TIME OF DAY INFLUENCES THE BRAIN’S IMMUNE RESPONSE TO A SYSTEMIC CHALLENGE

Circadian rhythms shape many aspects of immunity, but relatively few studies have examined whether circadian phase modulates the brain’s response to a systemic inflammatory challenge. Defining such temporal vulnerability is important for understanding why the severity of acute inflammatory insults, such as sepsis and delirium, can vary. We tested whether lipopolysaccharide (LPS) given in the inactive versus active phase produces distinct systemic and neuroinflammatory responses. Adult mice (6 ± 2 months) received LPS (500 µg/kg, intraperitoneal) at ZT1 (beginning of the inactive Phase) or ZT13 (beginning of the active phase). Activity was assessed in the open field 5hrs post challenge, and body temperature was measured at regular intervals. Whole body energy metabolism was measured by indirect calorimetry using the Promethion cage system. Mice were euthanised 24hrs post LPS. The hypothalamus was dissected for bulk RNA sequencing, one hemisphere was processed for flow cytometry, and frontal cortex and hippocampus from the opposite hemisphere were used for qPCR. LPS at ZT13 produced a more profound hypothermia than mice challenged at ZT1. Flow cytometry indicated heightened microglial activation with increased inflammatory signatures at ZT13, accompanied by greater recruitment of neutrophils and monocytes to the brain. Bulk hypothalamic transcriptomics revealed time of day dependent differences in blood brain barrier associated transcripts and genes involved in mitochondrial efficiency. qPCR in frontal cortex showed trends toward higher expression of oxidative stress pathways in ZT13 challenged mice. These data support a model in which the brain is more vulnerable to systemic LPS during the early active phase.