The Innate Immune Toll-Like Receptor-2 modulates the Depressogenic and Anorexiolytic Neuroinflammatory Response in Obstructive Sleep Apnoea

Polsek, D.; Cash, D.; Veronese, M.; Ilic, K.; Wood, T. C.; Milosevic, M.; Kalanj-Bognar, S.; Morrell, M. J.; Williams, S.; Gajovic, S.; Leschziner, G.; Mitrecic, D.; Rosenzweig, I.

doi:10.1101/2019.12.24.888206

bioRxiv · 10.1101/2019.12.24.888206

The Innate Immune Toll-Like Receptor-2 modulates the Depressogenic and Anorexiolytic Neuroinflammatory Response in Obstructive Sleep Apnoea

Polsek, D.·Cash, D.·Veronese, M.·Ilic, K.·Wood, T. C.·Milosevic, M.·Kalanj-Bognar, S.·Morrell, M. J.·Williams, S.·Gajovic, S.·Leschziner, G.·Mitrecic, D.·Rosenzweig, I.

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Abstract

BackgroundThe neurological mechanisms of the disease process of obstructive sleep apnea, the second most frequent sleep disorder, remain unclear whilst its links with several major neuropsychiatric disorders, such as depression, anxiety and even Alzheimers disorder, are increasingly recognised. A radical theory, that inflammation in the brain may underlie certain phenotypes of many of these disorders, has been proposed, and the microglial TLR2 system may serve as an important crossroad at the borderlands of several pathogenesis. This study undertook to investigate whether a neuroinflammatory response occurs under conditions of OSA, and whether it might be related to a modulated response due to TLR2 functionality in an established rodent model of OSA. MethodsThe effects of three weeks exposure to chronic intermittent hypoxia were monitored in mice with or without functional TLR2 (C57BL/6-Tyrc-Brd-Tg(Tlr2-luc/gfp)Kri/Gaj; TLR2-/-, C57BL/6-Tlr2tm1Kir), that were investigated by multimodal in vivo and ex vivo imaging, combining magnetic resonance and bioluminescence imaging and a variety of functional tests. ResultsAn acute neuroinflammatory response was demonstrated following the three days in the basal forebrain of mice, and more chronically in other parts of the frontal cortex. Adaptive changes in specific neurocircuitry were demonstrated, with significant links to agitated (mal)adaptive behaviour under episodes of stress, and an increased ability to gain weight. ConclusionsOur results suggest that microglial activation and an innate immune response might be the missing link underlying the pathogenesis of well known structural, psychologic and metabolic changes experienced by some patients with OSA.

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Polsek, D., Cash, D., Veronese, M., Ilic, K., Wood, T. C., Milosevic, M., Kalanj-Bognar, S., Morrell, M. J., Williams, S., Gajovic, S., Leschziner, G., Mitrecic, D., Rosenzweig, I.. 2019-12-26. The Innate Immune Toll-Like Receptor-2 modulates the Depressogenic and Anorexiolytic Neuroinflammatory Response in Obstructive Sleep Apnoea. https://doi.org/10.1101/2019.12.24.888206

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