0133 NLRP3 Inflammasomes Modulate Brain Vasohemodynamic Responses to Sleep Loss

Abstract Introduction Increased cerebral blood flow (CBF) is positively associated with non-rapid eye movement (NREM) sleep electroencephalogram (EEG) delta power, also known as slow-wave activity (SWA). The pro-inflammatory somnogenic cytokine interleukin-1 beta (IL-1β) can induce vasodilation and increase CBF. Nucleotide leucine-rich protein complex-3 (NLRP3) inflammasomes, which activate IL-1β, are increased in the cortex after sleep deprivation and increase SWA. We aimed to determine the relationship of NLRP3 inflammasomes on sleep loss-induced alterations in vasohemodynamics and SWA. Methods NLRP3 knock-out (KO) and wild-type (WT) mice underwent ad libitum sleep, 6 hours of sleep deprivation, or were given 10 ng of IL-1β or the vehicle intracerebroventricularly. SWA and CBF, blood velocity, and blood volume were determined concurrently during sleep/wake states using polysomnography and laser doppler flowmetry. Regional brain changes in CBF were determined using transponders, spectrophotometry, and fluorescent microspheres. Results SWA and CBF were significantly increased during the first 6 hours after sleep deprivation in WT but not NLRP3 KO mice. SWA and CBF significantly increased in the first 6 hours after IL-1β in both NLRP3 KO and WT mice. Additionally, alterations in cerebral blood velocity and volume demonstrated state specific changes that varied significantly during the transitions between states. SWA and CBF were significantly positively correlated during both ad libitum sleep and sleep after sleep deprivation in WT mice, although this relationship was not observed in NLRP3 KO mice. We also found significant phase-amplitude frequency coupling between SWA and CBF. Cortical changes CBF were significantly enhanced after sleep deprivation and IL-1β administration in WT mice, although were attenuated in the hypothalamus. NLRP3 KO mice showed these same regional effects in CBF after IL-1β but not sleep deprivation. Conclusion Our findings indicate that NLRP3 inflammasomes are involved in neurovascular coupling involving SWA. Support Department of Veterans Affairs IBX002823A (MRZ)