Abstract
BackgroundAberrant hippocampal neurogenesis is an important pathological feature of sepsis-associated encephalopathy. In the current study, we examined the potential role of the long noncoding RNA (lncRNA) sex-determining region Y-box 2 (SOX2) overlapping transcript (SOX2OT), a known regulator of adult neurogenesis in sepsis-induced deficits in hippocampal neurogenesis and cognitive function.MethodsSepsis was induced in adult C57BL/6 J male mice by cecal ligation and perforation (CLP) surgery. Randomly selected CLP mice were transfected with short interfering RNAs (siRNAs) against SOX2OT or SOX2, or with scrambled control siRNA. Cognitive behavior was tested 8–12 days post-surgery using a Morris water maze. Western blotting and RT-qPCR were used to determine expression of SOX2, Ki67, doublecortin (DCX), nestin, brain lipid-binding protein, and glial fibrillary acidic protein (GFAP) in the hippocampus. The number of bromodeoxyuridine (BrdU)+/DCX+ cells, BrdU+/neuronal nuclei (NeuN)+ neurons, and BrdU+/GFAP+ glial cells in the dentate gyrus were assessed by immunofluorescence.ResultsCLP mice showed progressive increases in SOX2OT and SOX2 mRNA levels on days 3, 7, and 14 after CLP surgery, accompanied by impaired cognitive function. Sepsis led to decrease in all neuronal markers in the hippocampus, except GFAP. Immunofluorescence confirmed the decreased numbers of BrdU+/DCX+ cells and BrdU+/NeuN+ neurons, and increased numbers of BrdU+/GFAP+ cells. SOX2OT knockdown partially inhibited the effects of CLP on levels of SOX2 and neuronal markers, neuronal populations in the hippocampus, and cognitive function. SOX2 deficiency recapitulated the effects of SOX2OT knockdown.ConclusionSOX2OT knockdown improves sepsis-induced deficits in hippocampal neurogenesis and cognitive function by downregulating SOX2 in mice. Inhibiting SOX2OT/SOX2 signaling may be effective for treating or preventing neurodegeneration in sepsis-associated encephalopathy.
Highlights
Aberrant hippocampal neurogenesis is an important pathological feature of sepsis-associated encephalopathy
SOX2 overlapping transcript (SOX2OT) knockdown ameliorated sepsis-induced cognitive dysfunction in mice with sepsis-associated encephalopathy Since cecal ligation and perforation (CLP) mice had impaired cognitive function and upregulated SOX2OT long noncoding RNA (lncRNA), which is known to regulate adult neurogenesis, we knocked down SOX2OT in vivo in order to examine whether this would mitigate the effects of CLP
2–4, regardless of SOX2OT levels, but CLP mice transfected with SOX2OT short interfering RNA (siRNA) had shorter escape latencies than mice with CLP alone (Fig. 4a), suggesting that SOX2OT knockdown improved learning and memory in sepsis mice
Summary
Aberrant hippocampal neurogenesis is an important pathological feature of sepsis-associated encephalopathy. Sepsis and its complications are the most frequent cause of high morbidity and mortality in the intensive care unit [1, 2], recent medical advances have substantially enhanced survival rates. Patients with sepsisassociated encephalopathy show various degrees of cognitive dysfunction, ranging from impaired consciousness to delirium that can persist for months to years after hospital discharge. These patients often require longterm medical interventions in order to regain function [2]. These adverse neurobehavioral consequences are often associated with reduced quality of life, poor prognosis, and increased morbidity and mortality [3]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
