Hippocampal Activated Microglia May Contribute to Blood-Brain Barrier Impairment and Cognitive Dysfunction in Post-Traumatic Stress Disorder-Like Rats.

Kun Ni,Yulin Huang,Shuai Yang,Juan Zhang,Li Jiang,Yue Liu,Rui Xu,Jixiang Zhu,Wei Zhang,Xuan Xu,Zhengliang Ma

doi:10.1007/s12031-022-01981-4

Abstract

Post-traumatic stress disorder (PTSD)-associated cognitive dysfunction significantly disturbs patients’ quality of life and will to live. However, its underlying mechanism is as yet unknown. Recent researches indicate that blood–brain barrier (BBB) breakdown is responsible for early cognitive dysfunction. Microglia might participate in remodeling of BBB-associated tight junction and regulating BBB integrity. Nevertheless, it is unclear whether microglia activation and BBB injury involve in PTSD-associated cognitive dysfunction. Hence, we established an animal model of PTSD, single prolonged stress (SPS), and investigated permeability changes in the hippocampus and further explored the effects of microglia on BBB remodeling. The Y maze was used to assess the changes of cognitive function. The sodium fluorescein (NaFlu) assay and western blotting analysis were employed to detect BBB integrity changes. Minocycline was administered to inhibit microglial activation. Immunofluorescence stains were used to assess the activation states in microglia. The results showed that SPS-exposed rats exhibited poorer cognitive performance, higher passage of NaFlu, and lower expression of tight junction proteins (occludin and claudin 5) in the hippocampus on the day after SPS, but no difference on the 7th day. Inhibition of microglial activation by minocycline attenuated poor cognitive performance and BBB impairment including the extravasation of NaFlu and protein levels of the tight junction. Taken together, the present study indicates that BBB impairment may underlie the shared pathological basis of PTSD and cognitive dysfunction. Microglial activation may involve in BBB remodeling at the early stage of SPS.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12031-022-01981-4.

Highlights

Post-traumatic stress disorder (PTSD) is a complex and debilitating illness triggered by terrifying events, which is often companied by cognitive impairment, chronic pain, and affective disorders (Compean and Hamner 2019)
Western blotting analysis revealed that the expression levels of claudin 5 (P < 0.01) and tight junction protein occludin (P < 0.001) significantly decreased in group single prolonged stress (SPS) (Fig. 3b)
Our findings show that rats exhibit working memory impairment at the early stage after SPS

Summary

Introduction

Post-traumatic stress disorder (PTSD) is a complex and debilitating illness triggered by terrifying events, which is often companied by cognitive impairment, chronic pain, and affective disorders (Compean and Hamner 2019). The prevalence of PTSD in the general population is estimated at approximately 7% and higher among people experienced major traumatic events before (Zhou et al 2021). Coronavirus disease 2019 (COVID-19) is a major source of traumatic stress for people around the globe since 2019. A meta-analysis revealed that the prevalence of PTSD among COVID-19 patients in the post-illness stage was up to 32.2% (Rogers et al 2020). PTSD with negative alterations in cognition and mood was markedly associated with high morbidity and disability (Brown et al 2020). Cognitive dysfunction in PTSD patients has proved to be a

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