The mechanistic role of microglia and IL10 in the regulation of pathological sleep disturbances - PROJECT SUMMARY/ABSTRACT
Insufficient sleep is associated with inflammation and adverse health. Inflammation modulates sleep and,
conversely, insufficient sleep induces inflammation. A bi-directional relationship between disrupted sleep and
inflammation represents a positive feedback loop that negatively impacts health; however, a substantial
knowledge gap exists regarding the molecular mechanisms by which inflammation induces and/or contributes
to sleep disturbances. Glia, specifically microglia, may facilitate the bi-directional interactions between
neuroinflammation and sleep. Although microglia serve an overall beneficial role, prolonged microglial activation
drives neuroinflammation and subsequent neurodegeneration. Interluekin-10 (IL10), an anti-inflammatory
cytokine released by microglia, inhibits the synthesis of pro-inflammatory cytokines; hence IL10 may be an ‘off-
switch’ for chronically activated microglia. Preliminary results from the PI’s laboratory demonstrated that
depleting microglia (<0.5%) does not change central cytokine concentrations. However, under inflammatory
conditions, induced by lipopolysaccharide (LPS) administration, mice with depleted microglia have elevated pro-
inflammatory cytokines, a sustained increase in NREM sleep, and significantly lower levels of IL10 compared to
control mice. These data suggest that microglia are necessary to modulate sleep triggered by inflammation.
Importantly, preliminary results indicated IL10 administration normalizes sleep after an inflammatory challenge.
We further show that IL10 administration after LPS in mice with depleted microglia, normalizes sleep and is
linked to an immediate increase in IL10 in the brain, as well as rapid microglia repopulation/activation in the
brain. This has led to the overarching hypothesis that microglia-mediated IL10 signaling is part of feedback
mechanisms that are responsible for normalizing sleep after an inflammatory challenge. This hypothesis will be
tested through the following specific aims: 1) Investigate the role of microglia and the IL10 axis in inflammation-
induced sleep disturbances; 2) Determine the influence of microglia-mediated IL10 on other central nervous
system cells after an inflammatory challenge; and 3) Investigate the extent to which IL10 replacement normalizes
sleep after an inflammatory challenge. Impact: Successful completion of these studies will elucidate novel
mechanisms that underlie inflammation-induced sleep disturbances and may open a new line of intervention to
treat inflammation-induced sleep disturbances.
