title: The NLRP3 inflammasome modulates sleep and NREM sleep delta power induced by spontaneous wakefulness, sleep deprivation and lipopolysaccharide.
abstract: 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-1β) 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-1β into its active form. SD enhances the cortical expression of the somnogenic cytokine IL-1β, 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-1β-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-1β. NLRP3, ASC, and IL1β mRNA, IL-1β 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.
authors.affiliation: Department of Psychiatry, Harvard Medical School and Veterans Affairs Boston Healthcare System, West Roxbury, MA 02132, USA. Electronic address: Mark_Zielinski@hms.harvard.edu.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Zielinski
authors.affiliation: Department of Psychiatry, Harvard Medical School and Veterans Affairs Boston Healthcare System, West Roxbury, MA 02132, USA.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Gerashchenko
authors.affiliation: Department of Psychiatry, Harvard Medical School and Veterans Affairs Boston Healthcare System, West Roxbury, MA 02132, USA.
authors.forename: Svetlana A
authors.initials: SA
authors.lastname: Karpova
authors.affiliation: Department of Psychiatry, Harvard Medical School and Veterans Affairs Boston Healthcare System, West Roxbury, MA 02132, USA.
authors.forename: Varun
authors.initials: V
authors.lastname: Konanki
authors.affiliation: Department of Psychiatry, Harvard Medical School and Veterans Affairs Boston Healthcare System, Brockton, MA 02301, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: McCarley
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Fayyaz S
authors.initials: FS
authors.lastname: Sutterwala
authors.affiliation: Department of Psychiatry, Harvard Medical School and Veterans Affairs Boston Healthcare System, West Roxbury, MA 02132, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Strecker
authors.affiliation: Department of Psychiatry, Harvard Medical School and Veterans Affairs Boston Healthcare System, West Roxbury, MA 02132, USA.
authors.forename: Radhika
authors.initials: R
authors.lastname: Basheer
mesh_terms: D000818:Animals; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000378:metabolism*; D017286:Polysomnography; D015398:Signal Transduction / Q000502:physiology; D012890:Sleep / Q000502:physiology*; D012892:Sleep Deprivation / Q000235:genetics / Q000378:metabolism*; D014851:Wakefulness / Q000502:physiology
chemical_list: D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein
keywords: Caspase-1; Cortex; EEG delta power; Inflammation; Interleukin-1 beta; Lipopolysaccharide; NLRP3 inflammasome; Sleep deprivation