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Circular RNAs (circRNAs) are a new and large group of non-coding RNA molecules that are abundantly expressed in the central nervous system. However, very little is known about their roles in traumatic brain injury. In this study, we firstly screened differentially expressed circRNAs in normal and injured brain tissues of mice after traumatic brain injury. We found that the expression of circLphn3 was substantially decreased in mouse models of traumatic brain injury and in hemin-treated bEnd.3 (mouse brain cell line) cells. After overexpressing circLphn3 in bEnd.3 cells, the expression of the tight junction proteins, ZO-1, ZO-2, and occludin, was upregulated, and the expression of miR-185-5p was decreased. In bEnd.3 cells transfected with miR-185-5p mimics, the expression of ZO-1 was decreased. Dual-luciferase reporter assays showed that circLphn3 bound to miR-185-5p, and that miR-185-5p bound to ZO-1. Additionally, circLphn3 overexpression attenuated the hemin-induced high permeability of the in vitro bEnd.3 cell model of the blood-brain barrier, while miR-185-5p transfection increased the permeability. These findings suggest that circLphn3, as a molecular sponge of miR-185-5p, regulates tight junction proteins’ expression after traumatic brain injury, and it thereby improves the permeability of the blood-brain barrier. This study was approved by the Animal Care and Use Committee of Chongqing Medical University of China (approval No. 2021-177) on March 22, 2021.

Abstract Sleep disorders (SD) are common sequelae following traumatic brain injury (TBI) and may be linked to mitochondrial oxidative stress dysregulation after TBI. Increasing evidence showed that circRNAs play crucial roles in nervous system diseases. However, the involvement of circRNAs in sleep disturbances after TBI is not characterized. In this study, differentially expressed circRNAs were identified by RNA sequencing. Sleep quality in TBI patients was assessed through sleep scales and electroencephalograms. Further experiments were conducted to investigate the role of circItm2b. We found that circItm2b was elevated and involved sleep disorder in TBI patients. Over-expression of circItm2b might aggravate sleep disturbances in mice after TBI. Mechanically, circItm2b regulates Nox4 expression through binding Sirt1, which influences mitochondrial oxidative stress-caused circadian protein losses. Moreover, the knockdown of circItm2b attenuated mitochondrial oxidative stress-induced circadian proteins losses via circItm2b/Sirt1/Nox4 axis after TBI, which might suggest that circItm2b may serve as a prognostic marker for improving sleep disorders and represent a promising therapeutic target for TBI-related sleep disturbances.