The mechanism of enriched environment repairing the learning and memory impairment in offspring of prenatal stress by regulating the expression of activity-regulated cytoskeletal-associated and insulin-like growth factor-2 in hippocampus

Abstract

Background: Prenatal stress can cause neurobiological and behavioral defects in offspring; environmental factors play a crucial role in regulating the development of brain and behavioral; this study was designed to test and verify whether an enriched environment can repair learning and memory impairment in offspring rats induced by prenatal stress and to explore its mechanism involving the expression of insulin-like growth factor-2 (IGF-2) and activity-regulated cytoskeletal-associated protein (Arc) in the hippocampus of the offspring.

Methods: Rats were selected to establish a chronic unpredictable mild stress (CUMS) model during pregnancy. Offspring were weaned on 21st day and housed under either standard or an enriched environment. The learning and memory ability were tested using Morris water maze and Y-maze. The expression of IGF-2 and Arc mRNA and protein were respectively measured by using RT-PCR and Western blotting.

Results: There was an elevation in the plasma corticosterone level of rat model of maternal chronic stress during pregnancy. Maternal stress's offspring exposed to an enriched environment could decrease their plasma corticosterone level and improve their weight. The offspring of maternal stress during pregnancy exhibited abnormalities in Morris water maze and Y-maze, which were improved in an enriched environment. The expression of IGF-2, Arc mRNA, and protein in offspring of maternal stress during pregnancy was boosted and some relationships existed between these parameters after being exposed enriched environment.

Conclusions: The learning and memory impairment in offspring of prenatal stress can be rectified by the enriched environment, the mechanism of which is related to the decreasing plasma corticosterone and increasing hippocampal IGF-2 and Arc of offspring rats following maternal chronic stress during pregnancy.

Keywords: Activity-regulated cytoskeletal-associated protein (Arc); Enriched environment; Insulin-like growth factor 2 (IGF-2); Learning and memory; Prenatal stress; Su-zhen Guan and You-juan Fu are coauthors of the paper..

Fig. 1

Experimental procedure of learning and memory of the offspring under maternal chronic stress rat during pregnancy

Fig. 2

The comparison of plasma corticosterone level between prenatal control group (PC group) and prenatal stress group (PS group). The figure shows that changes in plasma corticosterone level of PS were noted after stress model is established successfully. Each column represents mean ± SD. Number of animals in each group = 10. *P < 0.05 vs. PC group

Fig. 3

The comparison among OPC, OPS, OPC&EE and OPS&EE in plasma corticosterone level. Differences in corticosterone level were detected among OPC, OPS, OPC&EE, and OPS&EE. The plasma corticosterone level is the highest in OPS group, the lowest in the OPC&EE group. Data were respectively analyzed using One-way ANOVA, followed by LSD-t test to make comparison at the two different groups. Number of animals in each offspring group = 16 (50% male, 50% female)*P < 0.05 vs. OPC. #P < 0.05 vs. OPS

Fig. 4

The comparison among OPC, OPS, OPC&EE and OPS&EE in body weight. Differences in body weight were detected among OPC, OPS, OPC&EE, and OPS&EE. The body weight is the lowest in OPS group, the highest in the OPC&EE group; meanwhile, the body weight of OPS&EE is higher than OPS. Data were respectively analyzed using one-way ANOVA, followed by LSD-t test to make comparison at the two different groups. Number of animals in each offspring group = 16 (50% male, 50% female) *P < 0.05 vs. OPC. #P < 0.05 vs. OPS

Fig. 5

The comparison among OPC, OPS, OPC&EE and OPS&EE in spatial learning and memory in MWM test. Differences in the time of escape latency and the number of crossing platform were detected among OPC, OPS, OPC&EE, and OPS&EE. The time of escape latency was shorten and the number of crossing platform were improved by enriched environment in the OPS. Data were respectively analyzed using repeated measure ANOVA, followed by LSD-t test to make comparison at the two different groups. Number of animals in each offspring group = 16 (50% male, 50% female). (a The time of escape latency of the offspring in Morris water maze. b The number of crossing platform of the offspring in Morris water maze. *P < 0.05 vs. OPC. #P < 0.05 vs. OPS)

Fig. 6

The comparison among OPC, OPS, OPC&EE, and OPS&EE in learning and memory of Y-maze. Differences in the number of required training and the rate of correct response in Y-maze were detected among OPC, OPS, OPC&EE, and OPS&EE. The number of required training and the rate of correct response were improved by enriched environment in the OPS. Data were respectively analyzed using One-way ANOVA, followed by LSD-t test to make comparison at the two different groups. Number of animals in each offspring group = 16 (50% male, 50% female). (a The number of required training of the offspring in Y-maze. b The rate of correct response of the offspring in Y-maze. *P < 0.05 vs. OPC. #P < 0.05 vs. OPS)

Fig. 7

The comparison among OPC, OPS, OPC&EE, and OPS&EE in the IGF-2 mRNA and Arc mRNA expression in the offspring’ hippocampus. The IGF-2 mRNA and Arc mRNA expression of PS offspring were lower than it of PC offspring; however, they were boosted by EE. Data were respectively analyzed using one-way ANOVA, followed by LSD-t test to make comparison at the two different groups. Number of animals in each offspring group = 16 (50% male, 50% female). (a The determination of RNA purity. b The IGF-2 mRNA relative expression of offspring. c The Arc mRNA relative expression of offspring. *P < 0.05 vs. OPC. #P < 0.05 vs. OPS)

Fig. 8

The effects of enriched environment on the hippocampal IGF-2 and Arc protein expression in the offspring due to maternal stress of pregnancy. Differences in IGF-2 and Arc protein expression in the hippocampus were detected among four groups. The IGF-2 and Arc protein expression of PS offspring were lower than that of PC offspring; however, they were increased by EE. Data were respectively analyzed using One-way ANOVA, followed by LSD-t test to make comparison at the two different groups. Number of samples in each offspring group = 4 (50% male, 50% female) (a Electrophoresis results of IGF-2 and Arc protein expression in offspring. b IGF-2 protein expression in the hippocampus of offspring. c Arc protein expression in the hippocampus of offspring. *P < 0.05 vs. OPC. #P < 0.05 vs. OPS)