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In China,large numbers of the massive rural population moved to urban areas spurred by the economic boom and dramatic societal changes during the past two decades.However,most parents have not taken their children with them because they cannot afford to raise them in the city.An estimated 23-30 million children have remained in their rural communities to be cared for by a single parent,grandparents,or other relatives.Often neglected,they are known as "liushuoer tong" ("left-behind children").This separation of children from their parents is called maternal separation (MS),one type of early life stress.Accumulating evidence indicates that disruption of mother-infant interactions by MS leads to long-term effects on neuroendocrine levels and behaviors,involving an enhanced stress response; increased levels of anxiety,helplessness and anhedonia,and an increased propensity for the use of addictive drugs.Much of the scientific community relies on rodent models to examine the mechanisms of mental disorders,but the available reports on maternal separation models in rats and mice are conflicting.Therefore,we investigated the effects of maternal separation in C57BL/6J mice,In particular,what extent it can imitate the mental effects observed in humans.We imposed MS on mice by separating newborn C57BU6J pups from their dams for 3 hours daily from the 2"1 to the 15lh days.The behavior tests were started when the pups were 12-20 weeks old.The results show MS mice took longer to make choices,displaying excessive caution using decision-making tests,indicating c-fos passivation to stress in hippocampal areas CA1,DG,CeA and PFC.This suggests that MS alters the nerve development in these brain regions,influencing these brain areas-related functions,primarily cognitive function.MS did not significantly alter brain glucocorticoid receptor expression,but significantly decreased 11p-hydroxysteroid dehydrogenase expression in most brain regions,and highlighted higher level of corticosterone in the dexamethasone/corticotropin-releasing hormone test,which suggest that the hypothalamo-pituitary-adrenal axis of MS mice had become unstable.These changes are not enough to show the depression/anxiety-like behavior observed in humans,but increase the possibilities of depression/anxiety-like behavior.Social withdrawal,which is related to social cognitive dysfunction,is one of the main problems in depressive patients and people with histories of early life stress.Social recognition tests can detect the social interaction of rats and mice,partly reflecting their social cognitive function.The test consisted of two 4 minute exposures to a conspecific mouse of the same sex in a small metal mash cage (Franklin TB,PLoS ONE.2011;6(7): e21842.).The exposures were separated by a 35 minute retention interval,and the ratio between the Social Interactions of the two exposures was the Discrimination Ratio.MS mice were further stressed by restraining them for 3 hours per day in a 50 mL tube.This test showed that MS mice had no difference in social cognitive function from control mice under normal conditions,but after 14 days of restrained stress,the discrimination ratio of MS mice decreased markedly.These results illustrate that social interactions in MS mice were easier to deteriorate than in mice without a history of MS under a stress condition.Next,we increased the MS time to 8 hours per day,which resulted in mice with social cognition dysfunction under normal conditions.Changes in DNA methylation is one reason why the effects of early life stress remain in the body after childhood.The DNA methylation profile of MS mice may provide clues to identify these changes.We used NimbleGen mouse DNA methylation 3 * 720K promoters with a CpG island array to detect the whole genome methylation condition of MS mice (8 hours/day).The results show that 1 058 gene promoters were hyper-methylated and 718 gene promoters were hypo-methylated.Pathway analysis showed that hyper-methylated genes were related to "neuron development and differentiation","transcription regulator activity",and "pathways in cancer",while hypo-methylated genes were related to "Zinc fingers","small lung cell cancer",and "Parkinsons disease".These data may provide clues to identify the targets of gene transcription that decide cell fate altered by MS,such as development,differentiation or apoptosis,and death.