Sleep deprivation disrupts vestibular compensation by activating TLR4/NF-κB/NLRP3 signalling in the deafferented vestibular nuclei

We aimed to investigate whether sleep deprivation (SD) affects vestibular compensation and explore the underlying mechanisms. After unilateral labyrinthectomy (UL), adult mice were subjected to 6 h of SD for 5 days. Behavioural tests were performed to evaluate the vestibular recovery. RNA sequencing and bioinformatic analyses were conducted on the deafferented vestibular nuclei (VN) of UL mice with or without SD. Immunofluorescence and western blotting were used to verify the inflammatory responses, neuroplasticity, and pathways in the VN of UL+SD mice. Minocycline and TAK-242 were used to inhibit microglial activation and TLR4, respectively. Our findings suggest that SD significantly impaired vestibular compensation in UL mice. RNA sequencing identified upregulated immune- and inflammation-related pathways in the deafferented VN after SD, which was verified by microglial overactivation. Moreover, neuroplasticity was impaired, and inhibition of microglial proliferation with minocycline partially improved the impaired vestibular compensation during the early stages. Mechanistically, TLR4/NF-κB/NLRP3 pathway activation was predominantly involved in this process, and pharmacological inhibition of TLR4 inhibited NLRP3 activation in microglia and improved SD-induced vestibular compensation delay. Overall, this study illustrates that SD alters neuroplasticity and aggravates microglia-mediated neuroinflammation in deafferented VN by activating TLR4/NF-κB/NLRP3 signalling, which contributes to impaired vestibular compensation.