Abstract
The suprachiasmatic nucleus (SCN) of the hypothalamus is a nucleus that regulates circadian rhythms through the cyclic expression of clock genes. It has been suggested that circadian-rhythm-related, adverse postoperative events, including sleep disturbances and delirium, are partly caused by anesthesia-induced disruption of clock-gene expression. We examined the effects of multiple general anesthetics on the expression cycle of Period2 (Per2), one of the clock genes that regulate circadian rhythms in the SCN, and on the behavioral rhythms of animals. Rats were treated with sevoflurane, propofol, and dexmedetomidine for 4 h. The expression of Per2 in SCN was analyzed using in situ hybridization, and the behavioral rhythm before and after anesthesia was analyzed. Per2 expression in the SCN decreased significantly immediately after anesthesia in all groups compared with corresponding control groups. However, Per2 returned to normal levels within 24 h, and there was no phase change in the gene expression cycle or behavioral rhythm. This study suggests that acute suppression of Per2 expression may be a general phenomenon induced by general anesthesia, but that the molecular mechanism of the body clock is resilient to disturbances to some extent.
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Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
This study was supported by the Japanese Society for the Promotion of Science (JSPS) KAKENHI (Grants-in-Aid for Scientific Research, grant no. 18K06860 to H.O., 18K16499 to K.M.).
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418_2022_2113_MOESM1_ESM.tif
Supplementary file1 Fig. S1. Period2 (Per2) expression cycle and anesthetic treatment time. Schematic diagram of the anesthetic treatment paradigm used in this study and the approximate Per2 circadian fluctuation based on our previous study (Anzai et al. 2013). Anesthesia treatments were performed at the times indicated by gray vertical bars. (TIF 133 kb)
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Supplementary file2 Fig. S2. Quantitative method of Per2 expression by in situ hybridization (ISH). The intensity of Per2 expression was quantified based on eight-bit (0–255) grayscale images using ImageJ software. The difference between the values in the suprachiasmatic nucleus (SCN) and those in the background regions was quantified as the intensity of Per2 expression (Scale bars: 200 µm) (TIF 3693 kb)
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Supplementary file3 Fig. S3. Quantification of ISH signals in the SCN adjacent region used for background subtraction. The intensity of ISH signals were quantified from grayscale images using ImageJ. Panels (a), (b), and (c) show the quantification in the groups anesthetized from 8:00 to 12:00 and then brains sampled at 12:00 on the same day, 16:00 on the same day, and 12:00 on the next day, respectively (n = 4). (d) Quantification of the group anesthetized from 20:00 to 24:00 and brain sampled at 24:00 on the same day (n = 6). No significant differences were observed between anesthesia-treated groups and corresponding control groups in all groups measured. Values expressed as mean ± SEM. (TIF 1511 kb)
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Supplementary file4 Fig. S4. Measurements of body temperature and blood oxygen saturation (SpO2). (a) The body temperature of the rats during anesthetic treatment. Body temperature was measured at the rectum at 30 min intervals. (b) The SpO2 of the rats measured in the limbs at 30-min intervals during each anesthesia challenge. Values expressed as mean ± SEM (n = 4) (TIF 937 kb)
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Supplementary file5 Fig. S5. Activities before and after anesthetic treatment. Activities in all anesthesia and control groups were quantified for 24 h on the day before anesthesia and 24 h on the day after anesthesia. (*p < 0.05 (paired t-test)) (TIF 1604 kb)
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Supplementary file6 Fig. S6. Confirmation of staining specificities. Representative photomicrograph of negative control using sense probe (right panel); no nonspecific signals were observed in the SCN. The same images as Supplementary Fig. S2 were used for the positive controls for comparison (left panel). Scale bar: 200 µm (TIF 3802 kb)
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Mizuno, T., Higo, S., Kamei, N. et al. Effects of general anesthesia on behavioral circadian rhythms and clock-gene expression in the suprachiasmatic nucleus in rats. Histochem Cell Biol 158, 149–158 (2022). https://doi.org/10.1007/s00418-022-02113-0
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DOI: https://doi.org/10.1007/s00418-022-02113-0