Environmental enrichment restores memory functioning in mice with impaired IL-1 signaling via reinstatement of long-term potentiation and spine size enlargement

Abstract

Environmental enrichment (EE) was found to facilitate memory functioning and neural plasticity in normal and neurologically impaired animals. However, the ability of this manipulation to rescue memory and its biological substrate in animals with specific genetically based deficits in these functions has not been extensively studied. In the present study, we investigated the effects of EE in two mouse models of impaired memory functioning and plasticity. Previous research demonstrated that mice with a deletion of the receptor for the cytokine interleukin-1 (IL-1rKO), and mice with CNS-specific transgenic over-expression of the IL-1 receptor antagonist (IL-1raTG) display impaired hippocampal memory and long-term potentiation (LTP). We report here a corrective effect of EE on spatial and contextual memory in IL-1rKO and IL-1raTG mice and reveal two mechanisms for this beneficial effect: Concomitantly with their disturbed memory functioning, LTP in IL-1rKO mice that were raised in a regular environment is impaired, and their dendritic spine size is reduced. Both of these impairments were corrected by environmental enrichment. No deficiencies in neurogenesis or hippocampal BDNF and vascular endothelial growth factor secretion were found in IL-1rKO mice that were raised in a regular environment, and both of these variables were increased to a similar degree in enriched IL-1rKO and wild-type mice. These findings suggest that exposure to an enriched environment may be beneficial for individuals with impaired learning and memory related to genetic impairments of IL-1 signaling (and possibly other genetic causes), by reversing impairments in dentate gyrus LTP and spine size and by promoting neurogenesis and trophic factors secretion.

Figure 1.

Environmental enrichment improves contextual and spatial memory in mice with impaired IL-1 signaling. A, IL-1rKO mice that were raised in a regular environment (IL-1rKO-Reg; n = 13) displayed impaired contextual fear conditioning compared with their WT-regular controls (WT-Reg; n = 9). However, IL-1rKO mice that were raised in an enriched environment (IL-1rKO-Enr; n = 19) did not differ from their enriched WT controls (WT-Enr; n = 13). *p < 0.05 compared with WT regular. B, In contrast, IL-1rKO-Reg and IL-1rKO-Enr mice displayed normal auditory-cued fear conditioning, compared with their respective WT controls. Enrichment increased auditory-cued freezing in both strains. C, IL-1rKO-Reg mice (n = 13) displayed spatial memory impairment compared with their WT controls (n = 14) in the latency to reach a hidden platform during the last (ninth) trial. However, after environmental enrichment, IL-1rKO mice (n = 19) showed normal memory compared with their enriched WT controls (n = 13). *p < 0.01 compared with all other groups. D, IL-1rKO-Reg mice demonstrated significantly lower swimming speed compared with all other groups. Environmental enrichment significantly increased the swimming speed of IL-1rKO mice, but they still differed from their WT-Enr controls. *p < 0.01 compared with all other groups. E, This finding cannot serve as an exclusive explanation for the longer latency of IL-1rKO-Reg mice to reach the platform, because these mice displayed spatial memory impairment in the path length to reach the hidden platform as well, a parameter independent on swimming speed. Furthermore, IL-1rKO-Enr mice, which were also slower than their WT-Enr controls, showed normal memory using this parameter. *p < 0.02 compared with all other groups. F, IL-1raTG-Reg mice (n = 10) displayed impaired contextual fear conditioning compared with WT-Reg controls (n = 8). However, IL-1raTG-Enr mice (n = 12) did not differ from their enriched WT controls (n = 11). *p < 0.05 compared with WT-regular controls. G, In contrast, IL-1raTG-Reg and IL-1raTG-Enr mice displayed normal auditory cued-fear conditioning, compared with their respective WT controls. Environmental enrichment increased auditory-cued freezing in both strains. H, IL-1raTG-Reg mice (n = 8) displayed spatial memory impairment compared with their WT controls (n = 6), reflected by a longer latency to reach the hidden platform during the last trial. However, IL-1raTG-Enr mice (n = 12) showed normal memory compared with WT-Enr controls (n = 12). I, IL-1raTG-Reg mice did not differ from their WT-Reg controls in swimming speed, and environmental enrichment similarly increased the swimming speed of both WT and IL-1raTG mice. J, IL-1raTG-Reg mice also displayed spatial memory impairment in the path length to reach the hidden platform, whereas IL-1raTG-Enr mice showed normal memory using this parameter. *p < 0.01 compared with all other groups. Data presented as the mean ± SEM.

Figure 2.

Environmental enrichment did not restore the ability of IL-1rKO and IL-1raTG mice to respond to IL-1. A, B, In response to IL-1α injection, regular and enriched WT, but not regular and enriched IL-1rKO mice (n = 6 in all groups), exhibited a significant decrease in social exploration (A) and spatial exploration in the open field (B) compared with their saline injected controls. C, D, Similarly, regular and enriched WT, but not regular and enriched IL-1raTG mice (n = 6 in all groups), exhibited a significant decrease in social exploration (C) and spatial exploration in the open field (D) in response to IL-1α injection compared with their saline injected controls. Data presented as the mean ± SEM.

Figure 3.

Environmental enrichment restores the ability to express LTP in the DG in vivo in IL-1rKO mice. A, Baseline field potential responses in the dentate gyrus to perforant-path stimulation were similar in all groups, over a range of stimulus intensities. B, After HFS, WT mice that were raised in a regular environment (WT-Reg; n = 6) developed LTP of fEPSP slope, whereas IL-1rKO mice (IL-1rKO-Reg; n = 5) displayed reduced potentiation and no LTP. However, after environmental enrichment, both IL-1rKO mice (n = 6) and their WT controls (n = 6) showed normal LTP. Environmental enrichment improved LTP in both strains, and WT mice that were raised in either regular or enriched environment demonstrated stronger LTP. Data presented as the mean ± SEM. Representative traces are presented for WT Regular (left), IL-1rKO Regular (bottom right), and IL-1rKO enriched (top right).

Figure 4.

Environmental enrichment increases spine size in the DG in vivo in IL-1rKO mice. IL-1rKO-Reg mice (B, n = 4 mice, 19 dendrites, 568 spines) displayed lower dendritic spine size compared with their WT-Reg controls (A, n = 4 mice, 30 dendrites, 670 spines). However, IL-1rKO-Enr mice (D, n = 4 mice, 51 dendrites, 771 spines) did not differ from their WT-Enr controls (C, n = 4 mice, 34 dendrites, 819 spines). These data are represented quantitatively in E. No differences in dendritic spine density in the DG (F), the levels of hippocampal AMPA receptor subunit GluR-1 (G), or the hippocampal presynaptic protein synaptophysin (H) were observed between any of the groups. Data presented as the mean ± SEM. a.u., Arbitrary units.

Figure 5.

Environmental enrichment increases hippocampal neurogenesis, as well as BDNF and VEGF levels in both IL-1rKO and WT mice. Similar levels of cytogenesis and neurogenesis were observed in WT-Reg and IL-1rKO-Reg mice (representative figures A, B). Environmental enrichment increased both cytogenesis and neurogenesis levels in both WT and IL-1rKO mice (representative figures C, D). Slices were stained for DAPI (blue; E), BrdU (green; F), and Tuj-1 (red; G). Cytogenesis was assessed by counting the number of cells double-stained for DAPI and BrdU (marked by arrows), and neurogenesis was assessed by counting the number of cells triple-stained for DAPI, BrdU, and Tuj-1 (H) (E–H are a magnification of the cells marked by a white square in A). A quantitative summary of the data (n = 16 in all groups) is presented for cytogenesis (I) (*p < 0.0001 compared with WT-Reg; ^#p < 0.005 compared with IL-1rKO-Reg.), neurogenesis (J) (*p < 0.0001 compared with WT-Reg and IL-1rKO-Reg), and the percentage of neurons among newly generated cells (K) (*p < 0.05 compared with WT-Reg; ^#p < 0.005 compared with IL-1rKO-Reg). L, Environmental enrichment also increased BDNF levels in both WT and IL-1rKO mice (n = 5 in all groups). *p < 0.05 compared with WT-Reg and IL-1rKO-Reg. M, Environmental enrichment increased VEGF levels in both WT and IL-1rKO mice (n = 6 in all groups). *p < 0.05 compared with WT-Reg and IL-1rKO-Reg mice. Data presented as the mean ± SEM.