RÉSUMÉ
Objective @# To explore the mechanism of hippocampal corticotropin-releasing hormone ( CRH) receptor type 1 ( CRHR1 ) in chronic stress-induced learning and memory impairment in early aged mice．@*Methods@#C57BL /6J mice aged 12 －14 months were divided into two groups according to gender，and then divided into wild type (WT) group and hippocampal CRHR1 conditional gene knockout (KN) group according to genotype．Mice in each group were randomly divided into control group and stress group，and the stress group was subjected to chronic unpredictable stress ( CUS ) for 30 days． Genotyping of mice was performed using polymerase chain reaction ( PCR) ，agarose gel electrophoresis and real-time fluorescence quantitative PCR (RT-qPCR) ．The new object rec- ognition experiment and Morris Water maze measured learning and memory ability．Golgi-Cox staining was used to observe damage to hippocampal neuronal dendrites． The protein expressions of target protein of rapamycin (mTOR) ，p-mTOR (Ser2448) ，ribosomal protein S6 kinase ( p70S6K) and p-p70S6K ( Thr389 / Thr412 ) were detected by Western blot．Serum levels of corticotropin releasing hormone ( CRH) were measured by ELISA. @*Results @# Compared to mice without chronic stress，the cognitive coefficient of WT stress groups decreased after chron- ic stress，and the difference was statistically significant (P ＜0. 05) ，while there was no significant difference in cognitive coefficient of KN stress groups before and after chronic stress．Compared with the WT stress group，the escape latency of the WT control group was shortened (P＜0. 05) ，and the number of crossing the platform and tar- get quadrant increased (P ＜0. 01) ，and there was no significant difference in the KN groups above． Compared with the WT control group，the WT stress group had a significant reduction in the neuronal complexity in the hipp- ocampal CA1，CA3 and DG regions (P ＜0. 05) and significant reductions in the expression of p-mTOR and p- p70S6K in the hippocampus (P＜0. 05) ．There was no significant difference in the expression of p-mTOR between the KN stress group and the KN control group (P＞0. 05) ，except that the expression of p-mTOR in the hippocam- pus of the female group decreased (P＜0. 05) ．In addition，the serum level of CRH in the stress group was higher than that in the control group (P＜0. 01) ．@*Conclusion @#Hippocampal CRHR1 regulates learning and memory im- pairment and neuronal dendrite damage in early aged mice induced by chronic stress．The mechanism may be that high levels of CRH induced by chronic stress cannot bind to CRHR1 receptor，thereby enhancing the expression of down-regulated mTOR / p70S6K signaling pathway.
RÉSUMÉ
Objective @#To investigate the sex difference of the effects of chronic pregnancy stress on depression-like behavior in offspring adolescent mice and whether the amygdala is involved in mediating depression-like behavior and its possible mechanism．@*Methods @#Male and female of C57BL /6J mice were put in cage together．Pregnant mice were randomly divided into normal control group ( CON group) and chronic pregnancy stress group ( CPS group) ．The day of delivery was recorded as post-natal day(PND0) ．The offspring of different groups were divided into Female group and Male groupaccording to sex，respectively．From PND35，the depressive-like behavior of off- spring was monitored in different groups．Morphological structure of basolateral amygdala (BLA) cone neurone was observed by Golgi-Cox staining，and apoptosis of BLA neurone was detected by TUNEL．Serum corticotrophin-relea- sing hormone ( CRH) was detected by ELISA．The level of protein associated with amygdala mammalian target of rapamycin (mTOR) and phosphorylated mammalian target of rapamycin ［p-mTOR ( Ser2448) ］was detected by Western blot.@*Results @#Depression-like behavior was appeared in different sexual offspring by chronic pregnancy stress，and there was an interaction between chronic pregnancy stress and gender．In the forced swimming test，the immobility time of offspring in the CPS group prominently increased(Female: P＜0. 05，Male: P＜0. 001) ．Interest- ingly，compared with female offspring ，despairing behavior of male offspring was much more clearly observed in CPS group(P＜0. 05) ．Compared with offspring of CON group，the rate of sucrose preference was significantly re- duced in the female offspring of CPS group(P＜0. 05) ，while no obvious difference was observed in the male off- spring．Compared with the CON group，the density of neuronal dendrite branches in the BLA of offspring mice in the CPS group decreased(Female: P＜0. 01，Male : P＜0. 01) and the degree of neuronal apoptosis increased( Fe- male: P＜0. 001，Male : P ＜0. 001) ，the expression level of p-mTOR in amygdala of offspring mice in CPS group significantly decreased(Female: P＜0. 001，Male: P＜0. 001) ．Chronic pregnancy stress increased the serum CRH level of offspring mice(P＜0. 001) ，and the gender had significant influence on serum CRH level，the serum CRH level of female in CPS group was higher than that of male(P＜0. 05) ．@*Conclusion @#Chronic pregnancy stress leads to depression-like behavior in offspring adolescent mice，and the depression-like behavior has gender differences. In addition，chronic pregnancy stress leads to dendrite atrophy and apoptosis of BLA neurons in offspring mice，and the mechanism may be that the activation of mTOR in the amygdala of offspring mice is inhibited．CRH may be in- volved in mediating sex differences in depression-like behavior and BLA neuron damage in offspring induced by chronic pregnancy stress.