Microglia Are Necessary to Regulate Sleep after an Immune Challenge

Abstract

Microglia play a critical role in the neuroimmune response, but little is known about the role of microglia in sleep following an inflammatory trigger. Nevertheless, decades of research have been predicated on the assumption that an inflammatory trigger increases sleep through microglial activation. We hypothesized that mice (n = 30) with depleted microglia using PLX5622 (PLX) would sleep less following the administration of lipopolysaccharide (LPS) to induce inflammation. Brains were collected and microglial morphology was assessed using quantitative skeletal analyses and physiological parameters were recorded using non-invasive piezoelectric cages. Mice fed PLX diet had a transient increase in sleep that dissipated by week 2. Subsequently, following a first LPS injection (0.4 mg/kg), mice with depleted microglia slept more than mice on the control diet. All mice were returned to normal rodent chow to repopulate microglia in the PLX group (10 days). Nominal differences in sleep existed during the microglia repopulation period. However, following a second LPS injection, mice with repopulated microglia slept similarly to control mice during the dark period but with longer bouts during the light period. Comparing sleep after the first LPS injection to sleep after the second LPS injection, controls exhibited temporal changes in sleep patterns but no change in cumulative minutes slept, whereas cumulative sleep in mice with repopulated microglia decreased during the dark period across all days. Repopulated microglia had a reactive morphology. We conclude that microglia are necessary to regulate sleep after an immune challenge.

Microglial homeostasis disruption modulates non-rapid eye movement sleep duration and neuronal activity in adult female mice

“…However, in the case that it affected the results, this could indicate that we would have observed a stronger effect on the first day following the withdrawal of the PLX3397. Rowe et al, as well as our group recently obtained similar changes regarding the sleep duration in male mice using the same method (Corsi et al, 2021;Rowe et al, 2022). Similar findings were also recently observed in male and female mice by Liu et al, showing a reduction of stable wakefulness due to an increase in the transitions between wakefulness and NREM sleep using a transgenic model, through ceramide signaling.…”

“…It was also showed by Rowe et al that microglial depletion induced by PLX5622, a colonystimulating factor 1 receptor (CSF1R) inhibitor, could lead to an increased percentage of sleep time during the light period in male mice in the first week following complete microglial depletion (Rowe et al, 2022). Moreover, a study by our group shows that microglia can modulate sleep duration through the fractalkine signaling pathway in male mice (Corsi et al, 2021).…”

A 14-day pulse of PLX5622 modifies α-synucleinopathy in preformed fibril-infused aged mice of both sexes

“…Furthermore, only young animals of one sex were tested, or the sex was left unmentioned ( George et al, 2019 ; Guo et al, 2020 ; Jing et al, 2021 ; Oh et al, 2020 ; Stoll et al, 2023 ; Yang et al, 2018 ; Zhang et al, 2021a ). Although studies of microglia/macrophage repopulation after depletion are fewer, they have shown more consistently beneficial results in models of aging, acute brain injury, Alzheimer’s disease, intracerebral hemorrhage, inflammation, stroke, and parkinsonism ( Barca et al, 2022 ; Coleman Jr. et al, 2020 ; Elmore et al, 2018 ; Henry et al, 2020 ; Johnson et al, 2023 ; Li et al, 2021 ; Li et al, 2022 ; Rice et al, 2017 ; Rowe et al, 2022 ; Willis et al, 2020 ).…”