講師資料
Talks：
Towards Human Systems Biology of Sleep/Wake Cycles: The Role of Calcium and Phosphorylation in Sleep
Name：
Hiroki R. Ueda
Position：
Professor
Affiliation：
1. Systems Pharmacology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan,
2. Department of Systems Biology, Institute of Life Science, Kurume University, Japan.
Email：
Photo：
Research Interests：
Our research focuses on the systems biology of sleep, particularly the roles of calcium signaling and phosphorylation in regulating the sleep-wake cycles. By combining genetic, imaging and behavioral measurement techniques, including Triple-CRISPR, CUBIC and SSS, we have shown how calcium-dependent kinases and phosphatases control sleep homeostasis. Regarding the function of sleep, we recently proposed the WISE (Wake Inhibition Sleep Enhancement) mechanism as a new unified framework to understand the roles of sleep in neural plasticity and mental health.
Selected Publications：
1. Kinoshita FL, Yamada RG, Ode KL, Ueda HR. 2024. “Boundary Conditions for Synaptic Homeodynamics during the Sleep-Wake Cycle.” BioRxiv. https://doi.org/10.1101/2024.08.14.607872.
2. Kanaya HJ, Kuwajima K, Ito Y, Shinohara Y, Okubo Y, Shiono S, Tatsuki F, Ohno RI, Ukai H, Ukai-Tadenuma M, Sumiyama K, Fujishima H, Yamada RG, Tone D, Kiyonari H, Kikuchi M, Umehara T, Murayama T, Kanemaru K, Iino M, Ode KL, Hirokawa T, Ueda HR. Isoflurane activates the type 1 ryanodine receptor to induce anesthesia in mice. PLoS Biol. 2025 Jun 3;23(6):e3003172.
3. Wang Y, Cao S, Tone D, Fujishima H, Yamada RG, Ohno RI, Shi S, Matsuzawa K, Yada S, Kaneko M, Sakamoto H, Onishi T, Ukai-Tadenuma M, Ukai H, Hanashima C, Hirose K, Kiyonari H, Sumiyama K, Ode KL, Ueda HR. Postsynaptic competition between calcineurin and PKA regulates mammalian sleep-wake cycles. Nature. 2024 Dec;636(8042):412-421.
4. Chen YY, Evavold CL, Mann M, Davenport ER, McFall-Ngai M, Bienko M, Ueda HR, Tian L, Tjahjono N, Anikeeva P, Liu JG, Deans TL, Shen X. What tool or method do you wish existed? Cell. 2024 Aug 22;187(17):4433-4438.
5. Kon K, Ode KL, Mano T, Fujishima H, Takahashi RR, Tone D, Shimizu C, Shiono S, Yada S, Matsuzawa K, Yoshida SY, Yoshida Garçon J, Kaneko M, Shinohara Y, Yamada RG, Shi S, Miyamichi K, Sumiyama K, Kiyonari H, Susaki EA, Ueda HR. Cortical parvalbumin neurons are responsible for homeostatic sleep rebound through CaMKII activation. Nat Commun. 2024 Jul 18;15(1):6054.
Abstract：
Sleep is one of the great mysteries of life—why do we need it, and how does our brain regulate it? At the Sleep 2012 conference in Boston, we reached to a new way of thinking about sleep homeostasis. Instead of relying on the idea that sleep is triggered by specific "sleep substances," we hypothesized that sleep homeostasis could be sufficiently explained by the “wake substances”, such as calcium, and integration of their activity over time, such as calcium-dependent phosphorylation and dephosphorylation. This idea led us to explore the role of calcium and phosphorylation in sleep.
Building on pioneering Dr. Setsuro Ebashi’s discovery that calcium acts as a key signalling molecule in cells, we hypothesized that calcium might not only activate neurons but also help regulate sleep. To test this, we developed a powerful gene-editing technique called the Triple-CRISPR method in 2016, which allowed us to create genetically modified mice with over 95% efficiency(Sunagawa et al. 2016). Using this technique, we studied 25 different genes related to calcium channels and pumps and found that calcium plays a crucial role in sleep by acting as a brake on brain activity(Tatsuki et al. 2016).
We also developed CUBIC(Susaki et al. 2014; Tainaka et al. 2014), a method that makes brain and other tissues transparent, allowing us to see how calcium affects neurons. Our research further revealed that calcium-dependent kinases, such as CaMKIIα/β, store a “memory” of calcium activity and use it to regulate sleep(Tatsuki et al. 2016). We also identified three types of phosphorylation sites on these proteins that control when sleep begins, how long it lasts, and when it ends(Tone et al. 2022). Additionally, we found that other kinase and phosphatases, such as PKA, Calcineurin, and PP1, act as sleep switches in the excitatory post-synapse of excitatory neurons —some (PKA) keeping us awake, while others (PP1 and Calcineurin) help us sleep(Wang et al. 2024). Interestingly, both sleep-promoting phosphatases, Calcineurin and PP1, are directly and indirectly calcium-dependent. We have also discovered that the ryanodine receptor 1, a calcium channel within cells, is a molecular target of inhalational anesthetics(Kanaya et al. 2025), suggesting that anesthesia and sleep may share a common calcium-dependent mechanism.
Our discoveries also led to a new idea of sleep function called WISE (Wake Inhibition Sleep Enhancement) mechanism, where quiet wakefulness suppresses neuronal connections while deep sleep strengthens them(Kinoshita et al. 2024), challenging the traditional Synaptic Homeostasis hypothesis. This WISE mechanism also helps explain why chronic sleep deprivation can contribute to depression and why some fast-acting antidepressants increase deep sleep activity. By understanding how calcium and brain activity regulate sleep, we hope to unlock new ways to improve sleep health and develop better treatments for sleep disorders and mental health conditions.
2025年會：