Chronic Stress Impact Sex-related CRFR1 Expression And Behavior Deficits On AD Transgenic Mice

Objective: To demonstrate age-and sex-related differences impact behavior change and the expression of corticotropin-releasing factor receptor-1(CRFR1)in different brain region of C57/BL6 mice.Meanwhile,using chronic stressed APP/PS1 transgenic mice to investigate behavioral affection and CRF/CRFR1-Gs-PKA downstream signaling in hippocampus.In this study,we investigate whether chronic stress impact sex-related CRF/CRF1 downstream signaling pathways mediate AD pathology and memory function deficits.Methods: C57/BL6 mice were randomly divided into 4 group(10 for each group):5-month-old male,5-month-old female,20-month-old male,20-month-old female.And using 21 days chronic unpredictable mild stress(CUMS)methods to build stress model with 6-month-old APP/PS1+ transgenic mice.Randomly separated APP/PS1+model into 4 groups(8-10 for each group): APP/PS1 male group,APP/PS1 female group,CUMS APP/PS1 male group,CUMS APP/PS1 female group.The behavioral test of open field,light/dark box and sucrose preference test were investigated anxiety-like behavior in animal models.Morris water maze and Novel object recognition test were investigated recognition memory and spatial learning.Using Western blot to detect expression of CRFR1 and PKA in different brain regions.Results:1.In this study,there is no significant difference of age-and sex-related anxiety-like behavior change in C56/ BL6 mice.In novel object recognition test,the 5-month-old females discrimination indices(%)was lower than males(P<0.05).With age increase,compare with 5-month-old females,20-month-old females was significant decreased(P<0.05).Compare with 5-month-old femaleand male C57/BL6 mice,20-month-old mice the expression of CRFR1 in amygdala and hypothalamus were significant decreased(P<0.05).However,the expression of CRFR1 in cortex of 20-month-old female and male mice was increased than 5-month-old females and males(P<0.05).In addition,the CRFR1 expression in hippocampus of 20-month-old males group was lower than females(P<0.05).2.After chronic stress,CUMS APP-Female group compare with CUMS APP-Male group the central travel distance was significant decreased,which showed anxiety-like behavioral changes(P<0.01).CUMS APP-Female group showed more memory function deficits than APP-Female group(P<0.05).Moreover,the expression of CRFR1 and PKA in CUMS APP-Female hippocampus was increased than APP-Female group(P<0.01),and CRFR1 expression in CUMS APP-Male hippocampus was lower than CUMS-Female group(P<0.05).Conclusion:1.Without stressors stimulation,the expression of CRFR1 in the hypothalamus and amygdala were decreased with age,but no sex-related anxiety-like behavioral changes in young and aged groups.In contract,the aged group,the expression of CRFR1 in the hippocampus and cerebral cortex were increased with age,and accompanied by cognitive memory function changes.Especially,the female group was more pronounced.2.APP / PS1 transgenic mice showed sex-related anxiety-like and cognitive memory function deficits after chronic unpredictable stress.Significantly,the protein expression of CRFR1 and PKA were increased in hippocampus of CUMS APP / PS1 transgenic mice,furthermore,the female group was more remarkable.