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A Drosophila model of sleep restriction therapy for insomnia

Molecular Psychiatry volume 26, pages 492–507 (2021)Cite this article

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Abstract

Insomnia is the most common sleep disorder among adults, especially affecting individuals of advanced age or with neurodegenerative disease. Insomnia is also a common comorbidity across psychiatric disorders. Cognitive behavioral therapy for insomnia (CBT-I) is the first-line treatment for insomnia; a key component of this intervention is restriction of sleep opportunity, which optimizes matching of sleep ability and opportunity, leading to enhanced sleep drive. Despite the well-documented efficacy of CBT-I, little is known regarding how CBT-I works at a cellular and molecular level to improve sleep, due in large part to an absence of experimentally-tractable animals models of this intervention. Here, guided by human behavioral sleep therapies, we developed a Drosophila model for sleep restriction therapy (SRT) of insomnia. We demonstrate that restriction of sleep opportunity through manipulation of environmental cues improves sleep efficiency in multiple short-sleeping Drosophila mutants. The response to sleep opportunity restriction requires ongoing environmental inputs, but is independent of the molecular circadian clock. We apply this sleep opportunity restriction paradigm to aging and Alzheimer’s disease fly models, and find that sleep impairments in these models are reversible with sleep restriction, with associated improvement in reproductive fitness and extended lifespan. This work establishes a model to investigate the neurobiological basis of CBT-I, and provides a platform that can be exploited toward novel treatment targets for insomnia.

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Acknowledgements

We thank Kyunghee Koh, Philip Gehrman, and members of the Kayser Lab for helpful discussions. This work was supported by NIH grants F30AG058409 (SJB), T32HL07953 (SJB), R21HD083628 (MLP), K24AG055602 (MLP), K08NS090461 (MSK), and a pilot grant (to MSK) from the University of Pennsylvania Alzheimer’s Disease Core Center (P30-AG010124). Other support includes a Hearst Foundation Fellowship Award (SJB), and Burroughs Wellcome Career Award for Medical Scientists, March of Dimes Basil O’Connor Scholar Award, and Sloan Research Fellowship (MSK).

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Authors and Affiliations

  1. Department of Neuroscience, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA

    Samuel J. Belfer & Matthew S. Kayser

  2. Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA

    Samuel J. Belfer, Alexander G. Bashaw, Michael L. Perlis & Matthew S. Kayser

  3. Behavioral Sleep Medicine Program, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA

    Michael L. Perlis

  4. Center for Sleep and Circadian Neurobiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA

    Michael L. Perlis & Matthew S. Kayser

  5. Chronobiology Program, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA

    Matthew S. Kayser

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Belfer, S.J., Bashaw, A.G., Perlis, M.L. et al. A Drosophila model of sleep restriction therapy for insomnia. Mol Psychiatry 26, 492–507 (2021). https://doi.org/10.1038/s41380-019-0376-6

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