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Activation of basal forebrain astrocytes induces wakefulness without compensatory changes in sleep drive

Ingiosi AM, Hayworth, CR, Frank MG. BioRxiv, 2023.


Sleep drive is controlled by a homeostatic process that increases sleep duration and intensity based on prior time spent awake. Astrocytes influence this homeostatic process, but their precise role is unclear. We used chemogenetics to activate astrocytes in the basal forebrain of mice--a brain region important for sleep and wake expression and sleep homeostasis. Astroglial activation induced prolonged wakefulness without the expected homeostatic increase in sleep drive. These findings indicate that our need to sleep is driven by non-neuronal cells, and not only by time spent awake. These results also provide clues about sleep function and sleep disorders, such as insomnia.

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Noradrenergic signaling in astrocytes influences mammalian sleep homeostasis

Ingiosi AM, Frank MG. Clocks & Sleep, 2022.


In this paper we sought to understand what waking signals astrocytes respond to to modulate sleep expression and homeostasis by focusing on the wake-promoting neuromodulator noradrenaline (NA). We conditionally and selectively knocked out astroglial β2 adrenergic receptors (β2-AR) and assessed baseline sleep and recovery sleep after sleep deprivation. Conditional knockout of astroglial β2-AR increased active phase siesta duration under baseline conditions and reduced homeostatic compensatory changes in sleep consolidation and non-rapid eye movement slow-wave activity after sleep deprivation. Overall, these data indicated that astrocytes respond to NA to mediate sleep expression and homeostasis.


Goodnight, astrocyte: Waking up to astroglial mechanisms in sleep

Ingiosi AM, Frank MG. The FEBS Journal, 2022.


Our understanding of how sleep is regulated is largely rooted in the study of neurons. However, there is now evidence that non-neuronal cells may also play a role. In this review, we discuss recent findings supporting a role for astrocytes in sleep and sleep regulation with a focus on astroglial calcium signaling. We also suggest how this new evidence fits within a proposed neuronal–astroglial feedback model for sleep need.


Sleep and circadian rhythms: pillars of health - a Keystone Symposia report

Cable J, Schernhammer E, Hanlon EC, Vetter C, Cedernaes J, Makarem N, Dashti HS, Shechter A, Depner C, Ingiosi AM, Blume C, Tan X, Gottlieb E, Benedict C, Van Cauter E, St-Onge MP. Annals of the New York Academy of Sciences, 2021.


This summary of the research presented at the 2021 Keystone eSymposium on Sleep & Circadian Rhythms: Pillars of Health covers recent findings on the role of sleep and circadian rhythms in health and disease.


A role for astroglial calcium in mammalian sleep and sleep regulation

Ingiosi AM, Hayworth CR, Harvey DO, Singletary KG, Rempe MJ, Wisor JP, Frank MG. Current Biology, 2020. [preprint available: BioRxiv, 2019]

Mammalian sleep is characterized by dynamic changes in neuronal activity, and waking neuronal activity is thought to increase sleep need. Changes in other brain cells (glia) across the natural sleep-wake cycle and their role in sleep regulation are comparatively unexplored. We show that sleep is also accompanied by large changes in astroglial activity as measured by intracellular calcium concentrations in unanesthetized mice. These changes in calcium vary across different arousal states and are most pronounced in distal astroglial processes. We find that reducing intracellular calcium in astrocytes impaired the compensatory response to sleep deprivation. Thus, astroglial calcium changes dynamically across arousal states and is a component of the sleep homeostat.


Shank3 modulates sleep and expression of circadian transcription factors

Ingiosi AM*, Schoch H*, Wintler T, Singletary KG, Righelli D, Roser LG, Medina E, Risso D,
Frank MG, Peixoto L.  eLife, 2019. [preprint available: BioRxiv, 2018]

We studied the role of Shank3, a gene associated with autism, in sleep regulation. Mice lacking exon 21 of Shank3 have altered NREM spectral characteristics and take longer to fall asleep when sleep deprived. Difficulty falling asleep is a clinically relevant autism phenotype that aligns with data from individuals with Phelan-McDermid syndrome, a condition caused by a SHANK3 mutation or deletion that has a high incidence of autism. RNA-seq showed that sleep deprivation increases the downregulation of circadian transcription factors in Shank3 mutant mice compared to wild type. Shank3 mutant mice also have difficulty regulating wheel-running activity in constant darkness. Overall, this study shows that Shank3 is an important modulator of sleep and clock gene expression.


Sleep and immunomodulatory responses to systemic lipopolysaccharide in mice selectively expressing interleukin‐1 receptor 1 on neurons or astrocytes

Ingiosi AM and Opp MR. Glia, 2016.

We induced a systemic immune challenge with lipopolysaccharide (LPS) in two transgenic mouse lines that express interleukin-1 receptor 1 (IL1R1) only in the central nervous system and selectively on neurons or astrocytes. We found that neuronal IL1R1 plays a greater role in LPS‐induced suppression of rapid eye movement (REM) sleep and non-REM (NREM) delta power, whereas astroglial IL1R1 is more important for sleep fragmentation after LPS. Therefore, different aspects of central responses to LPS are modulated by IL1R1 in a cell type‐specific manner.


Selective contributions of neuronal and astroglial interleukin-1 receptor 1 to the regulation of sleep

Ingiosi AM, Raymond RM, Jr., Pavlova MN, Opp MR. Brain, Behavior, and Immunity, 2015.

Here we introduced two new transgenic mouse lines that express IL1R1 only in the central nervous system and selectively on neurons or astrocytes. We studied baseline sleep, homeostatic responses to sleep deprivation, and sleep and inflammatory response to interleukin-1β (IL-1) in vivo and in vitro. Some of the findings include 1) astroglial IL1R1 modulates homeostatic sleep responses to sleep deprivation and 2) selective IL1R1 expression on astrocytes or on neurons is not sufficient for IL-1 to induce sleep.


Sleep and immune function: glial contributions and consequences of aging

Ingiosi AM, Opp MR, Krueger JM. Current Opinion in Neurobiology, 2013.

This paper reviews the roles of astrocytes and microglia in mediating sleep and immune interactions as well as glial-associated molecular players in these interactions. We also discuss the contributions of astrocytes and microglia to changes in sleep-wake behavior and immunity associated with aging.


Sepsis-induced alterations in sleep of rats

Baracchi F, Ingiosi AM, Raymond RM, Jr. Opp MR. The American Journal of Physiology - Regulatory, Integrative and Comparative Physiology, 2011.

In this study, we wanted to investigate the impact of sepsis on sleep, the electroencephalogram, and brain temperature. Using the cecal ligation and puncture model (CLP), we found that sepsis increased NREM sleep, acutely suppressed REM sleep, and diminished NREM slow wave activity. The REM sleep suppression was mediated, in part, by activation of inhibitory GABAergic neurons in brainstem REM sleep nuclei. This study was the first to report that CLP-induced sepsis alters sleep and the EEG. Furthermore, it validated an animal model by which to investigate the effects of sepsis on the EEG. For these experiments, I preformed surgical procedures as well as developed and conducted immunohistochemical and stereological assays for the quantification of neurotransmitter activity in sleep regulatory nuclei.

More to come ...

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