Selected Publications

Basal forebrain circuit for sleep-wake control.  Xu, M., Chung, S., Zhang, S., Zhong, P., Ma, C., Chang, W., Weissbourd, B., Sakai, N., Luo, L., Nishino, S., Dan, Y. Nature neuroscience  2015 Nov; 18 (11): 1641-1647

Through investigation of the basal forebrain circuit,  this study reveals the basic organization of the circuit controlling sleep and wakefulness. Activity in four genetically defined cell types across sleep-wake cycles and mapped their neural connections were recorded. What the study discovered was the specification of different cell types to the either wakefulness or sleep promotion. Three basal forebrain cells (cholinergic, glutamatergic, and parvalbumin-positive neurons) were more active during wakefulness and REM sleep; additionally, activation of these neurons quickly induced wakefulness. Somatostatin-positive neurons promoted nonREM sleep, and inhibited the three REM promoting neurons. 

The Sleep-Promoting and Hypothermic Effects of Glycine are Mediated by NMDA Receptors in the Suprachiasmatic Nucleus Kawai, N., Sakai, N., Okuro, M., Karakawa, S., Tsuneyoshi, Y., Kawasaki, N., Takeda, T., Bannai, M., Nishino, S. NEUROPSYCHOPHARMACOLOGY 2015; 40 (6): 1405-1416

Kawai et. al investigated the use of glycine to improve sleep quality by examining the site of action and sleep promoting mechanism in rats. Oral application of glycine in rats experiencing acute sleep disturbance induced non REM sleep, shortened non REM sleep delay, and decreased core temperature. Oral and cerebrospinal fluid administration of glycine elevated blood flow close to the skin surface, resulting in heat loss; however, rats that were pretreated with N-methyl-D-aspartate receptor antagonists inhibited this heat loss. Additionally, glycine treatment only had observable effects when administered into the suprachiasmatic nucleus (SCN), and not in the MPO and dorsal subparaventricular zone, and SCN ablation resulted in no sleep-promoting and hypothermic effects by the glycine. These results suggest that administered glycine promotes sleep through peripheral vasodilation by activation of NMDA receptors in the SCN shell. 

Chronic Powder Diet After Weaning Induces Sleep, Behavioral, Neuroanatomical, and Neurophysiological Changes in Mice. Anegawa, E., Kotorii, N., Ishimaru, Y., Okuro, M., Sakai, N., Nishino, S. PloS one 2015; 10 (12)

Anegawa et. al compared sleep, physiological, and anatomical changes in mice fed either solid or powder food to understand the effects of a chronic powder diet on sleep patterns. Mice fed powder food exhibited less cranial bone development, significant weight gain, and reduced development of hippocampal nervous tissue. They also discovered negative changes to the sleep/wake rhythm, with mice sleeping more during active periods and less during rest periods. When undergoing food deprivation, powder fed mice exhibited reduced food-seeking behavior; these results indicate detrimental symptoms caused by abnormal energy metabolism and deleterious anatomical and neurological changes.

Noninvasive detection of sleep/wake changes and cataplexy-like behaviors in orexin/ataxin-3 transgenic narcoleptic mice across the disease onset Sato, M., Sagawa, Y., Hirai, N., Sato, S., Okuro, M., Kumar, S., Kanbayashi, T., Shimizu, T., Sakai, N., Nishino, S. EXPERIMENTAL NEUROLOGY  2014; 261: 744-751

In this paper, Sato et. al discuss the development of a non-invasive sleep monitoring system that identifies the wake and sleep patterns of mice and newly enables monitoring of newborn mice using a piezoelectric transducer. Using this system, they detected age-dependent changes in sleep fragmentation in narcoleptic mice models, at the time of disease onset in the very young mice. They also discovered that direct transition to REM sleep occurs specifically in these narcoleptic mice models, suggesting that these sudden REM episodes reflect or are cataplexy. 

Histamine from Brain Resident MAST Cells Promotes Wakefulness and Modulates Behavioral States PLOS ONE Chikahisa, S., Kodama, T., Soya, A., Sagawa, Y., Ishimaru, Y., Sei, H., Nishino, S. PLOS ONE  2013; 8 (10)

Chikahisa et. al examined the involvement of brain mast cells in the sleep-wake regulations, focusing on the release and effects of histamine in mast cell deficient mice. Baseline amounts of sleep/wake were similar between mast cell deficient mice and  their wild-type littermates, although deficient mice showed increased EEG delta power (used as a index for sleep intensity) and attenuated rebound response after sleep deprivation Injection of mast cell histamine releasing compound  48/80, enhanced wakefulness in wild type mice, but had no effect in the mast cell deficient mice; injection of H1 antagonists increased slow-wave sleep in wild type mice, but again had no effect in mast cell deficient mice. These deficient mice also failed to show food-seeking behavior during food deprivation, and exhibited higher anxiety and depression levels compared to their wild type littermates. The findings demonstrate the wake-promoting qualities of histamine released from brain mast cells and its pharmacological importance in sleep regulation and fundamental neurobehavior.

Wake-promoting effects of ONO-4127Na, a prostaglandin DP1 receptor antagonist, in hypocretin deficient narcoleptic mice Sagawa, Y., Sakai, N., Chikahisa, S., Sato, M., Chiba, S., Nishino, S. 21st Congress of the European-Sleep-Research-Society WILEY-BLACKWELL. 2012: 266–266 

Sagawa et. al evaluated the effectiveness of ONO-4127Na, a prostaglandin (PG) DP1 antagonist, as a wake-promoting compound in narcoleptic model mice,. ONO-4127Na administered in the basal forebrain promoted wakefulness in both control and narcoleptic mice; however, when administered in the hypothalamic area, it had no effect on sleep. ONO-4127Na also had no effect in PG DP1 receptor knockout mice, confirming that the compound mediates the wake-promoting effect  by blocking those receptors specifically in the basal forebrain area. Additionally, ONO-4127Na reduced direct transition to REM sleep, displaying anticataleptic effects that would be useful for the treatment of narcolepsy-cataplexy.

Amyloid-beta Dynamics Are Regulated by Orexin and the Sleep-Wake Cycle., Kang, JE, Lim, MM, Bateman, RJ, Lee, JJ, Smyth, LP, Cirrito, JR, Fujiki, N, Nishino, S, Holtzman, DM,  Science, 2009, Nov 13;326(5955):1005-7

In this paper, Kang et. al investigated the rise and fall of Amyloid-β (Aβ) accumulation in the interstitial fluid (ISF), testing the effects of orexin (a neuropeptide regulating arousal) and changes to the sleep-wake cycle. They found that chronic sleep restriction, as well as acute sleep deprivation and orexin infusion, significantly increased ISF Aβ levels; infusion of a dual orexin receptor antagonist, however, decreased ISF Aβ levels and Aβ plaque formation. High concentrations of ISF Aβ is a well-known symptom of Alzheimer’s disease; from this they concluded that the sleep-wake cycle and orexin play a significant role in the development of Alzheimer’s.