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

Abstract

The time we spend asleep is adjusted to previous time spent awake, and therefore believed to be under tight homeostatic control. Here, we establish microglia as a new cellular component of the sleep homeostat circuit. By using quantitative phosphoproteomics we demonstrate that microglia-derived TNFα controls thousands of phosphorylation sites during the sleep period. Substrates of microglial TNFα comprise sleep-promoting kinases and numerous synaptic proteins, including a subset whose phosphorylation status codes sleep need and determines sleep duration. As a result, lack of microglial TNFα attenuates the build-up of sleep need, as measured by slow wave activity, and prevents immediate compensation for loss of sleep. Together, we propose that microglia control sleep homeostasis by releasing TNFα that acts at the neuronal circuitry through dynamic control of phosphorylation. attenuates the build-up of sleep need, as measured by slow wave activity, and prevents immediate compensation for loss of sleep. Together, we propose that microglia control sleep homeostasis by releasing TNFα that acts at the neuronal circuitry through dynamic control of phosphorylation.

The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure

“…Also, in models of depression and anxiety disorders, the excitatory–inhibitory imbalance caused by astrocyte dysfunction has been implicated as an important pathogenic factor ( Zhou et al, 2019 ). In animal models, astrocytic IL-6 mediated anxiety ( Erta et al, 2015 ), and there is ample evidence for a role of glia, both astrocytes and microglia, in sleep regulation ( Pinto et al, 2022 ) and neuropsychiatric disorders [for a review see ( Mayegowda and Thomas, 2019 )]. For details on possible cellular mechanisms see ( Tay et al, 2017a ; Zhou et al, 2019 ).…”

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

“…Another pathway through which microglia could be involved in sleep regulation is through the production of cytokines such as IL-1 and TNF, which are known to be sleep-regulatory substances (Clinton et al, 2011). Accordingly, microglia-derived TNF was to modulate cortical protein phosphorylation during the sleep period, including sleep-promoting kinases and synaptic proteins (Pinto et al, 2022).…”

“…Microglial production of TNF is also involved in the phosphorylation of sleep-promoting kinases and numerous synaptic proteins (Pinto et al, 2022). Additionally, microglia may participate in the consolidation of learning and memory occurring during sleep by promoting the formation and elimination of dendritic spines (W. or by contributing to synaptic homeostasis, a downscaling process hypothesized to reduce the strength of weaker synapses during sleep Cirelli, 2020, 2003).…”