The Role of ATP in Sleep Regulation

One of the functions of sleep is to maintain energy balance in the brain. There are a variety of hypotheses related to how metabolic pathways interact with sleep/wake regulation. A major finding that demonstrates an interaction between sleep and metabolic homeostasis is the involvement of adenosine in sleep homeostasis. An accumulation of adenosine is supplied from ATP, which can act as an energy currency in the cell. Extracellularly, ATP can act as an activity-dependent signaling molecule, especially in regard to communication between neurons and glia, including astrocytes. Furthermore, the intracellular AMP/ATP ratio controls the activity of AMP-activated protein kinase, which is a potent energy regulator and is recently reported to play a role in the regulation of sleep homeostasis. Brain ATP may support multiple functions in the regulation of the sleep/wake cycle and sleep homeostasis

ATP and sleep

One of the functions of sleep is to maintain energy balance in the brain. There are a variety of hypotheses related to how metabolic pathways interact with sleep/wake regulation. A major finding that demonstrates an interaction between sleep and metabolic homeostasis is the involvement of adenosine in sleep homeostasis. An accumulation of adenosine is supplied from ATP, which can act as an energy currency in the cell. Extracellularly, ATP can act as an activity-dependent signaling molecule, especially in regard to communication between neurons and glia, including astrocytes. Furthermore, the intracellular AMP/ATP ratio controls the activity of AMP-activated protein kinase, which is a potent energy regulator and is recently reported to play a role in the regulation of sleep homeostasis. Brain ATP may support multiple functions in the regulation of the sleep/wake cycle and sleep homeostasis

Rotigotine suppresses sleep-related muscle activity augmented by injection of dialysis patients’ sera in a mouse model of restless legs syndrome

Idiopathic restless legs syndrome (RLS) has a genetic basis wherein BTBD9 is associated with a higher risk of RLS. Hemodialysis patients also exhibit higher rates of RLS compared with the healthy population. However, little is known about the relationship of BTBD9 and end-stage renal disease to RLS pathophysiology. Here we evaluated sleep and leg muscle activity of Btbd9 mutant (MT) mice after administration of serum from patients with either idiopathic or RLS due to end-stage renal disease (renal RLS) and investigated the efficacy of treatment with the dopamine agonist rotigotine. At baseline, the amount of rapid eye movement (REM) sleep was decreased and leg muscle activity during non-REM (NREM) sleep was increased in MT mice compared to wild-type (WT) mice. Wake-promoting effects of rotigotine were attenuated by injection of serum from RLS patients in both WT and MT mice. Leg muscle activity during NREM sleep was increased only in MT mice injected with serum from RLS patients of ideiopatic and renal RLS. Subsequent treatment with rotigotine ameliorated this altered leg muscle activity. Together these results support previous reports showing a relationship between the Btbd9/dopamine system and RLS, and elucidate in part the pathophysiology of RLS

Feeding Rhythm-Induced Hypothalamic Agouti-Related Protein Elevation via Glucocorticoids Leads to Insulin Resistance in Skeletal Muscle

Circadian phase shifts in peripheral clocks induced by changes in feeding rhythm often result in insulin resistance. However, whether the hypothalamic control system for energy metabolism is involved in the feeding rhythm-related development of insulin resistance is unknown. Here, we show the physiological significance and mechanism of the involvement of the agouti-related protein (AgRP) in evening feeding-associated alterations in insulin sensitivity. Evening feeding during the active dark period increased hypothalamic AgRP expression and skeletal muscle insulin resistance in mice. Inhibiting AgRP expression by administering an antisense oligo or a glucocorticoid receptor antagonist mitigated these effects. AgRP-producing neuron-specific glucocorticoid receptor-knockout (AgRP-GR-KO) mice had normal skeletal muscle insulin sensitivity even under evening feeding schedules. Hepatic vagotomy enhanced AgRP expression in the hypothalamus even during ad-lib feeding in wild-type mice but not in AgRP-GR-KO mice. The findings of this study indicate that feeding in the late active period may affect hypothalamic AgRP expression via glucocorticoids and induce skeletal muscle insulin resistance

雄性マウス頭蓋内肥満細胞が担う社会性行動の調節

Mast cells (MCs) exist intracranially and have been reported to affect higher brain functions in rodents. However, the role of MCs in the regulation of emotionality and social behavior is unclear. In the present study, using male mice, we examined the relationship between MCs and social behavior and investigated the underlying mechanisms. Wild-type male mice intraventricularly injected with a degranulator of MCs exhibited a marked increase in a three-chamber sociability test. In addition, removal of MCs in Mast cell-specific Toxin Receptor-mediated Conditional cell Knock out (Mas-TRECK) male mice showed reduced social preference levels in a three-chamber sociability test without other behavioral changes, such as anxiety-like and depression-like behavior. Mas-TRECK male mice also had reduced serotonin content and serotonin receptor expression and increased oxytocin receptor expression in the brain. These results suggested that MCs may contribute to the regulation of social behavior in male mice. This effect may be partially mediated by serotonin derived from MCs in the brain

Role of orexin in exercise-induced leptin sensitivity in the mediobasal hypothalamus of mice

Orexin is known as an important neuropeptide in the regulation of energy metabolism. However, the role of orexin in exercise-induced leptin sensitivity in the hypothalamus has been unclear. In this study, we determined the effect of transient treadmill exercise on leptin sensitivity in the mediobasal hypothalamus (MBH) of mice and examined the role of orexin in post-exercise leptin sensitivity. Treadmill running for 45 min increased the orexin neuron activity in mice. Intraperitoneal injection of a submaximal dose of leptin after exercise stimulated the phosphorylation of signal transducer and activator of transcription 3 (STAT3) in MBH of mice post-exercise compared with that in non-exercised mice, although intracerebroventricular (icv) injection of leptin did not enhance STAT3 phosphorylation, even after exercise. Icv injection of an orexin receptor antagonist, SB334867 reduced STAT3 phosphorylation, which was enhanced by icv injection of orexin but not by direct injection of orexin into MBH. Exercise increased the phosphorylation of extracellular signal-regulated kinases (ERKs) in the MBH of mice, while ERK phosphorylation was reduced by SB334867. Leptin injection after exercise increased the leptin level in MBH, whereas icv injection of SB334867 suppressed the increase in the leptin level in MBH of mice. These results indicate that the activation of orexin neurons by exercise may contribute to the enhancement of leptin sensitivity in MBH. This effect may be mediated by increased transportation of circulating leptin into MBH, with the involvement of ERK phosphorylation

ペルオキシソーム増殖因子活性化受容体アルファノックアウトマウスの絶食時における睡眠変化

Peroxisome proliferator-activated receptor alpha (PPARα) is a transcription factor that belongs to the nuclear receptor family and plays an important role in regulating gene expression associated with lipid metabolism. PPARα promotes hepatic fatty acid oxidation and ketogenesis in response to fasting. Because energy metabolism is known to affect sleep regulation, manipulations that change PPARα are likely to affect sleep and other physiological phenotypes. In this study, we examined the role of PPARα in sleep/wake regulation using PPARα knockout (KO) mice. Sleep, body temperature (BT), locomotor activity, arterial pressure (AP) and heart rate (HR) were recorded in KO mice and wild-type (WT) controls under ad libitum-fed conditions and 24-hour food deprivation (FD). KO and WT mice were identical in basal sleep amount, BT, mean AP and HR, although KO mice showed enhanced sleepiness (enhanced EEG slow-wave activity). In response to FD, KO mice showed a large drop in wakefulness and locomotor activity at the end of the dark phase, whereas WT mice did not. Similarly, AP and HR, which were suppressed by FD, decreased more in KO than in WT mice. Compared to WT mice, KO mice showed a reduced concentration of plasma ketone bodies and decreased mRNA expression of the ketogenic enzyme gene Hmgcs2 in the liver and brain under FD conditions. These results suggest that PPARα and/or lipid metabolism is involved in the maintenance of wakefulness and locomotor activity during fasting in mice

軽度な慢性ストレスはマウスの睡眠を障害し疼痛感受性を増大させる

Even though it has been well documented that stress can lead to the development of sleep disorders and the intensification of pain, their relationships have not been fully understood. The present study was aimed at investigating the effects of predictable chronic mild stress (PCMS) on sleep–wake states and pain threshold, using the PCMS rearing conditions of mesh wire (MW) and water (W) for 21 days. Exposure to PCMS decreased the amount of non-rapid eye movement (NREM) sleep during the dark phase. Moreover, the chronicity of PCMS decreased slow-wave activity (SWA) during NREM sleep in the MW and W groups in both the light and dark phases. Mechanical and aversively hot thermal hyperalgesia were more intensified in the PCMS groups than the control. Higher plasma corticosterone levels were seen in mice subjected to PCMS, whereas TNF-α expression was found higher in the hypothalamus in the W and the trigeminal ganglion in the MW group. The W group had higher expression levels of IL-6 in the thalamus as well. The PCMS paradigm decreased SWA and may have intensified mechanical and thermal hyperalgesia. The current study also suggests that rearing under PCMS may cause impaired sleep quality and heightened pain sensation to painful mechanical and aversively hot thermal stimuli

Mast cell involvement in glucose tolerance impairment caused by chronic mild stress with sleep disturbance

We have developed a chronic mild stress (MS) mouse model by simply rearing mice on a wire net for 3 weeks and investigated the effects of MS on glucose homeostasis and sleep. MS mice showed impaired glucose tolerance and disturbed sleep. One-week treatment with a histamine H1 receptor antagonist (H1RA) ameliorated the glucose intolerance and improved sleep quality in MS mice. MS mice showed an increased number of mast cells in both adipose tissue and the brain. Inhibition of mast cell function ameliorated the impairment in both glucose tolerance and sleep. Together, these findings indicate that mast cells may represent an important pathophysiological mediator in sleep and energy homeostasis

FGF21欠損マウスにおいて社会的ストレスが睡眠へ及ぼす影響

Although several previous studies have suggested a relationship between sleep and the stress response, the mechanism underlying this relationship remains largely unknown. Here, we show that fibroblast growth factor 21 (FGF21), a lipid metabolism-related hormone, may play a role in this relationship. In this study, we examined differences in the stress response between FGF21 knockout (KO) mice and wild-type (WT) mice after social defeat stress (SDS). When the amount of non-rapid eye movement (NREM) sleep, rapid eye movement (REM) sleep and wakefulness were averaged over the dark period after SDS, only KO mice showed significant differences in NREM sleep and wakefulness. In the social interaction test, KO mice seemed to be more prone to social avoidance. Our real-time (RT) -PCR results revealed that the mRNA expression of the stress- and sleep-related gene gamma-aminobutyric acid A receptor subunit alpha 2 was significantly lower in WT mice than in KO mice. Moreover, KO mice showed lower plasma levels of ketone bodies, which also affect sleep/wake regulation, than WT mice. These results suggested that FGF21 might influence sleep/wake regulation by inducing production of an anti-stress agent and/or ketone bodies, which may result in resilience to social stress