-0.461,p=0.041);IL-4 level was negatively correlated with social novelty preference of ASD rats(r=-0.461,p=0.041);Iba1 was positively correlated with IL-2 level(r=0.589,p=0.010).Conclusion: 1.6-week voluntary running wheel exercise intervention can 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.2.6-week of voluntary running wheel exercise cancan reduce the hippocampal neuroinflammation of ASD rats,reduce the levels of hippocampal cytokines IL-2 and IL-4,increase the levels of IL-7 and IL-10,and reduce the microglia in CA1 and CA3 subregions abnormal activation.Correlation analysis showed that the 6-week voluntary running wheel exercise improved the behavior of ASD rats may be related to the reduction of hippocampal neuroinflammation.