A postpartum enriched environment rescues impaired cognition and oxidative markers in aged mice with gestational inflammation

Abstract

Introduction: Previous studies have shown that gestational inflammation can accelerate age-associated cognitive decline (AACD) in maternal mice; enriched environments (EEs) have been reported to protect normally aging mice from AACD and improve mitochondrial function. However, it is unclear whether the nitrosative stress-related proteins tet methylcytosine dioxygenase 1 (TET1) and S-nitrosoglutathione reductase (GSNOR) are involved in the accelerated aging process of gestational inflammation and whether EEs can slow this process.

Methods: In this study, CD-1 female mice on the 15th day of pregnancy were injected with bacterial lipopolysaccharide (50 μg/kg; LPS group) or an equivalent amount of normal saline (CON group) from the abdominal cavity for 4 consecutive days. Twenty-one days after delivery, half of the LPS-treated mice were randomly selected for EE until the end of the behavioral experiment (LPS-E group). When the female rats were raised to 6 months and 18 months of age, the Morris water maze (MWM) was used to detect spatial learning and memory ability; RT-PCR and Western blots were used to measure the mRNA and protein levels of hippocampal TET1 and GSNOR.

Results: As for the control group, compared with 6-month-old mice, the spatial learning and memory ability of 18-month-old mice decreased, and the hippocampal TET1 and GSNOR mRNA and protein levels were decreased. Gestational inflammation exacerbated these age-related changes, but an EE alleviated the effects. Pearson's correlation analysis indicated that performance during the learning and memory periods in the MWM correlated with the levels of hippocampal TET1 and GSNOR.

Conclusions: Our findings suggest that gestational inflammation accelerates age-related learning and memory impairments and that postpartum EE exposure could alleviate these changes. These effects may be related to hippocampal TET1 and GSNOR expression.

Keywords: S-nitrosoglutathione reductase (GSNOR); aging; enriched environment; lipopolysaccharide; memory; tet methylcytosine dioxygenase 1 (TET1).

FIGURE 1

Timeline of experimental events. The pregnant mice were injected with LPS or saline from the abdominal cavity for four consecutive days starting from the 15th day of pregnancy. Weaned on the 21st day after childbirth, the mothers were divided into three groups based on whether the mice were exposed to an EE until the end of the experiment. The MWM test was performed at 6 and 18 months of age. Two weeks after the completion of the MWM test, the mice were sacrificed for follow‐up biochemical experiments. EE, enriched environment; CON, control group; LPS, lipopolysaccharide treatment group; LPS‐E, lipopolysaccharide plus enriched environment treatment group; MWM, Morris water maze

FIGURE 2

Performance in the Morris water maze (MWM) test. Average velocity (a,c,e), and distance (b,d,f) during the learning phase; percent distance swam and percent time swam (g,j) during the memory phase. Age and treatment had a significant effect on learning and memory performance in the MWM. Data are expressed as the mean ± SEM (n = 10 mice/group). ^*Significant differences compared with 6‐ or 18‐month‐old CON mice (^* p < .05, ^** p < .01); ^#Significant differences compared with 6‐ or 18‐month‐old LPS‐E mice (^# p < .05, ^## p < .01). 6, 6‐month‐old; 18, 18‐month‐old; CON, control group; LPS, lipopolysaccharide treatment group; LPS‐E, LPS plus enriched environment treatment group

FIGURE 3

Relative mRNA and protein levels of Tet1 and Gsnor in the hippocampus. (a) The protein bands after Western blotting. (b,c) Differences in Tet1 and Gsnor mRNA levels in the different groups. (d,e) Differences in TET1 and GSNOR levels in the different groups. ^*Significant differences compared with 6‐month‐old CON mice (^** p < .01); ^&Significant differences compared with 18‐month‐old CON mice (^&& p < .01); ^#Significant differences compared with 18‐month‐old LPS‐E mice (^# p < .05, ^## p < .01) (n = 6 mice/group). CON, control group; LPS, lipopolysaccharide treatment group; LPS‐E, LPS plus enriched environment treatment group