Age-associated suppression of exploratory activity during sickness is linked to meningeal lymphatic dysfunction and microglia activation

Peripheral inflammation triggers a transient, well-defined set of behavioral changes known as sickness behavior 1 – 3 , but the mechanisms by which inflammatory signals originating in the periphery alter activity in the brain remain obscure. Emerging evidence has established meningeal lymphatic vasculature as an important interface between the central nervous system (CNS) and the immune system, responsible for facilitating brain solute clearance and perfusion by cerebrospinal fluid (CSF) 4 , 5 . Here, we demonstrate that meningeal lymphatics both assist microglial activation and support the behavioral response to peripheral inflammation. Ablation of meningeal lymphatics results in a heightened behavioral response to IL-1β-induced inflammation and a dampened transcriptional and morphological microglial phenotype. Moreover, our findings support a role for microglia in tempering the severity of sickness behavior with specific relevance to aging-related meningeal lymphatic dysfunction. Transcriptional profiling of brain myeloid cells shed light on the impact of meningeal lymphatic dysfunction on microglial activation. Furthermore, we demonstrate that experimental enhancement of meningeal lymphatic function in aged mice is sufficient to reduce the severity of exploratory abnormalities but not pleasurable consummatory behavior. Finally, we identify dysregulated genes and biological pathways, common to both experimental meningeal lymphatic ablation and aging, in microglia responding to peripheral inflammation that may result from age-related meningeal lymphatic dysfunction.