Microglia modulate stable wakefulness via the thalamic reticular nucleus in mice

Abstract

Microglia are important for brain homeostasis and immunity, but their role in regulating vigilance remains unclear. We employed genetic, physiological, and metabolomic methods to examine microglial involvement in the regulation of wakefulness and sleep. Microglial depletion decreased stable nighttime wakefulness in mice by increasing transitions between wakefulness and non-rapid eye movement (NREM) sleep. Metabolomic analysis revealed that the sleep-wake behavior closely correlated with diurnal variation of the brain ceramide, which disappeared in microglia-depleted mice. Ceramide preferentially influenced microglia in the thalamic reticular nucleus (TRN), and local depletion of TRN microglia produced similar impaired wakefulness. Chemogenetic manipulations of anterior TRN neurons showed that they regulated transitions between wakefulness and NREM sleep. Their firing capacity was suppressed by both microglial depletion and added ceramide. In microglia-depleted mice, activating anterior TRN neurons or inhibiting ceramide production both restored stable wakefulness. These findings demonstrate that microglia can modulate stable wakefulness through anterior TRN neurons via ceramide signaling.

Microglial TNFα controls synaptic GABAARs, sleep slow waves and memory consolidation

“…Many of the latter, such as prostaglandin, BDNF, IL- 1β or TNFα, control synaptic plasticity and were independently shown to regulate sleep (Porkka-Heiskanen, 2013). Recent work highlights the ability of microglia to control sleep duration (Corsi et al, 2021; Liu et al, 2021); however, whether and how microglia-released factors shape sleep via modulation of synaptic plasticity remains unknown.…”

Effects of clozapine-N-oxide and compound 21 on sleep in laboratory mice

“…However, occasionally authors have mentioned that the use of CNO injections of up to 10 mg/kg may have affected the sleep of animals in DREADD-free control groups (Funk et al 2017) and recent work focussing on REM sleep regulation presented statistically significant effects of CNO doses higher than 5 mg/kg in the supplementary data (Varin, Luppi, and Fort 2018). Another well-controlled study found a slight increase in NREM sleep bout duration of control mice injected with 0.3 mg/kg CNO, while all other analysed parameters were unaffected by this small CNO dose (Liu et al 2021). This finding supports our effect size analysis indicating that NREM sleep bout duration is the sleep architectural parameter most strongly affected by CNO and C21 and that CNO can cause sleep-modulating effects at doses of 1 mg/kg CNO, and possibly below.…”

Microglial TNFα orchestrates brain phosphorylation during the sleep period and controls homeostatic sleep

“…TNFα is a signaling molecule known to control activation of phosphorylation pathways (15)(16)(17). In the brain, TNFα is mostly if not exclusively produced by microglia (18,19), which are active sensors of brain state (20)(21)(22) and have been recently proposed to participate in the regulation of sleep (23)(24)(25). We therefore hypothesized that microglia-derived TNFα is involved in phosphorylation-based control of sleep.…”