Environmental enrichment attenuates hippocampal neuroinflammation and improves cognitive function during influenza infection

Abstract

Recent findings from our lab have shown that peripheral infection of adult mice with influenza A/PR/8/34 (H1N1) virus induces a neuroinflammatory response that is paralleled by loss of neurotrophic and glial regulatory factors in the hippocampus, and deficits in cognitive function. Environmental enrichment has been shown to exert beneficial effects on the brain and behavior in many central nervous system (CNS) disorders, but its therapeutic potential during peripheral viral infection remains unknown. Therefore, the objective of the present study was to determine if long-term continuous exposure to environmental enrichment could prevent and/or attenuate the negative effects of influenza infection on the hippocampus and spatial cognition. Mice were housed in enriched or standard conditions for 4 months, and continued to live in their respective environments throughout influenza infection. Cognitive function was assessed in a reversal learning version of the Morris water maze, and changes in hippocampal expression of proinflammatory cytokines (IL-1β, IL-6, TNF-α, IFN-α), neurotrophic (BDNF, NGF), and immunomodulatory (CD200, CX3CL1) factors were determined. We found that environmental enrichment reduced neuroinflammation and helped prevent the influenza-induced reduction in hippocampal CD200. These changes were paralleled by improved cognitive performance of enriched mice infected with influenza when compared to infected mice in standard housing conditions. Collectively, these data are the first to demonstrate the positive impact of environmental enrichment on the brain and cognition during peripheral viral infection, and suggest that enhanced modulation of the neuroimmune response may underlie these beneficial effects.

Figure 1

Enriched environment cage. Environmental enrichment consisted of social interaction (n=5–8 mice in the cage), stimulation of exploratory behavior with objects such as toys and a set of tunnels, shelters, nesting materials, multiple locations of food and water ad libitum, and running wheels for voluntary exercise.

Figure 2

Change in body weight following influenza infection. Influenza infection induced loss of body weight in both standard environment (SE) and enriched environment (EE) influenza mice. Influenza-infected mice in SE lost more body weight at day 5–7 post-inoculation than infected EE mice. Data are represented as means ± SEM. (*p< 0.05 compared to control, ^# p< 0.05 SE FLU vs. EE FLU mice).

Figure 3

Morris water maze acquisition and probe trial. (A) Distance to reach the hidden platform over 5 days of acquisition training (* p< 0.01 SE FLU vs. all other groups). (B) Quadrant occupancy during probe trial performed 24 hours after the last day of acquisition training (** p< 0.05 target quadrant vs. non-target quadrants). Dashed line marks chance performance during testing.

Figure 4

Morris water maze reversal testing. Distance (pathlength) to reach the platform during reversal testing (average distance for 3 trial), * p< 0.05 influenza vs. control.

Figure 5

Impact of environment and influenza infection on hippocampal proinflammatory cytokine expression at day 7 post-inoculation. Environmental enrichment attenuated the influenza-induced increased in IL-1β (A) and TNF-α (B). Influenza infection induced IL-6 in both standard and enriched mice (C). * p< 0.05 compared to control, ^# p< 0.05 SE FLU vs. EE FLU.

Figure 6

Impact of environmental enrichment and influenza infection on hippocampal interferon cytokine expression at day 7 post-inoculation. Influenza infection induced IFN-α (A) and IFN-β (B) in both standard and enriched mice (* p< 0.05 compared to control).

Figure 7

Impact of environmental enrichment and influenza infection on hippocampal neurotrophic and immunomodulatory factor expression at day 7 post-inoculation. Environmental enrichment increased BDNF (A) and CX3CL1 expression (C). Influenza infection decreased the expression of BDNF, NGF and CX3CL1 in both enriched and standard housed mice (A,B,C). Environmental enrichment attenuated the influenza-induced decrease in CD200 (D). * p< 0.05 compared to control, ^# p< 0.05 standard vs. enriched housing.

Figure 8

Impact of environmental enrichment and influenza infection on expression of influenza virus and cytokines in the lung at day 7 post-inoculation. (A) Environmental enrichment attenuated the expression of influenza matrix (MI) protein. M1 expression was non-detectable (N.D.) in control samples. Influenza infection induced IFN-α (B) and IFN-β (C) and IFN-γ (D) in both standard and enriched mice. * p< 0.05 compared to control, ^# p< 0.05 SE FLU vs. EE FLU.

Figure 9

Impact of environmental enrichment and influenza on expression of inflammatory cytokines in the lung at day 7 post-inoculation. Influenza infection induced IL-1β (A), IL-6 (B) and TNF-α (C) in both standard and enriched mice. * p< 0.05 compared to control.