Study On The Improving Effect And Mechanism Of Voluntary Exercise On Anxiety-depression-like Behaviors Of Bullied Mic

Bullying is unwanted,aggressive behavior among school-age children that involves a real or perceived power imbalance.The behavior is repeated,or has the potential to be repeated,over time.Both kids who are bullied and who bully others may have serious,lasting problems.In recent years,the incidence of school bullying has remained high,far higher than public expectations,and it is pervasive across cultures.According to data released by united nations educational scientific and cultural organization(UNESCO)in2019,up to 35% of students worldwide are actively or passively involved in school bullying.Bullying has negative impact on the bullied ones in academic development,physical and mental health,and even threatens their lives.To date,bullying prevention and intervention strategy pay more attention on external intervention,but lack of means to strengthen individual’s psychological defense ability.Recently,physical exercise,as a simple,feasible,and popular prevention and intervention method with less side effects,gained extensive attention.Studies have shown that reasonable and regular sports can reduce the incidence of school bullying and psychological problems of bullied ones.Current researches regarding the effect of exercise on bullying mostly focus on cross-sectional and quasi-experimental study,which is not able to explain the causal relationship between variables.In addition,due to the limitation of reality,it is difficult to explore how physical exercise affects bullying-related neurophysiological changes in human subjects.Chronic social defeat stress(CSDS)can well mimic bullying.In this paradigm,each C57BL/6J mouse was introduced into the home cage of an aggressive and older CD1 resident aggressor every day,resulting in the former being defeated and causing chronic mental stress.CSDS conform the three major characteristics of bullying: repeatability,intentionality,and imbalance of power.Voluntary wheel running(VWR)is a paradigm that simulates spontaneous physical exercise.VWR are more practical and has more research significance in comparison to other exercise paradigms.In this study,the defeated C57BL/6J mice was used to simulate bullied individuals in bullying.Mice did voluntary wheel running for 21 days in their home cage before exposed to CSDS.We aimed to investigate whether 21-days VWR could prevent the development of CSDS-induced social avoidance,anxiety-and depressive-like behavior in defeated mice,and to explore underlying molecular mechanisms.Specifically,only male C57BL/6J wild-type mice were used in this study.Mice were randomly divided into four groups: VWR-CSDS,VWR + CSDS,SED-CSDS,and SED +CSDS.The VWR+CSDS group mice performed voluntary wheel running for 21 days in their home cage before they were exposed to CSDS,while SED+CSDS mice did not run before being exposed to CSDS.The other two groups of mice,the VWR-CSDS mice and the SED-CSDS mice,were stress-control mice;the former performed wheel running for 21 days,and the latter did not.We then used a series of behavioral assays to evaluate their anxietyand depression-like behaviors,such as social interaction(SI),sucrose preference(SP),open-field(OF),elevated plus maze(EPM)and tail suspension test(TST).Finally,we measured transcripts and protein levels for BDNF,IL-6 and GHSR1 a in the hippocampus of these mice by RT q-PCR and ELISA respectively.We found that:(1)The body weight of VWR mice was significantly lower than that of control SED mice.(2)SED + CSDS mice exhibited social avoidance,anhedonia,and increased anxiety.In details,SED + CSDS mice displayed less social interaction time,lower sucrose preference and less exploration in central arena of open field than SED-CSDS mice.(3)VWR+CSDS mice displayed less depression-and anxiety-like behavior and less social avoidance than SED+CSDS mice.Specifically,in comparison to SED+CSDS mice,VWR +CSDS mice spent more time exploring interaction area in social interaction test,exhibited higher sucrose/water ratio in sucrose preference test,and showed more open-arm exploration time in the elevated plus maze test.The hippocampal is very sensitive to stress.Both the volume and synaptic plasticity of the hippocampus were found to be reduced in bullied adolescents.Previously,our laboratory showed that the expression of GHSR1 a,IL-6,and BDNF in the hippocampus of CSDS-exposed mice were altered,which were closely associated with anxiety-and depression-like behaviors in stressed mice.Therefore,we further investigated in this study the effect of voluntary wheel running on expression of those factors in the hippocampus of defeated mice.We found that:(4)both transcripts and protein levels of BDNF and IL-6,and GHSR1 a protein were upregulated in the hippocampus of SED+CSDS mice compared to control SED-CSDS mice.(5)Voluntary wheel running prevented CSDS-induced upregulation of Ghsr1 a and Il-6 in the hippocampus.The m RNA transcription of Ghsr1 a and Il-6 in the hippocampus of VWR + CSDS mice were lower than SED + CSDS mice.(6)Voluntary wheel running prevented CSDS-induced upregulation of BDNF,IL-6 and GHSR1 a levels in the hippocampus.ELISA results showed that hippocampal concentration of BDNF,IL-6 and GHSR1 a were lower in VWR+CSDS mice than in SED + CSDS mice.In summary,we make the following conclusion:(1)VWR for 21 days prevents social avoidance,reduces depression-and anxiety-like behavior in bullied mice.(2)The suppressive effect of VWR on CSDS-induced affective dysfunction may be due to altered IL-6,BDNF and GHSR1 a expression in the hippocampus;however,the precise mechanisms remain to be uncovered.Accordingly,we suggest that sports should be included in developing school anti-bullying programs,to inspire sports interests and to train exercise habits.This strategy can not only improve the physical health of children and adolescents,but also effectively resist the social avoidance,anxiety and depression caused by bullying when they are bullied.