Friday, May 9, 2025
5/9/2025
Contribution of Glia to Sleep/Wake Disturbances in FXS - Sleep impairments are commonly reported in Fragile X syndrome (FXS) and autism spectrum disorders (ASD). Sleep impairments can have profound negative impact on brain development, cognition and general well-being however the underlying brain defects of sleep impairments in FXS are not well understood. While most research of sleep mechanisms have focused on neurons, recent studies revealed a critical role of astrocytes, a type of glia in the brain, as regulators of sleep and wake. Specifically, astrocyte Ca2+ signals exhibit distinct features across the sleep-wake cycle, are reduced during sleep compared to wakefulness and manipulating astrocyte Ca2+ signaling impacts sleep. Astrocytes in FXS have hyperexcitable Ca2+ signaling in culture and our preliminary data demonstrate the same in vivo. The goal of this proposal is to investigate the contribution of astrocytes and especially increased astrocyte Ca2+ signaling, to sleep impairments in FXS. We will ask the following important questions: How is sleep architecture impaired in FXS mouse models across development and adulthood and what is the contribution of astrocytes? In Aim 1 we will perform longitudinal telemetry to measure brain rhythms and behavior to determine the sleep architecture in the Fmr1 KO mice. To identify the contribution of astrocytes we will also record from astrocyte specific Fmr1 deletion (cKO) and restoration (cON) mice. Next, we will ask how is astrocyte Ca2+ signaling altered during sleep-wake cycle in FXS mouse models? In Aim 2 we will record cortical astrocyte Ca2+ activity with 2-photon microscopy in awake and naturally sleeping mice while monitoring brain rhythms and behavior. We will also image the dynamics of norepinephrine (NE) and NE-projections in the cortex. Finally, in Aim 3 we will determine the causal relationship between altered astrocyte Ca2+ signaling and sleep impairments using genetic and chemogenetic approaches and determine the impact on sleep- dependent synaptic plasticity. The approach is intellectually and technically innovative as a first study to link FXS sleep deficiency and altered cortical astrocyte Ca2+ activity and because it employs a novel combination of state-of-the-art approaches. The proposed research is significant because it is expected to provide critical knowledge of the molecular and cellular mechanisms by which sleep impairments are regulated in FXS. Ultimately, such knowledge is expected to guide the development of astrocyte-specific therapies for treatment of sleep impairments in FXS and autism spectrum disorder.
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