URINARY TRACT INFECTIONS AND HIPPOCAMPAL NEUROGENESIS: IS THERE A LINK?

Abstract

Previous studies have suggested a link between urinary tract infections (UTIs) and cognitive impairment in elderly patients. These patients have a higher risk for dementia and/or neuropsychiatric disorders. One possible contributing factor for UTI-induced cognitive changes, that has not yet been investigated, is a potential alteration in hippocampal neurogenesis. In this study, we aim to investigate the effect of UTI on hippocampal neurogenesis in a rat model of UTI. Adult male Sprague rats received intra-urethral injection of an Escherichia coli (E. coli) clinical isolate (108 CFU/mL) to induce UTI. Behavioral tests including the open field, Y-maze, T-maze, and novel object recognition were performed to assess anxiety-like behavior, exploration, spatial reference memory, cognitive ability and working memory, respectively. Rats were later injected with Bromodeoxyuridine analog (200mg/kg, i.p) and sacrificed at different timepoints. Levels of pro-inflammatory cytokines in bladder and urethra were measured by ELISA. Neurotrophins and proinflammatory cytokines mRNA expression in the hippocampus were determined by RT-PCR. Rats had confirmed infection as seen with CFU/mL \geq105 and had elevated concentrations of pro-inflammatory cytokines (IL-8 and IL-1β). Furthermore, rats with confirmed UTI exhibited higher thermal sensitivity on the abdominal skin overlying their urinary tract area. We found that UTI reduces proliferation of neural stem cells (NSCs) at an early time point post-infection (p.i.) (day 4) and neurogenesis at a later time point (day 34). This was associated with decreased expression in mRNA of BDNF, NGF, and FGF2 and elevated expression of IL-1β in the hippocampus at 6 hours post infection, but with no changes in optical intensity of microglia and astrocytes. In addition, infected rats spent less time exploring a novel arm in the Y-maze test on day 2 p.i. Treatment with anti-inflammatory drug did not revert the effect on NSCs, while treatment with antibiotic further decreased basal level of their proliferation. This study presents novel findings on the impact of urinary tract infections on hippocampal neurogenesis that could be correlated with cognitive impairment.