Principal Investigators: Masashi Yanagisawa & Hiromasa Funato
Disturbance of sleep/wake is not only a major medical and social problem by itself, but also a major risk factor for lifestyle diseases. Sleep problems can manifest as the major symptom in various neurological and psychiatric disorders. In recent years, the executive neural circuits and chemistry for sleep/wake switching have been actively studied, including those involving the hypothalamic neuropeptide orexin. However, the very fundamental mechanism of sleep/wake regulation, including the question as to what is the neural substrate for “sleepiness,” still remains mystery. Phenomenologically, sleep/wake is described to be influenced by three conceptually separate forces: 1) the circadian regulation from the suprachiasmatic nucleus; 2) the homeostatic regulation according to the sleep amount and quality in the recent past; and 3) the regulation by arousing emotive states. The exact mechanism and neuronal substrate for these pathways essentially remain as a black box. Even the basic question remains unanswered as to whether the supposed sleep homeostat is localized in a specific brain site or distributed throughout the brain.
Over 10 years of orexin research has convinced us that we have to boldly take new approaches to gain fundamental insights on the mechanism of sleep/wake regulation. Our approaches include real-time visualization and manipulation of the activity of multiple neurons within the sleep/wake regulatory circuits in freely behaving mice. We also carry out a large-scale forward genetic screen in a mutagenized cohort of mice, looking for new genes directly responsible for sleep/wake regulation. In a translational front, we aim at discovering and developing orexin receptor agonists in order to treat narcolepsy and other conditions associated with excessive sleepiness.
In 1988, Masashi Yanagisawa identified for the first time in the world the important role that endothelin plays on the cardiovascular system while at the University of Tsukuba. Ten years later, he showed that sleep/wakefulness is controlled by a single neuropeptide with his discovery of orexin. From 2001, he energetically pressed forward with ligand identification of orphan receptors for six years through the ERATO project. Yanagisawa succeeded in the identification of the endogenous ligand for the GPR103 orphan receptor, which is involved in the regulation of appetite and blood pressure. He was also successful in isolating and identifying the novel ligands (NPB/NPW) for the GPR7 orphan receptor. It has become clear that these neuropeptides play an important role in the regulation of energy metabolism and stress responses, emotions, etc.
During his graduate studies at the University of Tokyo, Hiromasa Funato analyzed the accumulation of age-related amyloid β protein. He discovered that amyloid β protein accumulation in the brain begins more than 20 years prior to the onset of Alzheimer's disease, and progresses slowly thereafter. In addition, he found that it is an oligomeric species of amyloid-β protein that accumulates the earliest in the human brain. Also, he revealed the molecular mechanism of initial axonal growth from the habenular nucleus to the interpeduncular nucleus. Afterwards, at the University of Texas he showed that the interpeduncular nucleus plays an important role in REM sleep. While there, he revealed the critical role that the orexin receptor type 2 plays in energy metabolism along with its great potential as a drug target. At Yamaguchi University, he has revealed the gene expression changes that are characteristic to patients and blood relatives with mood disorders.