Symposium
The molecular/cellular mechanisms and the roles of REM sleep in brain functions
シンポジウム
レム睡眠の分子神経基盤および脳機能における役割 |
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| 7月25日（木）9:00～9:20 第1会場（朱鷺メッセ 4F 国際会議室）
1S01m-1
レム睡眠を制御するニューロンの同定に基づくレム睡眠行動障害のメカニズムの解析
Yu Hayashi（林 悠）
筑波大学国際統合睡眠医科学研究機構（WPI-IIIS）
Over the night, our sleep cycles between two distinct states, rapid eye movement (REM) sleep and non-REM sleep. Abnormal balance of the two sleep states is a common and early symptom in various neurological disorders, suggesting that each sleep state plays crucial roles. Little is known, however, about the individual roles and neural substrates of these two states. These states are identified only in some vertebrate animals species and thus might be involved in higher order brain functions. We applied mouse genetics to functionally dissect neurons in the brainstem and identify neurons involved in regulating REM sleep and non-REM sleep. With this approach, we previously identified glutamatergic and GABAergic neurons in the pontine tegmental area that negatively regulate REM sleep (*). Recently, we further searched for molecular markers in this brain area that allow precise manipulation of neuronal subgroups. In one group of neurons, genetic inhibition led to a drastic decrease in REM sleep, suggesting that these neurons play an essential role in generating REM sleep. Moreover, the mice frequently exhibited aggressive movements during REM sleep, resembling REM sleep behavior disorder (RBD). RBD is a sleep disorder in which patients act out of their dreams and exhibit violent behavior during REM sleep. We expect that these neurons are a key to understanding the neural circuitry of REM/non-REM sleep and that our genetic mouse model provides important implications about the neural mechanisms of RBD. *Hayashi et al., Science 350, 957-961, 2015. | | 7月25日（木）9:20～9:40 第1会場（朱鷺メッセ 4F 国際会議室）
1S01m-2
睡眠・覚醒リズムのシステム生物学 ～NREM睡眠、REM睡眠の定義に向けて～
Hiroki R Ueda（上田 泰己）1,2,3
1東京大院医 WPI-IRCN, UTIAS
2東京大院システムズ薬理学
3理化学研究所(BDR)
The detailed molecular and cellular mechanisms underlying NREM sleep (slow-wave sleep) and REM sleep (paradoxical sleep) in mammals are still elusive. To address these challenges, we first constructed a simple computational model, which recapitulates the electrophysiological characteristics of the slow-wave sleep. Comprehensive bifurcation analysis predicted that a Ca2+-dependent hyperpolarization pathway may play a role in slow-wave sleep. To experimentally validate this prediction, we generate and analyze 26 KO mice, and found that impaired Ca2+-dependent K+ channels (Kcnn2 and Kcnn3), voltage-gated Ca2+ channels (Cacna1g and Cacna1h), or Ca2+/calmodulin-dependent kinases (Camk2a and Camk2b) decrease sleep duration, while impaired plasma membrane Ca2+ ATPase (Atp2b3) increases sleep duration. Genetical (Nr3a) and pharmacological intervention (PCP, MK-801 for Nr1/Nr2b) and whole-brain imaging validated that impaired NMDA receptors reduce sleep duration and directly increase the excitability of cells. Based on these results, we propose a hypothesis that a Ca2+-dependent hyperpolarization pathway underlies the regulation of sleep duration in mammals. In this talk, I will also describe how we identify essential genes (Chrm1 and Chrm3) in REM sleep regulation, and propose a plausible molecular definition of a paradoxical state of REM sleep.
References
1. Tatsuki et al. Neuron, 90(1) : 70-85 (2016).
2. Sunagawa et al, Cell Reports, 14(3):662-77 (2016).
3. Susaki et al. Cell, 157(3): 726-39, (2014).
4. Tainaka et al. Cell, 159(6):911-24(2014).
5. Susaki et al. Nature Protocols, 10(11):1709-27(2015).
6. Susaki and Ueda. Cell Chemical Biology, 23(1):137-57 (2016).
7. Tainaka et al. Ann. Rev. of Cell and Devel. Biol. 32: 713-741 (2016).
8. Ode et al. Mol. Cell, 65, 176-190 (2017).
9. Tatsuki et al, Neurosci. Res. 118, 48-55 (2017)
10.Ode et al, Curr. Opin. Neurobiol. 44, 212-221 (2017)
11. Susaki et al, NPJ. Syst. Biol. Appl. 3, 15 (2017)
12. Shinohara et al, Mol. Cell 67, 783-798 (2017)
13. Ukai et al, Nat. Protoc. 12, 2513-2530 (2017)
14. Shi and Ueda.BioEssays 40, 1700105 (2018)
15. Niwa et al, Cell report, 24, 2231-2247 (2018) | | 7月25日（木）9:40～10:00 第1会場（朱鷺メッセ 4F 国際会議室）
1S01m-3
ドラゴンの海馬における睡眠ステージ
Hiroaki Norimoto（乗本 裕明）
マックスプランク脳科学研究所
Most animal species sleep, from invertebrates to primates. We recently described the electrophysiological correlates of sleep in a reptile, the Australian dragon Pogona vitticeps. Neural recordings from a brain area called the dorsal ventricular ridge (DVR) revealed that these reptiles possess many features of mammalian slow-wave (SW) and rapid eye movement (REM) sleep, suggesting that dragons can be a useful model for studying these sleep stages and their alternation (Ref. 1). In this talk, we focus on the reptilian hippocampus. We observed sleep state alternation within the reptilian homologs of mammalian hippocampal CA1/CA3 and dentate gyrus (ref. 2). The SW and REM sleep patterns oscillated continuously with a period of ~80 seconds, consistent with earlier observations from the DVR. Furthermore, using an ex vivo intact brain preparation and micro-sectioned brain slices, we could reproduce aspects of the sleep oscillations observed in in vivo animals. Sleep oscillations seem to independently originate in the hippocampus, as well as the anterior part of the DVR. In the intact circuit, these two areas are tightly coordinated. Complimenting recent work on mammals (Ref.3), we hope to discuss the fundamental circuit mechanisms and functions of these sleep oscillations.
Reference
1. Shien-Idelson et al., Sceince, 2016, 352:590-595
2. Tosches et al., Science, 2018, 360:881-888
3. Norimoto et al., Science, 2018, 359:1524-1527 | | 7月25日（木）10:00～10:20 第1会場（朱鷺メッセ 4F 国際会議室）
1S01m-4
Experience and sleep-dependent synapse remodeling
Guang Yang（Yang Guang）
Columbia Univ
One prominent feature of brain development and plasticity is that a large number of new synapses are formed each day, but only a small fraction of them are stably maintained over time. Because up to 5-10% new synapses are formed daily, a selective process of pruning and maintaining new synapses is necessary for the brain to store new information continuously without disrupting previously-acquired memories. The mechanisms underlying this selective process remain unknown. The long duration of rapid eye movement (REM) sleep during early development coincides with the occurrence of extensive synapse formation and elimination, raising the possibility that REM sleep may affect the processes of synapse remodeling. Using in vivo two-photon microscopy to monitor changes of postsynaptic dendritic spines of layer 5 pyramidal neurons in the cortex of living animals, our studies show that REM sleep prunes and balances the number of newly-formed spines during development and after learning. Concurrently, REM sleep also strengthens and maintains a subset of new spines that are critical for neuronal circuit development and performance improvement after learning. Furthermore, REM sleep-dependent spine pruning and strengthening are mediated by NMDA receptor-dependent dendritic calcium spikes. Together, our findings indicate that REM sleep contributes to brain development, learning and memory storage by selectively pruning and maintaining new synapses via dendritic calcium spike-mediated mechanisms. | | 7月25日（木）10:20～10:40 第1会場（朱鷺メッセ 4F 国際会議室）
1S01m-5
睡眠中の記憶エングラムの再活動
Kaoru Inokuchi（井ノ口 馨）
Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Japan
The brain is capable of storing and recalling memories through a set of cells, termed engram cells, which are activated during experience. Activity in these cells corresponds to a specific event, ensuring recovery of that particular experience. However, it is unclear how these cells are organized to form the engram, mainly because of technical limitations that have made it difficult to identify both engram and non-engram cells during in vivo recording/imaging. Here, we show that contextual memory in the hippocampus is represented as distinct subsets of synchronous activity (defined by Ca2+ transients) that comprise several ensembles of engram cells. In contrast to non-engram cells, these ensembles maintain their activity not only during learning but also during post-learning sleep and retrieval sessions. We developed an imaging system with a miniature head-mounted fluorescent microscope with which we identified engram cells using the photoconvertible fluorescent protein Kikume Green Red (KikGR) and the c-fos-tet-tag system. We observed neuronal activity in the CA1 hippocampal area via Ca2+ influx and G-CaMP7. Engram cells exhibited repetitive activity, characterized by remarkable synchrony, upon exposure to a novel context. Population vector distance (PVD) analysis revealed that the activity pattern of engram cells was stable not only during learning but also across sleep and retrieval sessions. Furthermore, non-negative matrix factorization (NMF) analysis detected several engram-cell ensembles comprising collectively active neurons whose activities were repeated during encoding, sleep (NREM and REM), and re-exposure sessions; however, they were weaker in a different context. Replayed ensembles were more likely to be reactivated during the re-exposure session. By contrast, these features were not seen in non-engram cells. These results suggest that subgroups of ensembles represent distinct pieces of information, which are then orchestrated to form the entire contextual memory. | | 7月25日（木）10:40～11:00 第1会場（朱鷺メッセ 4F 国際会議室）
1S01m-6
レムおよびノンレム睡眠中のヒト脳計測信号からの夢内容解読
Yukiyasu Kamitani（神谷 之康）
京都大院情報
Dreaming is a subjective experience during sleep often accompanied by vivid visual experience. Previous research has attempted to link physiological states with dreaming but has not demonstrated how specific dream contents are represented in brain activity. The recent advent of machine learning-based analysis of neural signals has allowed for the decoding of stimulus- and task-induced brain activity patterns to reveal visual contents. We have extended this approach to decode human spontaneous brain activity associated with dreaming with the assistance by lexical/image databases and deep learning methods. We measure the brain activity of sleeping human subjects using fMRI while monitoring sleep stages by EEG. Subjects are awakened at various timings during sleep, and they gave a verbal report on the visual experiences just before awakening. We construct decoding models using stimulus-induced brain activity, and use them to analyze brain activity during sleep. Decoder outputs, on average, represented reported contents toward the time of awakening, while the individual time courses showed complex evolution. Our results demonstrate that specific dream contents are represented in activity patterns of visual cortical areas, which are shared by stimulus perception. This approach allows us to link dreaming and brain activity in terms of experienced contents, and might help better understand the functional roles of specific dream experiences and brain states. | |
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