Maternal care effects on the hippocampal transcriptome and anxiety-mediated behaviors in the offspring that are reversible in adulthood

Abstract

Early-life experience has long-term consequences on behavior and stress responsivity of the adult. We previously proposed that early-life experience results in stable epigenetic programming of glucocorticoid receptor gene expression in the hippocampus. The aim of this study was to examine the global effect of early-life experience on the hippocampal transcriptome and the development of stress-mediated behaviors in the offspring and whether such effects were reversible in adulthood. Adult offspring were centrally infused with saline vehicle, the histone deacetylase inhibitor trichostatin A (TSA), or the essential amino acid l-methionine. The animals were assessed in an unfamiliar open-field arena, and the hippocampal transcriptome of each animal was evaluated by microarray analysis. Here we report that TSA and methionine treatment reversed the effect of maternal care on open-field behavior. We identified >900 genes stably regulated by maternal care. A fraction of these differences in gene expression is reversible by either the histone deacetylase inhibitor TSA or the methyl donor l-methionine. These results suggest that early-life experience has a stable and broad effect on the hippocampal transcriptome and anxiety-mediated behavior, which is potentially reversible in adulthood.

Fig. 1.

TSA and methionine eliminate the maternal effect on behavioral responses to novelty stress. Shown is open-field behavior of TSA-treated (100 ng/ml), methionine-treated (100 μg/ml), and vehicle-treated adult offspring of high and low LG-ABN mothers during a 10-min testing session (n = 10 animals per group). (a) Mean ± SEM time spent exploring in the inner arena. ∗, P < 0.001, vehicle-treated adult offspring of low LG-ABN mothers vs. vehicle-treated offspring of high LG-ABN dams; ∗∗, P < 0.001, TSA-treated adult offspring of low LG-ABN mothers vs. vehicle- and methionine-treated offspring of low LG-ABN dams; ∗∗∗, P < 0.001, methionine-treated adult offspring of high LG-ABN mothers vs. vehicle- and TSA-treated offspring of high LG-ABN dams. (b) Mean ± SEM activity in the arena (n = 10 animals per group).

Fig. 2.

Direction of gene expression in hippocampal tissue from TSA-treated (100 ng/ml), methionine-treated (100 μg/ml), and vehicle-treated adult offspring of high and low LG-ABN mothers (n = 3 animals per group). (a) Percentage of mRNA transcripts increased, decreased, or unchanged by high LG-ABN. (b) Percentage of mRNA transcripts increased, decreased, or unchanged by TSA treatment. (c) Percentage of mRNA transcripts increased, decreased, or unchanged by methionine treatment. (d) Percentage of mRNA transcripts increased by high LG-ABN, TSA treatment, or both (Left) and the percentage of mRNA transcripts decreased by low LG-ABN, methionine treatment, or both (Right).

Fig. 3.

Distribution of maternal care-, TSA-, and methionine-responsive genes over different functional classes.

Fig. 4.

Methionine and TSA treatment eliminates the maternal effect on genes expressed within different functional classes. Shown is quantitative real-time PCR analysis of hippocampal gene expression in TSA-treated (100 ng/ml), methionine-treated (100 μg/ml), and vehicle-treated adult offspring of high and low LG-ABN mothers (n = 3 animals per group). (a) Mean ± SEM ATRX expression. ∗, P < 0.001, vehicle-treated offspring of high LG-ABN mothers vs. vehicle-treated offspring of low LG-ABN dams and methionine-treated offspring of high LG-ABN mothers; ∗∗, P < 0.01, TSA-treated offspring of low LG-ABN mothers vs. vehicle-treated offspring of low LG-ABN dams. (b) Mean ± SEM Reelin expression. ∗, P < 0.05, vehicle-treated offspring of high LG-ABN mothers vs. all other groups; ∗∗, P < 0.01, methionine-treated offspring of high LG-ABN mothers vs. vehicle-treated offspring of low LG-ABN mothers. (c) Mean ± SEM Vof-16 expression. ∗, P < 0.01, TSA-treated offspring of low LG-ABN mothers vs. vehicle-treated offspring of low LG-ABN dams; ∗∗, P < 0.001, methionine-treated offspring of high LG-ABN mothers vs. all other groups.