Characterization of circRNA-Associated-ceRNA Networks Involved in the Pathogenesis of Postoperative Cognitive Dysfunction in Aging Mice

Abstract

Postoperative cognitive dysfunction (POCD) is a clinical entity associated with declined cognitive function following surgery. It occurs more frequently in elderly patients. Recent studies have shown that circRNA-associated-ceRNA networks, constructed based on interactions between circRNA-miRNA and miRNA-mRNA, provide key insight into the molecular mechanisms underlying the pathogenesis of several neurological diseases. However, the mechanism of POCD remains undetermined. In this study, laparotomies were performed under isoflurane anesthesia on young (2-month-old) and aging (17-month-old) male C57BL/6 mice. The results showed that the aging mice were more likely than the young mice to develop POCD. Subsequently, differentially expressed circRNAs, miRNAs, and mRNAs were characterized by RNA sequencing the hippocampi of young and aging mice under control and surgery conditions. Six circRNAs, 6 miRNAs, and 203 mRNAs were identified to construct the circRNA-associated-ceRNA network for the control condition, while 13 circRNAs, 8 miRNAs, and 189 mRNAs were used for the circRNA-associated-ceRNA network for the surgery condition. Further Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of these two networks revealed that the circRNA-associated-ceRNA networks are involved in POCD pathogenesis though modulating the Wnt and VEGF signaling pathways, as well as neural processes associated with long-term synaptic depression and synaptic transmission. In particular, the mmu-miR-298-5P regulatory pathway identified in this study’s mouse model suggests that mm9_circ_009789- and mm9_circ_004229-associated-ceRNA networks as closely related to the occurrence of POCD through regulating PKC signaling pathway, neural cell apoptosis and glycolipid metabolism pathway. These findings provide possible insight into the role of the circRNA-associated-ceRNA networks, helping to unravel the complexity of the molecular pathogenesis of POCD.

Obese mice induced by high-fat diet have differential expression of circular RNAs involved in endoplasmic reticulum stress and neuronal synaptic plasticity of hippocampus leading to obesity-associated cognitive impairment

“…With the development of genome-wide analysis, RNA sequencing technology, and microarray analysis, increasing evidence indicates that circRNAs play an important role in various diseases, and CeRNA networks involving circRNAs, miRNAs, and mRNAs have been detected in many diseases, including cancers and AD-associated pathophysiology (Wang et al, 2018 ; Zhang Y. et al, 2019 ; Zhang et al, 2022 ). Although, it is well-established that circRNAs play an essential role in regulating neurodegenerative diseases, such as AD (Lo et al, 2020 ) and PD (Hanan et al, 2020 ), the mechanisms that respond to circRNAs changes in obesity-associated cognitive decline are not well-explored.…”

A crosstalk between circular RNA, microRNA, and messenger RNA in the development of various brain cognitive disorders

“…Also, the upregulation of circ_009789 and circ_004229 may act as a sponge of miR-298-5p to upregulate the expression of Prkcb and Zbtb4 in the hippocampus of aging mice. Here, PKC signaling pathway, neural cell apoptosis, and glycolipid metabolism pathway are involved in the development of working memory dysfunction after surgery (Zhang M. X. et al, 2022 ).…”

“…A lot of studies indicate that the crosstalk between circRNAs, miRNAs, and mRNA can participate in many pathophysiological processes in the development of cerebral diseases (or abnormal conditions), such as Alzheimer's disease (AD) (Lu et al, 2019 ; Li et al, 2022 ), Parkinson's disease (PD) (Wang et al, 2021 ; Liu et al, 2022 ), traumatic brain injury (TBI) (Huang X. J. et al, 2022 ; Zheng et al, 2022 ), stroke (Dai et al, 2021 ; Xu T. et al, 2022 ), and postoperative neurocognitive disorder (POND) (He et al, 2021 ; Wu et al, 2021 ; Zhang M. X. et al, 2022 ). However, they have failed to manage the aforementioned brain cognitive disorders with effective therapeutics and to uncover largely unknown underlying mechanisms.…”

Decoding competitive endogenous RNA regulatory network in postoperative cognitive dysfunction

“…Another microarray profiling highlighted three circRNAs (circ_22058, circ_44122, and circ_22673) as key elements in POCD ( Wu et al, 2021 ). Circ_009789- and circ_004229-associated ceRNA networks were identified to elucidate the mechanism underlying susceptibility to POCD in aged mice ( Zhang et al, 2022 ). CircShank3 may be involved in dexmedetomidine-mediated protection against POCD via targeting the p53 and NF-κB signaling pathways ( Cao et al, 2020 ).…”