Microglial Bmal1 Contributes to Diurnal Physiology and Retinal Homeostasis

Abstract

Circadian rhythms govern various physiological processes, including innate and adaptive immune responses. Microglia, the sentinels of the central nervous system (CNS), mediate synaptic remodeling and local immune responses that contribute to tissue homeostasis. Recent studies have uncovered that microglial surveillance behavior and cytokine production exhibit rhythmicity. Furthermore, disruption of clock gene expression in microglia impairs phagocytic capacity, metabolism, and inflammatory responses, suggesting that their dynamic functions are regulated in part by circadian rhythms. Given the growing recognition of circadian dysregulation in disease pathophysiology, elucidating molecular mechanisms of microglial chronobiology may reveal novel therapeutic strategies to resynchronize circadian rhythms with components of the immune system. Homeostatic rhythms and the implications of their disruption have yet to be explored in microglia that reside within the neurosensory retina, a tissue in the back of the eye that initiates visual transduction and relays photic information to the brain. In this study, we demonstrate that retinal microglia express rhythms in clock gene expression, morphology, and inflammatory markers that rely on the clock gene Bmal1. We also find that loss of Bmal1 in microglia is associated with a decline in retinal health and behavioral dysfunction in the mouse. Lastly, we demonstrate that Bmal1 deficiency also induces a senescent, disease-associated phenotype in microglia and transcriptomic reprogramming in the retinal parenchyma. These findings suggest that diurnal clock rhythms regulate microglia physiology within the retinal niche and contribute to homeostatic maintenance of the local tissue environment.