The NLRP3 inflammasome modulates sleep and NREM sleep delta power induced by spontaneous wakefulness, sleep deprivation and lipopolysaccharide.

Both sleep loss and pathogens can enhance brain inflammation, sleep, and sleep intensity as indicated by electroencephalogram delta (δ) power. The pro-inflammatory cytokine interleukin-1 beta (IL-1ß) is increased in the cortex after sleep deprivation (SD) and in response to the Gram-negative bacterial cell-wall component lipopolysaccharide (LPS), although the exact mechanisms governing these effects are unknown. The nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) inflammasome protein complex forms in response to changes in the local environment and, in turn, activates caspase-1 to convert IL-1ß into its active form. SD enhances the cortical expression of the somnogenic cytokine IL-1ß, although the underlying mechanism is, as yet, unidentified. Using NLRP3-gene knockout (KO) mice, we provide evidence that NLRP3 inflammasome activation is a crucial mechanism for the downstream pathway leading to increased IL-1ß-enhanced sleep. NLRP3 KO mice exhibited reduced non-rapid eye movement (NREM) sleep during the light period. We also found that sleep amount and intensity (δ activity) were drastically attenuated in NLRP3 KO mice following SD (homeostatic sleep response), as well as after LPS administration, although they were enhanced by central administration of IL-1ß. NLRP3, ASC, and IL1ß mRNA, IL-1ß protein, and caspase-1 activity were greater in the somatosensory cortex at the end of the wake-active period when sleep propensity was high and after SD in wild-type but not NLRP3 KO mice. Thus, our novel and converging findings suggest that the activation of the NLRP3 inflammasome can modulate sleep induced by both increased wakefulness and a bacterial component in the brain.

Chronic sleep restriction elevates brain interleukin-1 beta and tumor necrosis factor-alpha and attenuates brain-derived neurotrophic factor expression.

Acute sleep loss increases pro-inflammatory and synaptic plasticity-related molecules in the brain, including interleukin-1 beta (IL-1ß), tumor necrosis factor-alpha (TNF-α), and brain-derived neurotrophic factor (BDNF). These molecules enhance non-rapid eye movement sleep slow wave activity (SWA), also known as electroencephalogram delta power, and modulate neurocognitive performance. Evidence suggests that chronic sleep restriction (CSR), a condition prevalent in today's society, does not elicit the enhanced SWA that is seen after acute sleep loss, although it cumulatively impairs neurocognitive functioning. Rats were continuously sleep deprived for 18h per day and allowed 6h of ad libitum sleep opportunity for 1 (SR1), 3 (SR3), or 5 (SR5) successive days (i.e., CSR). IL-1ß, TNF-α, and BDNF mRNA levels were determined in the somatosensory cortex, frontal cortex, hippocampus, and basal forebrain. Largely, brain IL-1ß and TNF-α expression were significantly enhanced throughout CSR. In contrast, BDNF mRNA levels were similar to baseline values in the cortex after 1 day of SR and significantly lower than baseline values in the hippocampus after 5 days of SR. In the basal forebrain, BDNF expression remained elevated throughout the 5 days of CSR, although IL-1ß expression was significantly reduced. The chronic elevations of IL-1ß and TNF-α and inhibition of BDNF might contribute to the reported lack of SWA responses reported after CSR. Further, the CSR-induced enhancements in brain inflammatory molecules and attenuations in hippocampal BDNF might contribute to neurocognitive and vigilance detriments that occur from CSR.

A novel telemetric system to measure polysomnographic biopotentials in freely moving animals.

Mice are by far the most widely used species for scientific research and have been used in many studies involving biopotentials, such as the electroencephalogram (EEG) and electromyogram (EMG) signals monitored for sleep analysis. Unfortunately, current methods for the analysis of these signals involve either tethered systems that are restrictive and heavy for the animal or wireless systems that use transponders that are large relative to the animal and require invasive surgery for implantation; as a result, natural behavior/activity is altered. Here, we propose a novel and inexpensive system for measuring electroencephalographic signals and other biopotentials in mice that allows for natural movement. We also evaluate the new system for the analysis of sleep architecture and EEG power during both spontaneous sleep and the sleep that follows sleep deprivation in mice. Using our new system, vigilance states including non-rapid eye movement sleep (NREMS), rapid eye movement sleep (REMS), and wakefulness, as well as EEG power and NREMS EEG delta power in the 0.5-4 Hz range (an indicator of sleep intensity) showed the diurnal rhythms typically found in mice. These values were also similar to values obtained in mice using telemetry transponders. Mice that used the new system also demonstrated enhanced NREMS EEG delta power responses that are typical following sleep deprivation and few signal artifacts. Moreover, similar movement activity counts were found when using the new system compared to a wireless system. This novel system for measuring biopotentials can be used for polysomnography, infusion, microdialysis, and optogenetic studies, reduces artifacts, and allows for a more natural moving environment and a more accurate investigation of biological systems and pharmaceutical development.