Pre-infection physical exercise decreases mortality and stimulates neurogenesis in bacterial meningitis

Abstract

Physical exercise has been shown to increase neurogenesis, to decrease neuronal injury and to improve memory in animal models of stroke and head trauma. Therefore, we investigated the effect of voluntary wheel running on survival, neuronal damage and cell proliferation in a mouse model of pneumococcal meningitis. Mice were housed in cages equipped with voluntary running wheels or in standard cages before induction of bacterial meningitis by a subarachnoid injection of a Streptococcus pneumoniae type 3 strain. 24 hours later antibiotic treatment was initiated with ceftriaxone (100 mg/kg twice daily). Experiments were terminated either 30 hours or 4 days (short-term) or 7 weeks (long-term) after infection, and the survival time, inflammatory cytokines and corticosterone levels, neurogenesis in the dentate gyrus of the hippocampal formation and the cognitive function were evaluated in surviving mice. Survival time was significantly increased in running mice compared to control animals (p = 0.0087 in short-term and p = 0.016 in long-term experiments, log-rank test). At the end of the long-term experiment, mortality was lower in trained than in sedentary animals (p = 0.031, Fisher's Exact test). Hippocampal neurogenesis--assessed by the density of doublecortin-, TUC-4- and BrdU + NeuN-colabeled cells--was significantly increased in running mice in comparison to the sedentary group after meningitis. However, Morris water maze performance of both groups 6 weeks after bacterial meningitis did not reveal differences in learning ability. In conclusion, physical exercise prior to infection increased survival in a mouse model of bacterial meningitis and stimulated neurogenesis in the dentate gyrus of the hippocampal formation.

Figure 1

Running activity over 4 weeks. The mean daily running distance of the mice during voluntary wheel running exercise (n = 15) was recorded in km per day. (A) During the first 2 weeks, mice increased their wheel running capacity, which was accompanied by an improvement in maximum wheel running velocity (Vmax) during this episode. (B) Both performance parameters remained stable during the following plateau phase (mean ± standard error of the mean, SEM).

Figure 2

Comparison of survival during the course of meningitis with or without preceding running activity. Kaplan-Meier survival curves illustrating the course of Streptococcus pneumoniae meningitis, revealing increased survival in running mice (open squares) in comparison to sedentary controls (open circles) (P = 0.016, log-rank test, n = 48).

Figure 3

Increased hippocampal neurogenesis in running mice four days after bacterial meningitis. Four days after infection, the density of TUC-4- (A, B) as well as doublecortin-expressing (C, D) young neurons was significantly increased in the granule cell layer of the dentate gyrus after voluntary wheel running in comparison to sedentary mice. (B) and (D) represent the median and interquartile range of the densities of immunoreactive cells (example in A und C)/mm² dentate gyrus, P = 0.012 and P = 0.015, respectively, Mann–Whitney U-test, scale bar = 50 μm).

Figure 4

Increased hippocampal neurogenesis in runners seven weeks after bacterial meningitis. Detection of NeuN (A) and BrdU (B) by double-label fluorescent immunohistochemistry. Merger of both markers revealed a newly formed neuron 7 weeks after bacterial meningitis (C). There was a higher percentage of co-labeled BrdU + NeuN + neurons in running mice in comparison to sedentary controls (D) (median and interquartile range, P = 0.018, Mann–Whitney U-test, scale bar = 50 μm). BrdU: Bromodeoxyuridin; NeuN: Neuron-specific nuclear antigen.