Effects Of Prenatal Stress On Hippocampal Structure And Learning And Memory Ability Of Offspring Rats And Its Mechanism

Objective: In this study,an animal model of prenatal stress was established by subcutaneous injection of corticosterone(CORT)solution into pregnant rats during the third trimester of pregnancy to explore the effects of prenatal stress on the hippocampal structure and learning and memory ability of offspring and its mechanisms,so as to provide theoretical and experimental basis for the intervention and treatment of neurodevelopmental toxicity caused by prenatal stress.Methods: Thirty-six pregnant rats were divided into three groups:Control group,CORT low-dose group(10mg/kg)and CORT high-dose group(40mg/kg).CORT solution was exposed by subcutaneous injection.Pregnant rats in Control group received equal doses of saline containing1.6% dimethyl sulfoxide(DMSO)and 0.4% Tween-80.The duration of injection was 14 to 21 days of gestation,lasting for 8 days.A series of neurobehavioral experiments were conducted to verify whether the prenatal stress animal model was successfully established.On postnatal day(PND)7,14 and 28,6 offspring rats of each group were selected for hematoxylin and eosin(H&E)staining,nissl staining and immunohistochemical staining to observe the changes of hippocampal structure.Another 14 offspring rats were selected from each group and their hippocampal tissues were taken to make homogenate.The indexes of oxidative stress(MDA,GSH-Px,T-AOC)and inflammation(TNF-α,IL-1β)were measured using kits.The expressions of apoptosis factor(Caspase-3、Bax、Bcl-2)and synaptic associated protein(PSD-95)were detected by Western blotting.In addition,on postnatal day 28,12 offspring rats from each group were selected to conduct Morris water maze test to test learning and memory ability.Results:(1)Neurobehavioral experiments showed that compared with pregnant rats in Control group,CORT10 and CORT40 groups displayed significant anxiety-and depression-like behaviors,and there was a dose-response relationship,indicating that the prenatal stress animal model was successfully established.(2)Pathological staining showed that on postnatal day 7,14 and 28,the hippocampal CA1,CA3 and DG areas of offspring rats in CORT10 and CORT40 groups were changed to different degrees compared with Control group.H&E staining showed loose arrangement of cells and decreased number of layers.Nissl staining showed decreased number of Nissl bodies.Immunohistochemistry showed decreased expression of PSD-95.(3)Morris water maze test showed that on postnatal day 28,the learning and memory ability of offspring rats in CORT40 group was decreased compared with Control group.(4)On postnatal day 7,the levels of MDA,TNF-α and IL-1β in CORT10 and CORT40 groups were significantly increased compared with offspring rats in Control group,while the levels of GSH-Px and TAOC were significantly decreased.On postnatal day 14,the level of TNF-α in CORT10 and CORT40 groups was significantly increased compared with offspring rats in Control group,while the level of T-AOC was significantly decreased,and the level of IL-1β in CORT40 group was significantly increased.On postnatal day 28,the level of T-AOC in CORT40 group was significantly increased compared with offspring rats in Control group.(5)Western blotting showed that on postnatal day 7,14 and 28,the expression level of PSD-95 in CORT10 and CORT40 groups was significantly increased compared with offspring rats in Control group.On postnatal day 7,the expression level of Caspase-3 in CORT10 and CORT40 groups was significantly increased compared with offspring rats in Control group,and the ratio of Bax/Bcl-2 in CORT40 group was significantly increased.Conclusion: Prenatal stress can lead to impaired hippocampal structure and learning and memory ability in offspring rats,and there is a dose-response relationship,in which oxidative stress,inflammation and apoptosis play important roles.With the increase of age,the intensity of hippocampal injury,oxidative stress,inflammation and apoptosis decreased gradually,suggesting that the negative effects of prenatal stress on offspring may change with time.