Effects Of Environmental Stimulus In Fetal Period On HDAC₂ Levels And Correlations With Spatial Learning And Memory In CD-1 Mice

BackgroundEmerging evidence demonstrates that exposure to adverse factors during early life can accelerate brain aging,especially decline in learning and memory.Inflammation is the most common cause of early life exposing.Researches have shown that exposing to inflammatory conditions in early life can affect the cognitive function of the offspring across life.However,there are few studies on effects of life early exposing to adverse environment on the neurobiological changes in the middle-age.Histone deacetylase?HDAC₂?can modulate negatively synaptic plasticity and memory formation in hippocampus.Studies have indicated that altered HDAC₂ is closely related to central neurodegenerative diseases.Objective?1?To investigate the effect of environmental stimulation during early life?embryonic or adolescent?on learning and memory and hippocampal levels of HDAC₂ in CD-1 mice during young and middle-aged;?2?To explore the correlation between the hippocampal content of HDAC₂ and ability of spatial learning and memory.MethodsPregnancy CD-1 mice during the 15th to 17th days of gestation received intraperitoneally LPS?50?g/kg?or equal volume of saline every day.The offspring were weaned at 3 weeks of age.At the age of 2months,LPS-treated offspring mice randomly were given stress,riched environment or no treatment,while the control mice randomly were stressed or not treated.Finally,there were five groups in this study,including control group?CON?,CON-stressed group?CON-S?,LPS group?LPS?,LPS-stressed group?LPS-S?and LPS-enriched-environment group?LPS-E?.The stress types were randomly suspending,binding,lighting or fasting during nighttime in four consecutive days?a cycle?for seven cycles.The enriched-environment manipulation is to use large feeding cage?expanding activity space?,and place a new toy in it every week until the behavioral experiment to end.At the age of 3 months and15 months,16 mice randomly from each group received an assessment of learning and memory experiment i.e.,Morris water maze?MWM?.The hippocampal HDAC₂ level was detected using immunohistochemical method.ResultsMWM:In the learning phase,the swimming distance progressively declined over days,indicating these mice were able to learn the task?Ps<0.05?.The 15-CON had significantly longer swimming distance than the3-CON?P<0.05?.At 3 months of age,there was insignificant difference in swimming distance between the groups.At 15 months of age,the LPS-S had the longest swimming distance among all five groups.The LPS had significantly longer swimming distance than the CON-S,LPS-E and CON?Ps<0.05?.The swimming distance of CON-S was significantly longer than the LPS-E and CON?Ps<0.001?.The LPS-E had significantly longer swimming distance than the CON?P<0.05?.In the memory phase,the 15-CON had significantly lower percentage of distance in the target quadrant than the 3-CON?P<0.05?.At 3-month old,the LPS-S and LPS had significantly lower percentage of distance than CON?Ps<0.05?.The CON-S had significantly lower percentage of distance than CON?P<0.05?.But at 15-month old,LPS-S group had significantly lower percentage of distance than the LPS,CON-S,LPS-E and CON?Ps<0.05?.The LPS had significantly lower percentage of distance than the LPS-E and CON?P<0.05?.Hippocampal HDAC₂:HDAC₂ was found in the cell layers of all subareas?DG,CA1,CA3?in dorsal hippocampus.The 15-CON had significant higher levels of HDAC₂ than the 3-CON.At the 3-month old,no significantly different contents of HDAC₂ existed among the groups?Ps>0.05?.At the 15-month old,the LPS-S had the highest content of HDAC₂ in all groups?Ps<0.05?.The LPS had significantly higher HDAC₂ contents than the CON-S,LPS-E and CON?Ps<0.05?.The HDAC₂ contents of CON-S was significantly higher than CON?Ps<0.05?.The HDAC₂ contents of CON-S and LPS-E were similar.LPS-E had significantly higher HDAC₂ contents than the CON?P<0.05?.The HDAC₂ contents in dorsal hippocampus in the LPS-S,LPS,CON-S and LPS-E groups respectively correlated with the swimming distance in the learning phase positively and with the percentage of distance negatively in the memory phase at 3-month and 15-month-old ages.ConclusionsIn middle-aged CD-1 mice,the ability of learning and memory decreased,while the hippocampal HDAC₂ content increased.Inflammatory exposure in embryonic and chronic complex stress during puberty can synergistically exacerbate the effect of brain aging,but the rich environmental treatment can weaken this effect.The hippocampal HDAC₂ increased may be associated with the impairment of spatial learning and memory in the middle-aged mice who had been exposed to adverse environments in early life.