Towards Human Systems Biology of Sleep/Wake Cycle: The roles of Calcium and Phosphorylation Hypothesis of Sleep

The field of human biology confronts three major technological hurdles: the causation problem, complexity problem, and heterogeneity problem. To overcome these challenges, we’ve developed innovative approaches:

Mammalian next-generation genetics: Triple CRISPR for knockout (KO) mice and ES mice for knock-in (KI) mice enable causation studies without traditional breeding methods. Whole-body/brain cell profiling techniques: CUBIC allows comprehensive cell atlas construction to unravel cellular composition complexity. Accurate and user-friendly technologies for measuring sleep and awake states: ACCEL facilitates real-world monitoring of fundamental brain states, addressing human heterogeneity.

Integration of these technologies has led to significant progress in sleep research, particularly in understanding sleep regulation mechanisms and sleep functions. We’ve proposed the phosphorylation hypothesis of sleep, emphasizing the role of CaMKIIα/CaMKIIβ and calcium signaling pathways in inducing and sustaining sleep. Our studies also identified wake-promoting kinases and sleep-promoting phosphatase. Additionally, computational studies supported the Wake-Inhibition-Sleep-Enhancement (WISE) hypothesis, suggesting wakefulness inhibits synaptic efficacy while sleep enhances it.

During the talk, we’ll discuss our findings on muscarinic acetylcholine receptors (Chrm1 and Chrm3) as essential genes for REM sleep and their implications for psychiatric, neurodevelopmental, and neurodegenerative disorders. We will discuss new insights into psychiatric disorders, neurodevelopmental disorders, and neurodegenerative disorders derived from the phosphorylation hypothesis of sleep.

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Hiroki R. Ueda is a professor at the Graduate School of Medicine, The University of Tokyo. He obtained his Bachelor’s degree from the Faculty of Medicine at the University of Tokyo in 2000, and in 2004, he completed his Ph.D. at the same institution. In 2003, he was appointed as a team leader at RIKEN. Subsequently, in 2013, he assumed the position of full professor at the Graduate School of Medicine, The University of Tokyo. In 2016, Ueda made a groundbreaking discovery by identifying the sleep-promoting kinases, CaMKIIalpha and CaMKIIbeta. This finding led him to propose the phosphorylation hypothesis of sleep, which suggests that the phosphorylation-dependent regulation of the Ca2+-dependent hyperpolarization pathway underlies the regulation of sleep homeostasis in mammals. Furthermore, in 2018, he made another significant breakthrough by identifying the first essential genes of REM sleep, specifically muscarinic receptors M1 and M3. To further expedite his research endeavors, Ueda has pioneered innovative methods such as whole-brain and whole-body clearing and imaging techniques known as CUBIC. Additionally, he has contributed to the field of genetics by inventing next-generation mammalian genetic tools, including Triple-CRISPR and ES-mice methods. These advancements enable the streamlined production and analysis of knockout (KO) and knock-in (KI) mice without the need for traditional crossing methods.