Featured article of EJN issue 35-11: Novel biochemical manipulation of brain serotonin reveals a role of serotonin in the circadian rhythm of sleep/wake cycles
Eiko Nakamaru-Ogiso, Hiroyuki Miyamoto, Kozo Hamada, Koji Tsukada, Katsuji Takai
Department of Biomedical Chemistry, Institute of International Health, The University of Tokyo Graduate School of Medicine,
Tokyo, Japan
Serotonin (5-HT) neurons have been implicated in the modulation of many physiological functions, including mood regulation, feeding, and sleep. Impaired or altered 5-HT neurotransmission appears to be involved in depression and anxiety symptoms, as well as in sleep disorders. To investigate brain 5-HT functions in sleep, we induced 5-HT deficiency through acute tryptophan depletion in rats by intraperitoneally injecting a tryptophan-degrading enzyme called tryptophan side chain oxidase I (TSOI). After the administration of TSOI (20 units), plasma tryptophan levels selectively decreased to 1–2% of those of controls within 2 h, remained under 1% for 12–24 h, and then recovered between 72 and 96 h. Following plasma tryptophan levels, brain 5-HT levels decreased to ∼30% of the control level after 6 h, remained at this low level for 20–30 h, and returned to normal after 72 h. In contrast, brain norepinephreine and dopamine levels remained unchanged. After TSOI injection, the circadian rhythms of the sleep–wake cycle and locomotive activity were lost and broken into minute(s) ultradian alternations. The hourly slow-wave sleep (SWS) time significantly increased at night, but decreased during the day, whereas rapid eye movement sleep was significantly reduced during the day. However, daily total (cumulative) SWS time was retained at the normal level. As brain 5-HT levels gradually recovered 48 h after TSOI injection, the circadian rhythms of sleep–wake cycles and locomotive activity returned to normal. Our results suggest that 5-HT with a rapid turnover rate plays an important role in the circadian rhythm of sleep–wake cycles.
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Commentary:
Read the corresponding commentary by Paul N. Ketema on this article: Serotonin and sleep: breaking the cycle.
EJN Blog Supplemental Figures (not peer-reviewed)
| Figure 1. Somnogram of TSOI-injected rat housed in constant darkness. The arrow denotes the timing of TSOI (20 units) injection at around 12:00 in the subjective light period. The increased number of the switching events between sleep/wake phases was also observed after TSO injection under constant darkness. This suggests that 5-HT depletion causes sleep fragmentation regardless of light/dark stimuli. |  |
| Figure 2. Role of 5-HT in the circadian rhythm of sleep-wake cycles. We hypothesize that 5-HT is involved in maintaining the circadian rhythm of sleep/wake cycles by increasing the continuity of sleep and wake episodes, rather than simply promoting arousal or sleep. |  |
Biographical note:
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Eiko Nakamaru-Ogiso is currently a research assistant professor at the University of Pennsylvania Perelman School of Medicine. She studied Biochemistry and Neuroscience, and graduated from the University of Tokyo, and earned her Ph.D in 1998. She has studied roles of serotonin in brain function and neurotransmitter metabolism as an assistant professor of the Department of Biomedical Chemistry, the University of Tokyo Graduate School of Medicine. After she experienced a postdoctoral fellow at the Scripps Research Institute, she got involved in the study the structural and molecular mechanisms of mitochondrial NADH: quinone oxidoreductase (complex I). In 2007, she moved to University of Pennsylvania, and started her own laboratory in 2010. The focus of her research group is mitochondrial energy metabolism in human health and disease. The long-term goal of her research is to explore and uncover the underlying molecular mechanisms of neurodegenerative diseases caused by defective mitochondrial energy metabolism, which would greatly affect neurotransmitter metabolism. For questions, please email her at eikoo@mail.med.email.edu. |