Frontiers in molecular neuroscience · 2026
CircHomer1 may contribute to postoperative cognitive impairment by modulating Homer1b/mGluR5-associated signaling in the vCA1 region of aged mice.
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Ran Wei, Shen Yiwei, Yuan Ruixue, Gao Jin, Liang Ning
Аннотация
BACKGROUND: Postoperative delirium (POD) is a common and severe complication in elderly patients after surgery, primarily characterized by a decline in cognitive function.
METHODS: Presently, the pathogenesis of POD is still unclear, thus making it imperative to investigate the key mechanisms of its transcriptional regulation. Circular RNAs have been implicated in mental and cognitive disorders. Our previous circRNA profiling suggested that circRNAs may be involved in postoperative cognitive changes. In this study, we used Western blotting, immunofluorescence staining, transmission electron microscopy, and behavioral tests to investigate whether circHomer1 contributes to POD-like early postoperative neurocognitive impairment. In this study, we used Western-blot, immunofluorescence staining, transmission electron microscopy, and animal behavior tests to explore the mechanism by which circRNA mediates the progression of POD.
RESULTS: Three main findings are reported. First, tibial fracture surgery induced significant cognitive impairment in 12-14 month-old mice, as evidenced by reduced freezing time in contextual fear conditioning test and reduced center zone exploration time in open field test on postoperative day 3. Second, siRNA-mediated knockdown of circHomer1 in the ventral CA1 (vCA1) region significantly alleviated surgery-induced cognitive deficits, increased Homer1b mRNA expression, and upregulated mGluR5 and PSD-95 protein levels. Conversely, siRNA-mediated knockdown of Homer1b exacerbated cognitive impairment and reduced mGluR5 and PSD-95 expression, while lentivirus-mediated overexpression of Homer1b rescued both protein levels and cognitive function. Third, pharmacological activation of mGluR5 with the agonist CHPG improved cognitive performance and increased PSD-95 expression, whereas inhibition of mGluR5 with MPEP produced opposite effects.
CONCLUSIONS: This study suggests that circHomer1 in the vCA1 region may influence the cognitive function of elderly mice following tibial fracture surgery, potentially involving the Homer1b/mGluR5 signaling pathway, offering preliminary mechanistic insights into the role of circRNAs in brain function and disease.
METHODS: Presently, the pathogenesis of POD is still unclear, thus making it imperative to investigate the key mechanisms of its transcriptional regulation. Circular RNAs have been implicated in mental and cognitive disorders. Our previous circRNA profiling suggested that circRNAs may be involved in postoperative cognitive changes. In this study, we used Western blotting, immunofluorescence staining, transmission electron microscopy, and behavioral tests to investigate whether circHomer1 contributes to POD-like early postoperative neurocognitive impairment. In this study, we used Western-blot, immunofluorescence staining, transmission electron microscopy, and animal behavior tests to explore the mechanism by which circRNA mediates the progression of POD.
RESULTS: Three main findings are reported. First, tibial fracture surgery induced significant cognitive impairment in 12-14 month-old mice, as evidenced by reduced freezing time in contextual fear conditioning test and reduced center zone exploration time in open field test on postoperative day 3. Second, siRNA-mediated knockdown of circHomer1 in the ventral CA1 (vCA1) region significantly alleviated surgery-induced cognitive deficits, increased Homer1b mRNA expression, and upregulated mGluR5 and PSD-95 protein levels. Conversely, siRNA-mediated knockdown of Homer1b exacerbated cognitive impairment and reduced mGluR5 and PSD-95 expression, while lentivirus-mediated overexpression of Homer1b rescued both protein levels and cognitive function. Third, pharmacological activation of mGluR5 with the agonist CHPG improved cognitive performance and increased PSD-95 expression, whereas inhibition of mGluR5 with MPEP produced opposite effects.
CONCLUSIONS: This study suggests that circHomer1 in the vCA1 region may influence the cognitive function of elderly mice following tibial fracture surgery, potentially involving the Homer1b/mGluR5 signaling pathway, offering preliminary mechanistic insights into the role of circRNAs in brain function and disease.