| Backgrounds and ObjectiveWith the growing competition in the world, human populations inhabitenvironments with many different kinds of chronic stressors. maternal stressbefore or during or after pregnancy would harmful the development of brain inoffspring and lead to their behavior disorder in later life. Most of studies focusedon the effects of stress exposure during pregnancy. There are currently a fewexperiments that examine the effect of stress before pregnancy on offspring. Inour research, we use SD rats to investigate the effect of chronic unpredictablestress(CUS)before pregnancy on memory functions and serum corticosterone (COR)levels , as well as the expression of brain-derived neurotrophic factor (BDNF),N-methyl-D-aspartate (NMDA) receptors 2A (NR2A) and 2B (NR2B) receptors in thehippocampus of the offspring rats when they were two months postnatally.MethodsAdult female Sprague-Dawley (SD) rats were divided randomly into two groups:control group (n=8) and chronic unpredictable stress (CUS) group (n=12). All ratswere tested in the open field test and sucrose intake test before and after CUS.When the procedure of CUS finished (24 hours after the last stressor), female ratswere housed by pairs with a male for one week for mating. The day on which spermwas observed in vaginal smears was designated as embryonic day 0 (E0). The dayof delivery was designated as postnatal day 0 (PND0). When the offspring rats werePND60, they were divided according to their maternal group: offspring of controlgroup (n=60;30 females and 30 males) and offspring of CUS group (n=60;30 femalesand 30 males).The memory functions of their offspring were tested in the Morriswater maze. Serum COR levels were determined by using a standard radioimmunoassaykit. The expression of BDNF, NR2A and NR2B in the hippocampus of the offspringrats were studied by immunoreactivity quantitative analysis and real-time RT-PCR. Due to the sex effect,gender-specific comparisons were carried out.Results'Gain of body weight in maternal rats exposed to CUS was significantly slowerthan in controls(P<0.05).Before CUS,there was no difference in the total distance,central distance, peripheral distance of open field test between two maternalgroups (P>0.05).After CUS,the total distance ,the peripheral distance and thecentral distance of CUS group was lower than control group (P<0.01) and also lowerthan that before CUS (P<0.01). Before CUS, total water consumption, the sucrosecomsumption and sucrose preference ratio between two group was no significantdifferences(P>0.05). After CUS, total water consumption showed no differencebetween groups, but the sucrose comsumption and sucrose preference ratio of CUSgroup were lower than control group(P<0.01), and also lower than that beforeCUS(P<0.01).'In 4-day training period of Morris water maze test,the escape latencies(EL)of female offspring in CUS group ,(53.7±12.2)s,(35.7±19.3)s,(29.9±13.7)s respectively, were longer than female offspring in control group(44.8±19.2)s,(30.9±18.4)s,(21.7±15.8)s respectively,on the first,second,fourth day(P<0.05), especially on the fourth day(P<0.01).The EL of male offspring inCUS group(26.9±20.1)s was longer than male offspring in control group(17.1±16.0)s only on the fourth day(P<0.01). In the probe test, no significantdifferences in the total swimming path or the swimming speed were identified inthe offspring of two group(P>0.05). The differences in the number of times thatthe rat crossed the position where the platform had been were significantly reducedin both female(2.6±1.7)and male(2.9±2.3)offspring of CUS groups than thesame gender offspring of control group,(4.6±3.0)and(4.9±3.4)respectively.Thedistance of platform surrounding area of CUS group in female(596.5±253.1)cmand male(702.8±287.2)cm offspring were shorter than control in in female(985.6±208.9)cm and male(1126.2±215.3)cm offspring(P<0.01).'CUS induced a significant increase in serum COR levels of the offspring rats in female(128.9±7.3)ng/ml and male(116.5±10.9)ng/ml than control group infemale(119.9±9.0)ng/ml and male(105.4±10.4)ng/ml offspring(P<0.01).'Immunoreactivity quantitative analysis shows that the immunoreactive cellnumbers of BDNF in CA3 and DG sub-regions in the female offspring of CUS group(9.67±1.86),(10.17±2.23)was decreased than control group(16.67±2.16), (16.83±1.32),as well as the male offspring of CUS group(11.8±2.37),(11.83±1.60)comparing with control group (17.50±1.79),(17.0±0.89)(P<0.01). Theimmunoreactive cell numbers of NR2B in CA3 and DG sub-regions in the femaleoffspring of CUS group(10.50±1.76),( 9.17±2.41)was decreased than controlgroup(15.3±1.87), (15.63±2.40),as well as the male offspring of CUS group(11.50±1.22),(11.29±1.05)comparing with control group (16.13±1.97),(17.50±1.52)(P<0.01),but NR2A levels were not altered between the offspring of the two groupsin both female and male(P>0.05).'RT-PCR shows that the level of BDNF mRNA in the hippocampus of femaleoffspring of CUS group(4.55±0.37)was less than control group(6.65±0.26),aswell as male offspring of CUS group(4.75±0.30)comparing with control group(6.77±0.20)(P<0.01). The level of NRAB mRNA in the hippocampus of femaleoffspring of CUS group(1.13±0.14)was less than control group(2.25±0.14),aswell as male offspring of CUS group(1.20±0.14)comparing with control group(2.27±0.16)(P<0.01).No significant difference in the levels of NR2A mRNA wasdetected between offspring of CUS and offspring of control groups in both femaleand male(P>0.05).'Bivariate correlations demonstrated correlations between both escapelatency, and COR level with BDNF. Offspring rats of CUS with higher COR level havedecreased BDNF expression in the hippocampal also exhibited longger escape latencyin the Morris water maze test. Also, there were significant positive correlationsbetween BDNF and NR2B. The offspring rats of CUS with lower BDNF expression inthe hippocampal had lower NR2B.Conclusion 'In our research, the EL of CUS offspring group were prolonged than the controloffspring group,the number of times that the rat crossed the position where theplatform had been were reduced in both female and male offspring of CUS groupsthan the same gender offspring of control group, the distance of platformsurrounding area in offspring of CUS group were shorter than control offspringin Morris water maze,which suggested that spatial probe ability were decreasedand their learning and memory function were impaired.'Significant correlations were observed between the expression of BDNF,NR2B and memory function as well as COR level of offspring rats in our study. Ratswith higher COR levels had lower BDNF and NR2B expression in hippocampi and impairedtheir learning and memory function in the Morris water maze test. These findingssuggest that the offspring of pregestational stress having fewer synapses arerelated to a dysfunctional HPA responsivity to stressor and BDNF,NR2B expressionmay be in part mediated by COR.'In our study, pregestational stress can increase serum corticosterone levelsand reduce the expression of BDNF and NR2B in the hippocampus of offspring. Thesealterations are associated with impairment of learning and memory function in theadult offspring. These data suggest that stress before pregnancy might have aprofound influence on brain development of offspring ,that may persist into andbe manifested in adulthood . |
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