A meningeal circadian clock and brain state co-ordinately enhance macromolecular clearance during wake

Abstract

The removal of brain waste is thought to be regulated by the circadian clock and sleep-wake cycle. A meningeal scavenger cell population, called mural Lymphatic Endothelial Cells (muLECs), uptake macromolecules from the cerebrospinal fluid (CSF) and are poised to clear soluble brain waste. Whether CSF clearance is regulated across the 24-hour day is unknown. Using a quantitative, in vivo assay in zebrafish, we show that the capacity of muLECs to remove macromolecules is highest during the waking day. The muLEC protein uptake is regulated by a cell-autonomous circadian oscillator that drives rhythmic protein levels of Mannose Receptor 1a (Mrc1a); in contrast, lipoprotein uptake increases as a function of time spent awake. Thus, circadian and brain state cues independently maximize muLECs function during wake. Consistently, muLECs are required for normal recovery after the heightened metabolic demand of a seizure, suggesting that muLEC clearance contributes to both normal and disrupted brain homeostasis. Impact StatementA meningeal scavenger cell population called Mural Lymphatic Endothelial Cells preferentially clear macromolecules from the CSF during the waking day, and this uptake is regulated independently by brain state and circadian cues in a substrate-specific manner.