Environmental enrichment improves learning and memory and long-term potentiation in young adult rats through a mechanism requiring mGluR5 signaling and sustained activation of p70s6k

Abstract

Previous studies from our lab have demonstrated that mild cognitive impairments identified early in life are predictive of cognitive deficits that develop with age, suggesting that enhancements in cognition at an early age can provide a buffer against age-related cognitive decline. Environmental enrichment has been shown to improve learning and memory in the rodent, but the impact of enrichment on synaptic plasticity and the molecular mechanisms behind enrichment are not completely understood. To address these unresolved issues, we have housed 2-month old rats in environmentally enriched (EE), socially enriched (SE), or standard housing (SC) and conducted tests of learning and memory formation at various time intervals. Here we demonstrate that animals that have been exposed to one month of social or environmental enrichment demonstrate enhanced learning and memory relative to standard housed controls. However, we have found that after 4months EE animals perform better than both SE and SC groups and demonstrate an enhanced hippocampal LTP. Our results demonstrate that this LTP is dependent on mGluR5 signaling, activation of ERK and mTOR signaling cascades, and sustained phosphorylation of p70s6 kinase, thus providing a potential target mechanism for future studies of cognitive enhancement in the rodent.

Keywords: Environmental enrichment; Metabotropic glutamate receptor; Morris water maze; Object recognition; Young rats; p70s6 kinase.

Fig. 1

Environmental enrichment consisted of 6 animals housed in a 2 × 2′ cage with various objects and enriching toys changed weekly. Social enrichment cages were identical, except they lacked toys.

Fig. 2

1 month of social and environmental enrichment enhances learning and memory. (A) SE and EE groups perform equally well in the hidden platform training phase of the MWM, and both groups perform significantly better than SC rats on days 2 and 4 of training. (B) EE and SE groups perform significantly better than SC animals in NOR. (EE, n = 6; SE, n = 6; SC, n = 4).

Fig. 3

After 4 months of enrichment, EE animals display superior learning and memory compared to SE and SC groups. (A) EE and SE animals swim significantly shorter distances than SC groups during the hidden platform phase of MWM. (B) EE rats display significantly more platform crossings during the probe trial than SE and SC groups. (EE, n = 6; SE, n = 6; SC, n = 4) (C) EE animals outperform both SE and SC groups in NOR. (EE, n = 12; SE, n = 12; SC, n = 8).

Fig. 4

Environmental enrichment results in LTP expression through a mechanism dependent on mGluR5 signaling and subsequent activation of the ERK and mTOR signaling pathways. (A) Rats exposed to 4 months of EE express LTP using a subthreshold 0.5 TBS, whereas SE and SC groups do not. (B) No difference in input/output curves was observed between groups. (C) No differences in paired pulse facilitation were observed between groups. (D) The application of DHPG results in LTP expression in SE animals to levels similar to those observed in EE. (E) Application of the mGluR5 antagonist MPEP, but not the mGluR1 antagonist LY367385, inhibits LTP in EE animals. (F) MPEP does not diminish the synaptic response seen in SE controls. (G) Application of rapamycin or U0126 significantly reduces LTP in EE rats. (H) Rapamycin and U0126 have no significant effect on potentiation in SE controls.

Fig. 5

(A) Slices harvested immediately after 0.5 TBS revealed no differences in the expression of mTOR, pMTOR, ERK, pERK, or p-p70s6k in EE and SE animals. At 30 min, p-p70s6k was the only protein with increased expression in EE compared to SE groups. All other proteins displayed similar levels of expression. (B) Analysis of pmTOR expression indicates no significant changes in the expression of pmTOR between EE and SE groups. (C) Analysis of pERK expression indicates no significant changes in the expression of pERK between EE and SE groups. (D) Analysis of p-p70s6k indicates a sustained phosphorylation in enriched animals relative to SE. Stim = 0.5 TBS.

Fig. 6

Sustained phosphorylation of p70s6k is necessary for LTP in enriched animals. (A) The p70s6k inhibitor PF impairs LTP in enriched animals. (B) PF does not impact the synaptic response seen in SE animals. (C) OA enhances LTP in SE animals to levels similar to those seen in EE following 0.5 TBS. (D) OA does not enhance LTP in EE animals. (E) Western blot analysis reveals that p-p70s6k expression is significantly sustained 30 min following 0.5 TBS and that this expression is inhibited by rapamycin in EE rats. OA enhances p-p70s6k expression in SE rats. Results are quantified in panel F. Stim = 0.5 TBS. NS = non-stimulated slices.