Effects Of Maternal Separation On Hippocampal Mitochondrial Dynamics And Cognitive Function In Aged Maternal Mice

BackgroundAging alters people’s lives,especially the cognitive impairment caused by aging has become a key factor affecting the quality of life of the elderly.The specific mechanism of age-related cognitive decline remains unclear.To reduce people’s burden of life and delay learning and memory impairment caused by aging,we urgently need to explore the underlying mechanism of age-related cognitive decline.The free radical theory of senescence in the mechanism by which senescence occurs is widely recognized.The theory holds that mitochondria play a central role,and that their integrity and function,which are mainly regulated by mitochondrial dynamics,are essential to aging and age-related neurological diseases（such as Alzheimer’s disease）.The fusion and fission processes of mitochondrial dynamics are mediated by mitofusin2（Mfn2）and dynamin-related protein 1（Drp1）respectively.Thus,the variations in mitochondrial dynamics are tightly related to aging and many age-related neurological diseases.However,few studies have been reported on the changes in mitochondrial fission and fusion during aging.It is important to study the effects of stress on cognition and its relationship with aging because stress not only causes age-related hippocampal-dependent learning and memory impairment but also accelerates or exacerbates aging.Maternal separation（MS）is a paradigm widely used in rodents to study early-life adversities’ behavioral,emotional,and cognitive effects on offspring.However,the postnatal period is a vulnerable period for mothers,and any stress experienced during this period is likely to have unique effects on them.And it is not clear whether certain stress（maternal separation）in the postnatal period affects maternal cognition and behavior.ObjectiveFirstly,in aged SAMP8 maternal mice,the impact of maternal separation on cognitive function is investigated.Then,we explore the effects of maternal separation on the related parameters of hippocampal mitochondrial dynamics（Drp1 m RNA,Mfn2 m RNA,and Drp1,Mfn2 protein levels）in aged SAMP8 maternal mice.Finally,in aged SAMP8 maternal mice,we discuss the correlation between cognitive function and hippocampal mitochondrial dynamics.MethodsFirstly,SAMP8 pregnant mice were randomly assigned to the maternal separation group,control group,namely MS group,CON group.Then the two groups were divided into two age groups（3-month-old and 9-month-old）respectively.Finally,there were four groups: 3-month maternal separation group（3-MS group）,3-month control group（3-CON group）,9-month maternal separation group（9-MS group）,9-month control group（9-CON group）.After the pregnant mice delivered normally,mother-child separation was performed in all MS groups on the 7th day after delivery,and the separation was performed from 08:00 to 11:00 a.m.,i.e.,for 3 hours,for 10 consecutive days.All control groups did not take any special measures.Finally,maternal mice were evaluated their spatial learning and memory abilities subjecting the Morris water maze at the ages of 3 and 9 months（six mice were randomly chosen in each group）,and then the Quantitative Real-time PCR was applied to detect the relative content of m RNAs related to hippocampal mitochondrial dynamics,and the expression level of hippocampal mitochondrial dynamics-related proteins was measured by Western blot.Results1)Behavioral experiment（Morris water maze）: The escape latency was reduced in the 3-month-old CON group（P< 0.05）and the escape latency in the 9-month-old MS group was extended（P< 0.05）compared with the 9-month-old CON group.Compared with the 9-month-old CON group,the percentage of target quadrant residence time increased in the 3-month-old CON group（P < 0.05）,and the 9-month-old MS group had a decreased percentage of target quadrant residence time（P < 0.05）.2)The changes in hippocampal mitochondrial dynamics: Compared with the 3-month CON group,the hippocampal Drp1 m RNA content and protein level were increased（P< 0.05）,and Mfn2 m RNA content and protein level were decreased（P < 0.05）in the9-month CON group.And compared to the 9-month CON group,the hippocampal Drp1 m RNA content and protein level were increased（P < 0.05）,and Mfn2 m RNA content and protein level were decreased（P < 0.05）in the 9-month MS group.The same results were obtained in the 3-month MS group compared with the 3-month CON group.3)The correlation between cognition and hippocampal mitochondrial dynamics: In9-month-old CON and MS groups,escape latency was positively correlated with the m RNA and protein levels of Drp1 in the hippocampus（P < 0.05）,but negatively correlated with the m RNA and protein levels of Mfn2（P < 0.05）;The percentage of residence time in the target quadrant was negatively correlated with the levels of Drp1 m RNA and protein in the hippocampus（P < 0.05）,but positively correlated with the levels of Mfn2 m RNA and protein（P < 0.05）.There were no significant correlations between the parameters of hippocampal mitochondrial dynamics and the escape latency and the residence time percentage in the target quadrant in the 3-month-old groups.SummaryThe spatial learning and memory abilities decreased in aged SAMP8 maternal mice,and the effect was worsened by maternal separation.The increased hippocampal Drp1 m RNA and protein expression and the descending hippocampal Mfn2 m RNA and protein expression may be associated with the age-related cognitive impairment caused by accelerated maternal separation in aged SAMP8 maternal mice.