Cleanup at the right time A common mechanism underlies the molecular clock of microglia and neuronal activity in metabolic and memory control

Microglia are the brain’s resident macrophages with immune-modulating and phagocytic capabilities. Microglia engulf apoptotic cells, cellular debris, unwanted synapses, and pathogens, as well as release inflammatory cytokines and neurotrophic factors to optimize the surrounding microenvironment and shape the neural circuits. Disruption of microglial function results in deficits in cognition and energy balance. Moreover, the microglial function is controlled by an intrinsic circadian rhythm. The endogenous circadian clock function plays a crucial role in the control of cellular metabolism that subsequently affects overall physiological functions. Here, we found that core clock gene-Bmal1 deficiency robustly enhances the microglial phagocytic capacity under HFD conditions and during cognitive processes. This enhancement was associated with reduced POMC neuronal loss in the hypothalamus when mice are fed a HFD, and was also related to the formation of more mature spines in the hippocampus during the learning process. Microglial-specific Bmal1 knockout mice were protected from HFD-induced obesity and presented increased memory performance. Additionally, Bmal1 deficiency decreases gene expression of pro-inflammatory cytokines and increases gene expression of anti-oxidative and anti-inflammatory factors in microglial BV-2 cells. These changes protect the BV-2 cells from LPS and palmitic acid-induced inflammation. Our data suggest that the molecular clock in microglial cells could be a new target to treat metabolic and cognitive disorders, as well as neuron-inflammatory diseases.