Molecules involved in innate immunity affect sleep and circadian oscillators and vice versa. Sleep-inducing inflammatory molecules are activated by increased waking activity and pathogens. Pathologies that alter inflammatory molecules, such as traumatic brain injury, cancer, cardiovascular disease, and stroke often are associated with disturbed sleep and electroencephalogram power spectra. Moreover, sleep disorders, such as insomnia and sleep disordered breathing, are associated with increased dysregulation of inflammatory processes. Inflammatory molecules in both the central nervous system and periphery can alter sleep. Inflammation can also modulate cerebral vascular hemodynamics which is associated with alterations in electroencephalogram power spectra. However, further research is needed to determine the interactions of sleep regulatory inflammatory molecules and circadian clocks. The purpose of this review is to: 1) describe the role of the inflammatory cytokines interleukin-1 beta and tumor necrosis factor-alpha and nucleotide-binding domain and leucine-rich repeat protein-3 inflammasomes in sleep regulation, 2) to discuss the relationship between the vagus nerve in translating inflammatory signals between the periphery and central nervous system to alter sleep, and 3) to present information about the relationship between cerebral vascular hemodynamics and the electroencephalogram during sleep.
Introduction Most traumatic brain injuries (TBI) are mild to moderate and can cause persistent dysregulated sleep, although the mechanisms are not well understood. Interleukin-1 beta (IL-1β) is a pro-inflammatory molecule that is activated in the cortex after waking activity and pathogenic challenge and alters non-rapid eye movement (NREM) sleep and electroencephalogram (EEG) delta power. Nucleotide-binding domain leucine rich family pyrin containing 3 (NLRP3) inflammasomes sense changes in their local environment to stimulate caspase-1 to activate IL-1β into its mature form. We previously found that NLRP3 inflammasomes are increased in the cortex after acute sleep loss and contribute to increased NREM sleep and EEG delta power after sleep loss and toxin challenge. We aimed to determine if NLRP3 inflammasomes contribute to the persistent dysregulated sleep caused by TBI. Methods Using 2-3-month-old mice lacking NLRP3 and C57BL/6J wild-type control mice, we assessed sleep states and sleep state episode durations and frequencies prior to TBI, and 24 h, 2-weeks, and 2 months after mild or moderate TBI using polysomnography. TBI occurred in the frontal cortex from a controlled cortical impact device. Additional mice received identical treatments serving as a TBI procedural control but received a craniectomy without the TBI. Results Similar sleep findings were observed between the craniectomy control group and baseline measures. However, when compared to baseline values, mice lacking NLRP3 had attenuations in the significant increased amounts of NREM sleep and EEG delta power occurring 24 h after TBI and the significant reductions in NREM sleep and EEG delta power seen 2 months after TBI that were observed in wild-type mice. These effects were similar in moderate and mild TBI groups. Mice lacking NLRP3 were not found to exhibit the fragmented sleep after mild or moderate TBI that was found to persist from 24 h to 2 months post-TBI in the wild-type mice. These effects were evident by significant increased frequencies of waking episodes induced by the TBIs. Conclusion Our findings suggest that NLRP3 inflammasomes contribute to dysregulated sleep occurring acutely or more persistently after TBI. Support (if any) Career Development Award IBX002823 (MZ) and Merit Review Award I01RX001144 (GK) from the United States Department of Veterans Affairs
Introduction Mild traumatic brain injuries (TBI) induce persistent dysregulated sleep, reactive oxygen species (ROS), and inflammation. Nucleotide-binding domain leucine rich family pyrin containing 3 (NLRP3) inflammasomes are protein complexes that stimulate caspase-1 to activate the somnogenic pro-inflammatory cytokines IL-1β and IL-18. ROS induce thioredoxin interacting protein (TXNIP) to activate NLRP3 inflammasomes by inhibiting thioredoxin which inhibits ROS. We previously found that mice lacking NLRP3 have increased non-rapid-eye movement (NREM) sleep and slow-wave activity (SWA) 24 h after mild TBI, but at 2 months post-injury theses values are reduced. Following up on this, we sought to determine the activity of NLRP3 inflammasomes in glia and neurons after mild TBI. Methods Two-month-old mice lacking NLRP3, and wild-type mice received a craniectomy and mild TBI via controlled cortical impact or sham. Frontal and somatosensory cortices were collected without a TBI and at 24 h and 2 months post-TBI. Microglia, astrocytes, and neurons were isolated using fluorescent-activated cell sorting, and reactive oxygen species (ROS), RNA and protein were quantified using RT-PCR and ELISAs. Significance was set at p < 0.05. Results RNA, protein, and ROS control treatment values were similar for both genotypes in cortical microglia, astrocytes, and neurons. In wild-type mice, NLRP3, IL-1β, IL-18, caspase-1, and TXNIP expression along with ROS values were significantly greater and thioredoxin expression was significantly less in cortical microglia, astrocytes, and neurons 24 h and 2 months post-TBI. In wild-type cortical microglia, astrocytes, and neurons NLRP3, IL-1β, and TXNIP expression levels were significantly greater in these cell types 2 months vs. 24 h post-TBI. Wild-type mice caspase-1 activity and NLRP3, IL-18, IL-1β, and TXNIP protein levels, were significantly greater and thioredoxin protein levels were significantly less in both cortical areas 24 h and 2 months post-TBI. Mice lacking NLRP3 showed significant increased values of TXNIP but reduced thioredoxin expression and protein levels 24 and 2 months post-TBI but no significant differences in other measures. Conclusion Our findings suggest that TBI induces persistent oxidative stress, TXNIP, and NLRP3 inflammasome activation in cortical glia and neurons that likely contributes to sleep dysregulation. Support (if any) Merit Review Award (I01BX005379)(MRZ) and SPiRE Award (I21RX003722)(GBK) Department of Veterans Affairs
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