Studying the Effect of Chronic Peripheral Inflammation, Specifically Urinary Tract Infection-like via LPS, on Neuroplasticity

Abstract

Introduction: Neurogenesis is the process by which new neurons are produced from neural stem cells in the brain. This process might be affected by multiple factors such as neuroinflammation, aging, oxidative stress, and brain injury. Neuroinflammation or systemic inflammation can be potentially caused by several extrinsic or intrinsic factors and are often associated with alterations in neurogenesis. Previous clinical observations report cognitive deficits in patients exhibiting symptoms of urinary tract infections (UTI). In our laboratory, we have shown that E-coli induced UTI caused a significant decrease in neurogenesis and impaired cognitive and memory skills. Consequently, we would expect that lipopolysaccharide (LPS) instillation, an outer membrane component of gram negative bacteria such as E.Coli, into the urinary bladder might also have an adverse impact on neurogenesis. Therefore, more work is needed to explore the effect of chronic inflammation via LPS on neurogenesis and brain plasticity.

Objective: Here, we aim to investigate the effect of LPS-induced urinary bladder inflammation on the general and cognitive-like behavior in rats and its potential correlation with impaired hippocampal neurogenesis.

Methods: Adult male Sprague-Dawley rats received four transurethral instillations of LPS every 24 hours over a period of 4 days, to mimic chronic UTI-associated inflammation. Control/Sham groups were instilled with sterile saline. Bromodeoxyuridine (BrdU) analog was injected 24 hours before euthanizing the rats to assess hippocampal neural stem cells (NSCs) proliferation or 4 weeks before euthanasia to assess hippocampal neurogenesis. In addition, a battery of behavioral tests including heat sensitivity, open field, Y-maze, and Object Recognition (NOR) tests were used to assess thermal pain, spontaneous/exploratory motor behavior, cognitive ability and working memory, respectively.

Results: Chronic LPS-induced inflammation in the urothelium has shown increased thermal sensitivity in the paw and abdomen. Also, LPS injected rats have displayed affected motor and exploratory behavior as well as possible anxiety-like behavior. Additionally, induction of LPS into the urinary bladder has decreased the level of proliferation and neurogenesis of neural stem cells. Moreover, mRNA levels of cytokines were shown to increase in LPS injected rats in the hippocampus and bladder compared to the sham group.

Conclusion/Future Perspectives: This study demonstrates that chronic inflammation induced by repetitive instillations of LPS in the urinary bladder is associated with decreased hippocampal neurogenesis and impairment of cognitive-like behavior in rats. As such, this will provide experimental evidence about the association of UTI and cognitive disorders reported in clinical observations. This study will open a window for therapeutic approaches based on the link between inflammation of urothelium and the increased levels of inflammatory markers in the brain and in particular, the hippocampal formation.