Microglial homeostasis disruption modulates non-rapid eye movement sleep duration and neuronal activity in adult
Katherine Picard1, Giorgio Corsi2, Fanny Decoeur3
1Axe Neurosciences, Centre de recherche du CHU de Québec-Université Laval, Québec, QC, Canada; Département de médecine moléculaire, Université Laval, Québec, QC, Canada; Division of Medical Sciences, University of Victoria, Victoria, BC, Canada.
Abstract:
Sleep is a natural physiological state, tightly regulated through several neuroanatomical and neurochemical systems, which is essential to maintain physical and mental health. Recent studies revealed that the functions of microglia, the resident immune cells of the brain, differ along the sleep-wake cycle. Inflammatory cytokines, such as interleukin-1β and tumor necrosis factor-α, mainly produced by microglia in the brain, are also well-known to promote sleep. However, the contributing role of microglia on sleep regulation remains largely elusive, even more so in females. Given the higher prevalence of various sleep disorders in women, we aimed to determine the role of microglia in regulating the sleep-wake cycle specifically in female mice. Microglia were depleted in adult female mice with inhibitors of the colony-stimulating factor 1 receptor (CSF1R) (PLX3397 or PLX5622), which is required for microglial population maintenance. This led to a 65-73% reduction of the microglial population, as confirmed by immunofluorescence staining against IBA1 (marker of microglia/macrophages) and TMEM119 (microglia-specific marker) in the reticular nucleus of the thalamus and primary motor cortex. The spontaneous sleep-wake cycle was evaluated at steady-state, during microglial homeostasis disruption and after complete microglial repopulation, upon cessation of treatment with the inhibitors of CSF1R, using electroencephalography (EEG) and electromyography (EMG). We found that microglia-depleted female mice spent more time in non-rapid eye movement (NREM) sleep and had an increased number of NREM sleep episodes, which was partially restored after microglial total repopulation. To determine whether microglia could regulate sleep locally by modulating synaptic transmission, we used patch clamp to record spontaneous activity of pyramidal neurons in the primary motor cortex, which showed an increase of excitatory synaptic transmission during the dark phase. These changes in neuronal activity were modulated by microglial depletion in a phase-dependent manner. Altogether, our results indicate that microglia are involved in the sleep regulation of female mice, further strengthening their potential implication in the development and/or progression of sleep disorders. Furthermore, our findings indicate that microglial repopulation can contribute to normalizing sleep alterations caused by their partial depletion.
Insights
Microglia, the brain's immune cells, play a key role in regulating sleep-wake cycles in female mice. Depleting microglia increased non-rapid eye movement sleep, highlighting their importance in sleep health.
Area of Science:
- Neuroscience
- Immunology
- Sleep Science
Background:
- Sleep is a vital physiological state regulated by complex neurobiological systems.
- Microglia, the brain's resident immune cells, have emerging roles in sleep regulation, but their specific function in females is unclear.
- Women exhibit a higher prevalence of sleep disorders, necessitating research into sex-specific sleep mechanisms.
Purpose of the Study:
- To investigate the role of microglia in regulating the sleep-wake cycle in female mice.
- To determine if microglial depletion impacts sleep architecture and neuronal activity in females.
- To assess the potential for microglial repopulation to restore normal sleep patterns.
Main Methods:
- Microglial depletion in adult female mice using colony-stimulating factor 1 receptor (CSF1R) inhibitors (PLX3397 or PLX5622).
- Evaluation of sleep-wake cycles using electroencephalography (EEG) and electromyography (EMG).
- Assessment of neuronal activity in the primary motor cortex using patch clamp electrophysiology.
Main Results:
- Microglia depletion significantly increased non-rapid eye movement (NREM) sleep duration and episode number in female mice.
- Excitatory synaptic transmission in the primary motor cortex was altered in a phase-dependent manner following microglial depletion.
- Partial restoration of sleep patterns was observed after microglial repopulation.
Conclusions:
- Microglia are integral to the regulation of the sleep-wake cycle in female mice.
- Microglial function is implicated in the sex-specific prevalence of sleep disorders.
- Microglial repopulation may offer a therapeutic avenue for normalizing sleep disturbances.
