Abstract Introduction Traumatic brain injuries (TBIs) can induce oxidative stress and neuroinflammation, including nucleotide-binding domain, leucine-rich-containing family pyrin domain-containing 3 (NLRP3) inflammasome activation, and dysregulation of sleep and slow-wave activity. Under oxidative stress, thioredoxin-interacting protein (TXNIP) binds to and activates NLRP3, leading to the formation of the NLRP3 inflammasome complex. NLRP3 inflammasomes activate the somnogenic molecules interleukin-1 beta and interleukin-18 and are critical for regulating homeostatic non-rapid-eye movement sleep (NREMS) and slow-wave activity (SWA). We hypothesized that mice lacking TXNIP TXNIP knockout (KO) mice would have reduced NREMS and SWA responses to TBI. Methods Two-month-old male and female TXNIP KO and wild-type control mice underwent surgery for polysomnography, and baseline sleep and electroencephalogram (EEG) power analyses were performed for a 24-hour period. Thereafter, the mice were subjected to mild/moderate TBI in the frontal cortex using a controlled cortical impact device or underwent identical treatments without injury (i.e., SHAM). Sleep and EEG power analyses were conducted 24-36 hours and 2 months post-injury. Results No significant differences in baseline spontaneous NREMS, rapid eye movement sleep, or wake state amounts or EEG power spectra were found between TXNIP KO and control mice. TBI caused a significant enhancement in NREMS and SWA 24 h after the injury in wild-type mice when compared to baseline and SHAM controls, which was significantly attenuated in TXNIP KO mice. At the 2 months post-injury timepoint, significant increases in waking episode frequencies were found, indicating enhanced sleep fragmentation in wild-type but not TXNIP KO mice when compared to baseline values or SHAM mice. Significant reductions in NREMS and SWA were also observed in wild-type mice 2 months after TBIs compared to the baseline and SHAM groups, although these attenuations in NREMS and SWA were not found in TXNIP KO mice. Conclusion The results of this study suggest that oxidative stress from TBI partially activates TXNIP to dysregulate NREMS and SWA from TBIs. These findings also suggest that NLRP3 inflammasomes, which are dependent on TXNIP for activation, are involved in the NREMS and SWA responses to TBI. Support (if any) Department of Veteran Affairs I01BX005379 (MRZ) and I21RX003722 (MRZ)
Carey et al. (Fri,) studied this question.