Altered microbiota drive prelimbic cortex suppression and lower pain thresholds after sleep deprivation

Sleep disturbances are increasingly recognized as a lifestyle factor for abnormal pain perception. Recent studies highlight the critical role of gut microbiota in maintaining physiological balance and reveal a bidirectional relationship between microbiota alterations, sleep disorders, and pathological pain. This study investigates the potential role of microbiota in linking sleep deprivation to abnormal pain. Using a chronic sleep deprivation (CSD) model in mice, we observed significantly lower pain thresholds compared to controls. Brain-wide functional ultrasound imaging revealed reduced cerebral blood volume responses to pinprick stimulation in the prelimbic cortex (PrL) of CSD mice, indicating decreased neuronal activity during pain processing. This finding was confirmed by fiber photometry of calcium influx and c-Fos staining in the PrL. Importantly, chemogenetic activation of PrL neurons effectively reversed CSD-induced pain hypersensitivity. CSD also caused significant microbiota alterations, including increased diversity and changes in specific genera associated with brain function-related metabolic pathways. Fecal microbiota transplantation (FMT) demonstrated a causal relationship, as control mice that received microbiota from CSD mice developed pain hypersensitivity, whereas CSD mice that received control microbiota exhibited restored pain thresholds Notably, FMT-induced pain behavior changes correlated with PrL activity alterations. Our study indicates that CSD suppresses PrL activity and causes pain hypersensitivity through alterations in gut microbiota. This study emphasizes the gut-brain axis as a critical pathway in the interplay between sleep deprivation and pain regulation.