# Neurobiology of sleeping behaviors

Emi Hasegawa, Yo Oishi, Daniel Kroeger, Tomomi Tsunematsu, Yves Dauvilliers

► To cite this version:

Emi Hasegawa, Yo Oishi, Daniel Kroeger, Tomomi Tsunematsu, Yves Dauvilliers. Neurobiology of sleeping behaviors. Frontiers in Behavioral Neuroscience, 2023, 17, pp.1131920. 10.3389/fn-beh.2023.1131920. hal-04606876

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<figure><img src="image_1.png" /></figure>
Neurobiology of sleeping behaviors

Emi Hasegawa, Yo Oishi, Daniel Kroeger, Tomomi Tsunematsu, Yves

Dauvilliers

► To cite this version:

Emi Hasegawa, Yo Oishi, Daniel Kroeger, Tomomi Tsunematsu, Yves Dauvilliers. Neurobiology of sleeping behaviors. Frontiers in Behavioral Neuroscience, 2023, 17, pp.1131920. 10.3389/fnbeh.2023.1131920. hal-04606876

HAL Id: hal-04606876

https://hal.science/hal-04606876v1

Submitted on 10 Jun 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>
<figure><img src="image_2.png" /></figure>

OPEN ACCESS

EDITED AND REVIEWED BY

Sona Nevsimalova,
Charles University, Czechia

*CORRESPONDENCE

Emi Hasegawa

hasegawa.emi.3s@pharm.kyoto-u.ac.jp

SPECIALTY SECTION

This article was submitted to
Individual and Social Behaviors,
a section of the journal
Frontiers in Behavioral Neuroscience

RECEIVED 26 December 2022

ACCEPTED 02 January 2023

PUBLISHED 17 January 2023

CITATION

Hasegawa E, Oishi Y, Kroeger D, Tsunematsu T and Dauvilliers Y (2023) Editorial: Neurobiology of sleeping behaviors.

Front. Behav. Neurosci. 17:1131920.

doi: 10.3389/fnbeh.2023.1131920

COPYRIGHT

© 2023 Hasegawa, Oishi, Kroeger, Tsunematsu and Dauvilliers. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Editorial: Neurobiology of sleeping
behaviors

Emi Hasegawa<sup>1,2,3*</sup>, Yo Oishi<sup>2,3</sup>, Daniel Kroeger<sup>4</sup>,
Tomomi Tsunematsu<sup>5,6</sup> and Yves Dauvilliers<sup>7,8</sup>

¹Department of Systems Biology, Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan, ²International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Japan, ³Faculty of Medicine, University of Tsukuba, Tsukuba, Japan, ⁴Department of Anatomy, Physiology, and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States, ⁵Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan, ⁶Creative Interdisciplinary Research Division, Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, Sendai, Japan, ⁷National Reference Centre for Orphan Diseases Narcolepsy Rare Hypersomnias, Sleep Unit, Department of Neurology, CHU Montpellier, University of Montpellier, Montpellier, France, ⁸Institute for Neurosciences of Montpellier (INM), University of Montpellier, INSERM, Montpellier, France

KEYWORDS

wakefulness, sleep-wake cycle, sleep disturbances, REM sleep, NREM sleep

Editorial on the Research Topic
Neurobiology of sleeping behaviors

Although the interest in the neurobiology of sleep has increased year by year, the functions and control mechanisms of this behavioral state remain relatively unclear (Sehgal and Mignot, 2011, Mander et al., 2017). The fact that virtually all living organisms on earth have sleep highlights the importance of this biological process. Lack of sleep increases the risk of interfering with daily life and developing a variety of diseases. Therefore, it is clear that the physiological function of sleep is very important in maintaining life activities.

Through evolution, the brain and body structure have become more complex, resulting in more diversified patterns and expressions of sleep. The duration of daytime and nighttime sleep, but also its organization over the 24-h varies among animal species. Sleep is usually assessed by electroencephalogram (EEG), which provides an indirect measure of the dense neural network driving sleep and wake states in the brain. Therefore, sleep is altered when normal neurodevelopment is disrupted by internal and external factors. This also provides an opportunity to understand the mechanisms and possible functions of sleep by experimentally modulating internal (e.g., genetics) and external (e.g., drugs) factors. In one recent study, Wang et al. (2022) showed that ubiquitin, which is involved in various biological phenomena such as protein degradation, DNA repair, translation regulation, and signal transduction, is important for neurodevelopment. Shi et al. focused on the ubiquitin ligase gene, Ube3a, and examined its effects on sleep patterns and circadian rhythms. Since the authors found that Ube3a is also expressed in neurons of the suprachiasmatic nucleus (SCN), the center of circadian rhythm, they investigated its effects on circadian rhythm and sleep. They found that under the environment-dependent influence of steady-state light (LL), the mice showed lower activity under in LL. Under LD (light-dark, 12:12 cycles), hourly assessments of wake, non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep revealed that these mice had increased wakefulness, reduced NREM sleep, and REM sleep compared WT mice.
<figure><img src="image_2.png" /></figure>

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## OPEN ACCESS

EDITED AND REVIEWED BY
Sona Nevsimalova,
Charles University, Czechia

*CORRESPONDENCE

Emi Hasegawa

hasegawa.emi.3s@pharm.kyoto-u.ac.jp

SPECIALTY SECTION

This article was submitted to
Individual and Social Behaviors,
a section of the journal
Frontiers in Behavioral Neuroscience

RECEIVED 26 December 2022

ACCEPTED 02 January 2023

PUBLISHED 17 January 2023

CITATION

Hasegawa E, Oishi Y, Kroeger D, Tsunematsu T and Dauvilliers Y (2023) Editorial: Neurobiology of sleeping behaviors.

Front. Behav. Neurosci. 17:1131920.

doi: 10.3389/fnbeh.2023.1131920

COPYRIGHT

© 2023 Hasegawa, Oishi, Kroeger, Tsunematsu and Dauvilliers. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

# Editorial: Neurobiology of sleeping behaviors

Emi Hasegawa¹,²,³*, Yo Oishi²,³, Daniel Kroeger⁴, Tomomi Tsunematsu⁵,⁶ and Yves Dauvilliers⁷,⁸

¹Department of Systems Biology, Division of Bioinformatics and Chemical Genomics, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan, ²International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Japan, ³Faculty of Medicine, University of Tsukuba, Tsukuba, Japan, ⁴Department of Anatomy, Physiology, and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL, United States, ⁵Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan, ⁶Creative Interdisciplinary Research Division, Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, Sendai, Japan, ⁷National Reference Centre for Orphan Diseases Narcolepsy Rare Hypersomnias, Sleep Unit, Department of Neurology, CHU Montpellier, University of Montpellier, Montpellier, France, ⁸Institute for Neurosciences of Montpellier (INM), University of Montpellier, INSERM, Montpellier, France

KEYWORDS

wakefulness, sleep-wake cycle, sleep disturbances, REM sleep, NREM sleep

## Editorial on the Research Topic
### Neurobiology of sleeping behaviors

Although the interest in the neurobiology of sleep has increased year by year, the functions and control mechanisms of this behavioral state remain relatively unclear (Sehgal and Mignot, 2011, Mander et al., 2017). The fact that virtually all living organisms on earth have sleep highlights the importance of this biological process. Lack of sleep increases the risk of interfering with daily life and developing a variety of diseases. Therefore, it is clear that the physiological function of sleep is very important in maintaining life activities.

Through evolution, the brain and body structure have become more complex, resulting in more diversified patterns and expressions of sleep. The duration of daytime and nighttime sleep, but also its organization over the 24-h varies among animal species. Sleep is usually assessed by electroencephalogram (EEG), which provides an indirect measure of the dense neural network driving sleep and wake states in the brain. Therefore, sleep is altered when normal neurodevelopment is disrupted by internal and external factors. This also provides an opportunity to understand the mechanisms and possible functions of sleep by experimentally modulating internal (e.g., genetics) and external (e.g., drugs) factors. In one recent study, Wang et al. (2022) showed that ubiquitin, which is involved in various biological phenomena such as protein degradation, DNA repair, translation regulation, and signal transduction, is important for neurodevelopment. Shi et al. focused on the ubiquitin ligase gene, Ube3a, and examined its effects on sleep patterns and circadian rhythms. Since the authors found that Ube3a is also expressed in neurons of the suprachiasmatic nucleus (SCN), the center of circadian rhythm, they investigated its effects on circadian rhythm and sleep. They found that under the environment-dependent influence of steady-state light (LL), the mice showed lower activity under in LL. Under LD (light-dark, 12:12 cycles), hourly assessments of wake, non-rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep revealed that these mice had increased wakefulness, reduced NREM sleep, and REM sleep compared WT mice.
Fujiyama et al. aimed to address the question of “neuronal functions and circuits of sleep” by investigating the contribution of the cerebellum to sleep/wake control. They examined sleep phenotypes in a mouse model in which the midbrain and rhombencephalon region 1 (Ptf1a) genes were conditionally knocked out and the entire cerebellum was deleted. They demonstrate that mice lacking the cerebellum retain relatively intact overall sleep/wake parameters, but that these mice have decreased delta power during NREM sleep and REM sleep time during the dark phase. While the authors acknowledge that this knockout model might also affect a limited number of neurons elsewhere in the brain, the study quite conclusively demonstrates that the overall role of the cerebellum to sleep/wake control is rather limited and thus confirms the number of prior lesion studies.

Geng et al. focused on the relationship between the thyroid system and Restless Leg Syndrome (RLS), a sleep disorder associated with dopaminergic dysfunction. While dopamine controls thyroid systems by downregulation of thyroid stimulating hormone (TSH) and thyroid hormones, the link between thyroid systems and RLS is unclear. They compared thyroid function between RLS patients and healthy subjects and found that RLS patients had significantly higher serum TSH levels, but not T4 or T3 hormone levels, and higher prevalence of subclinical hypothyroidism. They also found that serum TSH levels are higher in good-sleeper patients compared with poor-sleeper patients. Their data indicate the imbalanced thyroid system and sleep patterns in RLS patients, and they hypothesize that the thyroid system may contribute to the development of RLS.

It is not always clear whether altered sleep is the result of an underlying disorder or the cause of the disorder. For example, sleep disturbances are very prevalent in patients suffering from neurodegenerative diseases, but whether sleep is a contributing factor in these diseases is unknown. Minakawa proposed an interrelationship between sleep disorders and neurodegenerative Parkinson's disease (PD) and Alzheimer's disease (AD). Sleep disturbances impact the susceptibility to developing or the progression of PD and AD is resolved by epidemiological and experimental studies. These suggested that the exacerbation of PD and AD pathology is related to negative impact of sleep disturbances as previously reported (Dauvilliers, 2007). However, detecting subtle changes in sleep early in the disease process can sometimes be challenging. Gong et al. investigated the relationship between drug treatment and changes in prefrontal cortex (PFC) functional patterns in patients with chronic insomnia to find new means of

detecting sleep disorders in human. They found that functional near-infrared spectroscopy could be a useful tool for assessing sleep status potentially guiding pharmacotherapy. These clinical findings and methods will help clarify the relationship between sleep disorders and neurodegenerative diseases.

As described above, the molecular and neural regulation of sleep-wake and sleep function is gradually becoming clearer, but the physiological significance of sleep is still poorly understood. In addition, the relationship between sleep disorders and neurodegenerative diseases remains to be elucidated. To shed further light on these questions many diverse research reports are needed in addition to those published in this Research Topic. We sincerely hope that this Research Topic will act as a catalyst for future the sleep research.

## Author contributions

All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

## Acknowledgments

We would like to thank all authors who made original contributions to this topic and all reviewers who promoted the quality of the manuscript with their comments.

## Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

## Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

## References

Dauvilliers, Y. (2007). Insomnia in patients with neurodegenerative conditions. *Sleep Med.* 8(Suppl. 4), S27–S34. doi: 10.1016/S1389-9457(08)70006-6

Mander, B. A., Winer, J. R., and Walker, M. P. (2017). Sleep and human aging. *Neuron* 94, 19–36. doi: 10.1016/j.neuron.2017.02.004

Sehgal, A., and Mignot, E. (2011). Genetics of sleep and sleep disorders. *Cell* 146, 194–207. doi: 10.1016/j.cell.2011.07.004

Wang, G., Li, Q., Xu, J., Zhao, S., Zhou, R., Chen, Z., et al. (2022). Somatic genetics analysis of sleep in adult mice. *J. Neurosci.* 42, 5617–5640. doi: 10.1523/JNEUROSCI.0089-22.2022
Fujiyama et al. aimed to address the question of “neuronal functions and circuits of sleep” by investigating the contribution of the cerebellum to sleep/wake control. They examined sleep phenotypes in a mouse model in which the midbrain and rhombencephalon region 1 (Ptf1a) genes were conditionally knocked out and the entire cerebellum was deleted. They demonstrate that mice lacking the cerebellum retain relatively intact overall sleep/wake parameters, but that these mice have decreased delta power during NREM sleep and REM sleep time during the dark phase. While the authors acknowledge that this knockout model might also affect a limited number of neurons elsewhere in the brain, the study quite conclusively demonstrates that the overall role of the cerebellum to sleep/wake control is rather limited and thus confirms the number of prior lesion studies.

Geng et al. focused on the relationship between the thyroid system and Restless Leg Syndrome (RLS), a sleep disorder associated with dopaminergic dysfunction. While dopamine controls thyroid systems by downregulation of thyroid stimulating hormone (TSH) and thyroid hormones, the link between thyroid systems and RLS is unclear. They compared thyroid function between RLS patients and healthy subjects and found that RLS patients had significantly higher serum TSH levels, but not T4 or T3 hormone levels, and higher prevalence of subclinical hypothyroidism. They also found that serum TSH levels are higher in good-sleeper patients compared with poor-sleeper patients. Their data indicate the imbalanced thyroid system and sleep patterns in RLS patients, and they hypothesize that the thyroid system may contribute to the development of RLS.

It is not always clear whether altered sleep is the result of an underlying disorder or the cause of the disorder. For example, sleep disturbances are very prevalent in patients suffering from neurodegenerative diseases, but whether sleep is a contributing factor in these diseases is unknown. Minakawa proposed an interrelationship between sleep disorders and neurodegenerative Parkinson's disease (PD) and Alzheimer's disease (AD). Sleep disturbances impact the susceptibility to developing or the progression of PD and AD is resolved by epidemiological and experimental studies. These suggested that the exacerbation of PD and AD pathology is related to negative impact of sleep disturbances as previously reported (Dauvilliers, 2007). However, detecting subtle changes in sleep early in the disease process can sometimes be challenging. Gong et al. investigated the relationship between drug treatment and changes in prefrontal cortex (PFC) functional patterns in patients with chronic insomnia to find new means of

detecting sleep disorders in human. They found that functional near-infrared spectroscopy could be a useful tool for assessing sleep status potentially guiding pharmacotherapy. These clinical findings and methods will help clarify the relationship between sleep disorders and neurodegenerative diseases.

As described above, the molecular and neural regulation of sleep-wake and sleep function is gradually becoming clearer, but the physiological significance of sleep is still poorly understood. In addition, the relationship between sleep disorders and neurodegenerative diseases remains to be elucidated. To shed further light on these questions many diverse research reports are needed in addition to those published in this Research Topic. We sincerely hope that this Research Topic will act as a catalyst for future the sleep research.

## Author contributions

All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

## Acknowledgments

We would like to thank all authors who made original contributions to this topic and all reviewers who promoted the quality of the manuscript with their comments.

## Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

## Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

## References

Dauvilliers, Y. (2007). Insomnia in patients with neurodegenerative conditions. *Sleep Med.* 8(Suppl. 4), S27–S34. doi: 10.1016/S1389-9457(08)70006-6

Mander, B. A., Winer, J. R., and Walker, M. P. (2017). Sleep and human aging. *Neuron* 94, 19–36. doi: 10.1016/j.neuron.2017.02.004

Sehgal, A., and Mignot, E. (2011). Genetics of sleep and sleep disorders. *Cell* 146, 194–207. doi: 10.1016/j.cell.2011.07.004

Wang, G., Li, Q., Xu, J., Zhao, S., Zhou, R., Chen, Z., et al. (2022). Somatic genetics analysis of sleep in adult mice. *J. Neurosci.* 42, 5617–5640. doi: 10.1523/JNEUROSCI.0089-22.2022