A pontine-medullary loop crucial for REM sleep and its deficit in Parkinson's disease

Mitsuaki Kashiwagi; Goichi Beck; Mika Kanuka; Yoshifumi Arai; Kaeko Tanaka; Chika Tatsuzawa; Yumiko Koga; Yuki C Saito; Marina Takagi; Yo Oishi; Masanori Sakaguchi; Kousuke Baba; Masashi Ikuno; Hodaka Yamakado; Ryosuke Takahashi; Masashi Yanagisawa; Shigeo Murayama; Takeshi Sakurai; Kazuya Sakai; Yoshimi Nakagawa; Masahiko Watanabe; Hideki Mochizuki; Yu Hayashi

doi:10.1016/j.cell.2024.08.046

A pontine-medullary loop crucial for REM sleep and its deficit in Parkinson's disease

Cell. 2024 Sep 17:S0092-8674(24)00975-9. doi: 10.1016/j.cell.2024.08.046. Online ahead of print.

Authors

Mitsuaki Kashiwagi¹, Goichi Beck², Mika Kanuka³, Yoshifumi Arai¹, Kaeko Tanaka³, Chika Tatsuzawa³, Yumiko Koga³, Yuki C Saito³, Marina Takagi³, Yo Oishi⁴, Masanori Sakaguchi⁴, Kousuke Baba², Masashi Ikuno⁵, Hodaka Yamakado⁵, Ryosuke Takahashi⁵, Masashi Yanagisawa⁶, Shigeo Murayama⁷, Takeshi Sakurai⁴, Kazuya Sakai⁸, Yoshimi Nakagawa⁹, Masahiko Watanabe¹⁰, Hideki Mochizuki², Yu Hayashi¹¹

Affiliations

¹ International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
² Department of Neurology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.
³ International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
⁴ International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
⁵ Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto 605-8507, Japan.
⁶ International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Japan Life Science Center for Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁷ Department of Neurology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan; Brain Bank for Neurodevelopmental, Neurological and Psychiatric Disorders, Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Suita, Osaka 565-0871, Japan; Department of Neurology and Neuropathology (the Brain Bank for Aging Research), Tokyo Metropolitan Institute for Geriatrics and Gerontology, Itabashi-Ku, Tokyo 173-0015, Japan.
⁸ Integrative Physiology of the Brain Arousal System, Lyon Neuroscience Research Center, INSERM U1028-CNRS UMR5292, School of Medicine, Claude Bernard University Lyon 1, 69373 Lyon, France.
⁹ Division of Complex Biosystem Research Institute of Natural Medicine, University of Toyama, Toyama, Toyama 930-0194, Japan.
¹⁰ Department of Anatomy, Faculty of Medicine, Hokkaido University, Sapporo, Hokkaido 060-8638, Japan.
¹¹ International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan; Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan. Electronic address: yuhayashi@g.ecc.u-tokyo.ac.jp.

PMID: 39303715
DOI: 10.1016/j.cell.2024.08.046

Abstract

Identifying the properties of the rapid eye movement (REM) sleep circuitry and its relation to diseases has been challenging due to the neuronal heterogeneity of the brainstem. Here, we show in mice that neurons in the pontine sublaterodorsal tegmentum (SubLDT) that express corticotropin-releasing hormone-binding protein (Crhbp⁺ neurons) and project to the medulla promote REM sleep. Within the medullary area receiving projections from Crhbp⁺ neurons, neurons expressing nitric oxide synthase 1 (Nos1⁺ neurons) project to the SubLDT and promote REM sleep, suggesting a positively interacting loop between the pons and the medulla operating as a core REM sleep circuit. Nos1⁺ neurons also project to areas that control wide forebrain activity. Ablating Crhbp⁺ neurons reduces sleep and impairs REM sleep atonia. In Parkinson's disease patients with REM sleep behavior disorders, CRHBP-immunoreactive neurons are largely reduced and contain pathologic α-synuclein, providing insight into the mechanisms underlying the sleep deficits characterizing this disease.

Keywords: Lewy bodies; Parkinson’s disease; RBD; REM sleep; REM sleep behavior disorder; brainstem; chemogenetics; mouse; optogenetics.