A novel circular RNA, circIgfbp2, links neural plasticity and anxiety through targeting mitochondrial dysfunction and oxidative stress-induced synapse dysfunction after traumatic brain injury

Abstract

Traumatic brain injury (TBI) can lead to different neurological and psychiatric disorders. Circular RNAs (circRNAs) are highly expressed in the nervous system and enriched in synapses; yet, the underlying role and mechanisms of circRNAs in neurological impairment and dysfunction are still not fully understood. In this study, we investigated the expression of circRNAs and their relation with neurological dysfunction after TBI. RNA-Seq was used to detect differentially expressed circRNAs in injured brain tissue, revealing that circIgfbp2 was significantly increased. Up-regulated hsa_circ_0058195, which was highly homologous to circIgfbp2, was further confirmed in the cerebral cortex specimens and serum samples of patients after TBI. Moreover, correlation analysis showed a positive correlation between hsa_circ_0058195 levels and the Self-Rating Anxiety Scale scores in these subjects. Furthermore, knockdown of circIgfbp2 in mice relieved anxiety-like behaviors and sleep disturbances induced by TBI. Knockdown of circIgfbp2 in H2O2 treated HT22 cells alleviated mitochondrial dysfunction, while its overexpression reversed the process. Mechanistically, we discovered that circIgfbp2 targets miR-370-3p to regulate BACH1, and down-regulating BACH1 alleviated mitochondrial dysfunction and oxidative stress-induced synapse dysfunction. In conclusion, inhibition of circIgfbp2 alleviated mitochondrial dysfunction and oxidative stress-induced synapse dysfunction after TBI through the miR-370-3p/BACH1/HO-1 axis. Thus, circIgfbp2 might be a novel therapeutic target for anxiety and sleep disorders after TBI.

Protective effects and regulatory pathways of melatonin in traumatic brain injury mice model: Transcriptomics and bioinformatics analysis

“…Jiang et al (2019) profiled 191 differentially expressed circRNAs in the CCI model, which may be related to inflammation, cell death, and repair of damage. The previous study of our group revealed the protective role of circLphn3 in the bloodbrain barrier after TBI (Cheng et al, 2022) and identified the circPtpn14/miR-351-5p/5-LOX axis might be a new mechanism regulating the effect of Mel against TBI (Wu et al, 2022), in addition, we found that to inhibit circIgfbp2 could alleviate the synapse dysfunction caused by mitochondrial dysfunction and oxidative stress through the miR-370-3p/BACH1/HO-1 axis after TBI (Du et al, 2022). Nevertheless, there is a lack of studies investigating the transcriptomics analysis of Mel intervention in TBI.…”

Circular RNA expression profiles and functional predication after restraint stress in the amygdala of rats

“…Previous studies have verified that circRNAs are particularly enriched in the nervous system and accumulate with age. Another possibility is to analyze circRNA variation that may cause hysteresis compared to the pace of change within the behavior ( Du et al, 2022 ; Dong et al, 2023 ; Hosaka et al, 2023 ). The long-term changes in circRNAs in the amygdala after restraint stress warrant further investigation.…”

“…Over the last decade, many researchers have revealed that circRNAs can function as microRNA sponges, interact with RNA-binding proteins (RBPs), modulate alternative splicing and transcription, and even translate into polypeptides ( Patop et al, 2019 ; Huang et al, 2020 ; Xiao et al, 2022 ). Accumulating evidence indicates that circRNAs are involved in neurological disorders, including ischemic brain injury, Alzheimer’s disease, and PTSD ( Mo et al, 2020 ; Su et al, 2021 ; Du et al, 2022 ). Due to their specific features, circRNAs can serve as diagnostic and prognostic biomarkers for some central nervous system disorders.…”

Expression characteristics of circular RNA in human traumatic brain injury

“…Moreover, knockdown of circRNA_009194 improved neurological outcomes in TBI ( 18 ). Furthermore, inhibition of circIgfbp2 alleviated mitochondrial dysfunction and oxidative stress-induced synapse dysfunction after TBI ( 19 ). In our study, we examined circRNAs expression profiles from six TBI patients.…”