Behavioral, cellular, and molecular changes in two animal models of bipolar disorder mania: sleep deprivation-induced mice and Clock-mutant mice

Abstract Sleep disturbances are prevalent in bipolar disorder (BD) patients, and the circadian locomotor output cycles kaput (Clock) gene plays a significant role in this process. The role of microglia (the brain-resident immune cells) in mediating this process remains uncertain. In this study, our findings showed that sleep loss induces mania-like behavior, microglial loss, and time-dependent gene expression changes. Moreover, diurnal oscillations in circadian rhythm-associated and inflammation-related gene expression in the mouse prefrontal cortex (PFC) were altered following sleep deprivation (SD). Further correlative analysis revealed correlations in gene expression between marker genes for microglia and Clock genes. In addition, the Clock mutation induces mania-like behavior, inhibition of neural activity, and microglial loss. Transcriptomic analysis revealed significant alterations in inflammatory pathways, circadian rhythm-related pathways, and the major histocompatibility protein complex in ClockΔ19 mice. Subsequent correlative analysis demonstrated significant correlations in gene expression among inflammation-, circadian rhythm-, and synapse-related genes within the PFC and hypothalamus of both male and female ClockΔ19 mice. In conclusion, our findings demonstrated behavioral, cellular, and molecular changes in SD-induced mice and Clock-mutant mice models. Microglia and CLOCK were associated with mania-like behaviors. Future research will likely focus on microglia-targeted approaches for the diagnosis and treatment of BD.