Sleep-wake behavior and responses to sleep deprivation of mice lacking both interleukin-1 beta receptor 1 and tumor necrosis factor-alpha receptor 1

Abstract

Data indicate that interleukin (IL)-1 beta and tumor necrosis factor-alpha (TNFalpha) are involved in the regulation of non-rapid eye movement sleep (NREMS). Previous studies demonstrate that mice lacking the IL-1 beta type 1 receptor spend less time in NREMS during the light period, whereas mice lacking the p55 (type 1) receptor for TNFalpha spend less time in NREMS during the dark period. To further investigate roles for IL-1 beta and TNFalpha in sleep regulation we phenotyped sleep and responses to sleep deprivation of mice lacking both the IL-1 beta receptor 1 and TNFalpha receptor 1 (IL-1R1/TNFR1 KO). Male adult mice (IL-1R1/TNFR1 KO, n=14; B6129SF2/J, n=14) were surgically instrumented with EEG electrodes and with a thermistor to measure brain temperature. After recovery and adaptation to the recording apparatus, 48 h of undisturbed baseline recordings were obtained. Mice were then subjected to 6h sleep deprivation at light onset by gentle handling. IL-1R1/TNFR1 KO mice spent less time in NREMS during the last 6h of the dark period and less time in rapid eye movement sleep (REMS) during the light period. There were no differences between strains in the diurnal timing of delta power during NREMS. However, there were strain differences in the relative power spectra of the NREMS EEG during both the light period and the dark period. In addition, during the light period relative power in the theta frequency band of the REMS EEG differed between strains. After sleep deprivation, control mice exhibited prolonged increases in NREMS and REMS, whereas the duration of the NREMS increase was shorter and there was no increase in REMS of IL-1R1/TNFR1 KO mice. Delta power during NREMS increased in both strains after sleep deprivation, but the increase in delta power during NREMS of IL-1R1/TNFR1 KO mice was of greater magnitude and of longer duration than that observed in control mice. These results provide additional evidence that the IL-1 beta and TNFalpha cytokine systems play a role in sleep regulation and in the alterations in sleep that follow prolonged wakefulness.

Fig. 1

Percentage of recording time spent in Wake (A) NREMS (B) and REMS (C); EEG delta power (0.5–4.0 Hz) during artifact-free epochs of NREMS (D); brain temperature (E). Values were obtained from B6129SF/J control mice (sleep n = 14, open symbols; brain temperature n = 7, thin line) and IL-1R1/TNFR1 KO mice (sleep n = 14, filled symbols; brain temperature n = 7, thick line) during undisturbed baseline recordings. For visual clarity, data (means ± SEM) for sleep parameters are presented in 2 h intervals whereas brain temperature data are presented in 10 min intervals. Values for EEG delta power during NREMS (D) are presented as percentage from the 24 h mean (depicted by the zero line). Statistics were performed on 6 h time blocks. Single asterisk (*) indicates a statistical difference of p < 0.05 whereas double asterisk (**) indicates a statistical difference of p < 0.01. The black bar on the X-axis indicates the dark portion of the light–dark cycle.

Fig. 2

State-specific EEG power spectra obtained from undisturbed B6129SF2/J control mice (n = 14, thin line) and IL-1R1/TNFR1 KO mice (n = 14, thick line) during both the light (A, C and E) and the dark (B, D and F) periods of the 24 h light–dark cycle. Spectral analyses were conducted on frequencies from 0.5 to 30 Hz, but graphic presentation is limited to frequencies from 0.5 to 20 Hz. Plots depict absolute spectra (insets) or normalized spectra. Spectra were normalized as a percentage of total power across all frequencies for specific behavioral states within the 12 h light or dark period (see Section 2), and are plotted as mean ± SEM for each frequency bin. Statistical analyses were performed on bins in the delta (0.5–4.5 Hz) and theta (6.0–9.0 Hz) frequency bands for NREMS and REMS, respectively. A single asterisk (*) indicates a statistical difference of p < 0.05, whereas double asterisks (**) denote statistical differences of p < 0.01.

Fig. 3

Percentage of recording time spent in NREMS (A and B) and REMS (C and D); EEG delta power (0.5–4.0 Hz) during artifact-free epochs of NREMS (E and F); brain temperature (G and H). Values were obtained from B6129SF/J control mice (sleep n = 14; brain temperature n = 7: right column) and IL-1R1/TNFR1 KO mice (sleep n = 14; brain temperature n = 7: left column) during undisturbed baseline recordings (open symbols) and during and after sleep deprivation (filled symbols). For visual clarity, data (means ± SEM) for sleep parameters are presented as in 2 h intervals whereas brain temperature data are presented in 10 min intervals. Values for EEG delta power during NREMS (E and F) are presented as percentage from the 24 h average baseline value (depicted by the zero line). Statistics were performed on 6 h time blocks. Single asterisk (*) indicates a statistical difference of p < 0.05 whereas double asterisk (**) indicates a statistical difference of p < 0.01. The crosshatched bar on the X-axis indicates the sleep deprivation period whereas the black bar indicates the dark portion of the light–dark cycle.

Fig. 4

Mouse strain differences from baseline values (depicted by the zero lines) after sleep deprivation in: percentage time spent in Wake (A) NREMS (B) and REMS (C); EEG delta power (0.5–4.0 Hz) during artifact-free epochs of NREMS (D); brain temperature (E). Values were obtained from B6129SF/J control mice (sleep n = 14, open symbols; brain temperature n = 7, thin line) and IL-1R1/TNFR1 KO mice (sleep n = 14, filled symbols; brain temperature n = 7, thick line). For visual clarity, data (means ± SEM) for sleep parameters are presented in 2 h intervals as whereas brain temperature data are presented in 10 min intervals. Statistics were performed on 6 h time blocks. Single asterisk (*) indicates a statistical difference of p < 0.05 whereas double asterisk (**) indicates a statistical difference of p < 0.01. The crosshatched bar on the X-axis indicates the sleep deprivation period whereas the black bar indicates the dark portion of the light–dark cycle.