Effects Of Prenatal Exposure To Inflammation And Adolescent Stress On Cognition And Synaptic Proteins In Aged CD-1 Mice

Background: Numerous studies have shown that infectious inflammation in the embryo has an adverse effect on the development of the individual's nervous system,which will directly lead to changes in cognitive behavior in the elderly.The protein expression in presynaptic and postsynaptic changes can be used to assess synaptic plasticity and further assess learning and memory.Previous studies have shown that changes in the expression levels of certain synaptic proteins,such as Synaptotagmin-1,Syntaxin-1 and postsynaptic density protein 95,are associated with age-associated impairment of spatial learning and memory ability(AISLM).However,most studies have only stayed at the level of protein molecules and have not studied more deeply the mechanisms of AISLM.Has the level of m RNA in upstream of synaptic proteins changed,and is it related to AISLM? Are other synaptic proteins in the synaptic structure also associated with AISLM? Such as the activity-related cytoskeleton-related protein(Arc).Whether embryonic exposure to inflammation combined with adolescent stress will affect AISLM and expression of synaptic proteins provides a new idea for exploring the mechanism of brain aging and finding effective ways to prevent brain aging.Objectives: To investigate the effects of embryonic exposure to inflammation and puberty stress on spatial learning and memory,expression of hippocampal synaptic protein and m RNA(Acr and Syt-1)in aged CD-1 mice.Methods: In our study,CD-1 pregnant mice received intraperitoneal injection of LPS(50 ?g/kg)or normal saline daily at 15-17 days of gestation,and some of the offspring were randomly selected and given stress at the age of puberty(2 months),that is mice were randomly selected to hang,bind,light or fast at night every day,four days a cycle,a total of seven cycles.At this time,the mice were divided into four groups: control group(CON),control + stress group(CON + S),LPS group(LPS),and LPS + stress group(LPS + S).Morris water maze(MWM)was used to assess the spatial learning and memory abilities of offspring at the age of 3 months and 15 months.The mice were sacrificed 15 days after the MWM test,and brain tissues were taken out and saved.Immunohistochemistry and Western Blotting were used to detect the expression of hippocampal synaptic proteins Arc and Syt-1.RNA-scope was used to detect the expression levels of Arc m RNA and Syt-1 m RNA in different subregions of hippocampus.Analyze all data using appropriate statistical methods.Results:(1)Morris water maze: Compared with the 3-month-old CON group,the swimming distance of the 15-month-old CON mice in the learning period was significantly longer,and the percentage of the distance in the target quadrant of the memory period was significantly reduced(Ps < 0.05).Compared with the CON group of the same age,the swimming distance in the learning period of the mice aged 3 and 15 months was significantly longer,and the distance of the mice in the LPS was longer than that of the CON + S group and significantly shorter than that of the LPS + S(Ps < 0.05);The percentage of distance in the target quadrant of the memory period of mice in different treatment groups was significantly reduced,and the percentage of distance in the LPS was significantly lower than that in the CON + S group and higher than that in the LPS + S(Ps < 0.05).(2)Synaptic protein expression: Compared with the 3-month-old CON group,the levels of total Arc and syt-1 protein in hippocampus and the levels of Arc and Syt-1 m RNA in subregions of 15-month-old CON mice were significantly increased(Ps < 0.05).Compared with the CON group of the same age,the expression levels of Arc and Syt-1 protein at different treatment groups at 3 and 15 months mice were significantly increased(Ps < 0.05),and the LPS and LPS + S groups were significantly higher than those in the CON + S group(especially LPS + S group)(Ps < 0.05).In addition,in the 3 and 15-month,the expression of Arc m RNA in CA1 and CA3 subregions in the LPS + S groups were significantly higher than in the CON,CON + S,and LPS groups(Ps < 0.05).Arc m RNA levels in the 15 months LPS group were significantly higher than those in the CON(CA1 and CA3)and CON+S group(CA3)(Ps < 0.05).The Syt-1 m RNA of mice in the 3 months LPS + S group was significantly higher in the CA3 subregion than in the CON,CON + S,and LPS groups(Ps < 0.05).The levels of Syt-1 m RNA in the CA1 and CA3 subregions of 15 months LPS and LPS+S groups were significantly higher than those of CON(Ps < 0.05),and the level of Syt-1 m RNA in 15 months LPS group were significantly higher than that of CON(CA1 and CA3)and CON+S group(CA3)(Ps < 0.05).(3)Correlation analysis showed that the increase of Arc and Syt-1 protein levels in the 3 months LPS,LPS + S group and 15 months four groups were significantly positively related to the distance during the learning period(Ps < 0.05),and negatively correlated with the percentage of distance in the target quadrant during the memory period(Ps < 0.05).The percentage of swimming distance was significantly negatively correlated(Ps < 0.05).The changes of Arc m RNA and Syt-1 m RNA expression in the CA1 and CA3 hippocampal subregions of mice were significantly related to changes in learning and memory abilities(Ps < 0.05).Conclusions: Embryonic exposure to inflammation or adolescent stress can aggravate AISLM and the expression of Syt-1 and Arc in hippocampai,and both embryonic inflammation and chronic adolescent stress have a synergistic worsening effect.