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Sleep disturbances can contribute to cognitive decline and neuropsychiatric disorders. However, the underlying mechanisms of these processes are poorly understood. The present study evaluated the effects of a chronic sleep disorder (CSD) on long-term memory formation and anxiety-like behavior in our originally established mouse model of psychophysiological stress-induced CSD characterized by disrupted circadian rhythms of wheel-running activity and sleep-wake cycles. Model mice are continuously exposed to mild stress imposed by perpetually staying on a running-wheel to avoid water. The findings of novel object recognition (NORT) and open field (OFT) tests showed that CSD impaired recognition memory and elicited anxiety-like behavior, respectively. These results suggested that the CSD impaired cognitive function and emotional status. Thus, this CSD model could be useful for studying the underlying mechanisms of neurobehavioral difficulties caused by sleep disorders. We then examined the hippocampal mRNA expression of genes associated with learning and memory, and anxiety and depression. The CSD increased the mRNA expression of Crhr1, Ngf and Phlpp1, and suppressed that of Ace, Egr2 and Slc6a4. Based on the functions of these genes, we inferred that the increase in Crhr1 mRNA was associated with the pathogenesis of psychiatric conditions, whereas mRNA levels of the other five genes were directed towards symptom relief. Upregulating hippocampal Crhr1 expression might contribute in part to the activation of corticotropin-releasing hormone (CRH)-CRH receptor1 signaling that mediates CSD-evoked mental disorders.

We previously reported that dietary heat-killed Lactobacillus brevis SBC8803 affects sleep in mice and humans. The present study examined whether SBC8803 improves psychophysiological stress-induced chronic sleep disorders (CSD) using a mouse model characterized by disrupted circadian rhythms of wheel-running activity and sleep-wake cycles. Mice were fed with a diet supplemented with 0.5% heat-killed SBC8803 for 6 wk and imposed stress-induced CSD for last 2 wk. Dietary SBC8803 suppressed the reduction in wheel-running activity induced by CSD. Electroencephalography (EEG) revealed that SBC8803 significantly restored wakefulness and increased non-rapid eye movement (NREM) sleep during the second half of the active phase during CSD. The CSD-induced reduction in EEG slow wave activity, a marker of NREM sleep intensity, during the beginning of the inactive phase was significantly improved by SBC8803 supplementation. These findings suggest that dietary heat-killed SBC8803 confers beneficial effects on insomnia and circadian sleep disorders induced by psychophysiological stress.

Acute or chronic effects of consuming or skipping breakfast on cognitive performance in humans are controversial. To evaluate the effects of chronically skipping breakfast (SB) on hippocampus-dependent long-term memory formation, we examined hippocampal gene expression and applied the novel object recognition test (NORT) after two weeks of repeated fasting for six hours from lights off to mimic SB in mice. We also examined the effects of SB on circadian rhythms of locomotor activity, food intake, core body temperature (CBT) and sleep-wake cycles. Skipping breakfast slightly but significantly decreased total daily food intake without affecting body weight gain. Locomotor activity and CBT significantly decreased during the fasting period under SB. The degree of fasting-dependent CBT reduction gradually increased and then became stabilized after four days of SB. Electroencephalographic data revealed that repeated SB significantly decreased the duration of wakefulness and increased that of rapid eye movement (REM) and of non-REM (NREM) sleep during the period of SB. Furthermore, total daily amounts of wakefulness and NREM sleep were significantly decreased and increased, respectively, under SB, suggesting that SB disrupts sleep homeostasis. Skipping breakfast significantly suppressed mRNA expression of the memory-related genes, Camk2a, Fkbp5, Gadd45b, Gria1, Sirt1 and Tet1 in the hippocampus. Recognition memory assessed by NORT was impaired by SB in accordance with the gene expression profiles. These findings suggested that chronic SB causes dysregulated CBT, sleep-wake cycles and hippocampal gene expression, which results in impaired long-term memory formation.

Objectives Cocoa contains many chemical compounds that affect the physiological functions of experimental animals and humans. The present study used a mouse model characterized by disrupted circadian rhythms of locomotor activity and sleep-wake cycles to determine whether natural cocoa improves chronic sleep disorders (CSDs) induced by psychophysiological stress. Methods Mice were fed a high-fat, high-sucrose diet supplemented with 2.0% natural cocoa and stressed for 30 d to induce CSDs. Results Dietary cocoa restored the amplitude reduction of day-night activity rhythms by improving reduced nocturnal wheel-running activities during CSDs. Electroencephalography revealed that dietary cocoa significantly ameliorated CSD-induced increases in wakefulness during the first half of the inactive phase and in nonrapid eye movement sleep during the first half of the active phase. The attenuation of circadian rapid eye movement sleep rhythms and increased electroencephalography slow-wave activity (a marker of nonrapid eye movement sleep intensity) induced by CSDs improved in mice supplemented with cocoa. Dietary cocoa notably did not affect wheel-running activity rhythms or sleep-wake cycles under normal conditions. Dietary cocoa significantly increased the hypothalamic mRNA expression of Hspa1 a that encodes HSP70 and is associated with sleep regulation. Furthermore, Hspa1 a expression was not induced by CSDs in mice supplemented with cocoa. Conclusions These findings suggest that dietary cocoa exerts beneficial effects on insomnia and circadian sleep disorders induced by psychophysiological stress.

Sleep disturbances are associated with various metabolic diseases such as hypertension and diabetes. We had previously established a mouse model of a psychophysiological stress-induced chronic sleep disorder (CSD) characterized by disrupted circadian rhythms of wheel-running activity, core body temperature, and sleep-wake cycles. To evaluate the underlying mechanisms of metabolic disorders induced by CSD, we created mice with CSD for six weeks and fed them with a high-fat diet. Glucose intolerance with hyperglycemia resulted, although plasma insulin levels and body weight increases were identical between control and CSD mice. Gluconeogenesis and glycolysis were enhanced and suppressed, respectively, in the livers of CSD mice, because the mRNA expression of Pck1 was significantly increased, whereas that of Gck and Pklr were significantly decreased in the CSD mice. Adipose inflammation induced by the high-fat diet seemed suppressed by the CSD, because the mRNA expression levels of Adgre1, Ccl2, and Tnf were significantly downregulated in the adipose tissues of CSD mice. These findings suggest that CSD impair glucose tolerance by inducing gluconeogenesis and suppressing glycolysis. Hyperphasia with hypoleptinemia, hypercorticosteronemia, and increased plasma free fatty acids might be involved in the impaired glucose metabolism under a CSD. Further studies are needed to elucidate the endocrine and molecular mechanisms underlying the associations between sleep disorders and impaired glucose homeostasis that consequently causes diabetes.

The master clock in the suprachiasmatic nucleus synchronizes peripheral clocks via humoral and neural signals in mammals. Insulin is thought to be a critical Zeitgeber (synchronizer) for peripheral clocks because it induces transient clock gene expression in cultured cells. However, the extent to which fluctuations in feeding-dependent endogenous insulin affect the temporal expression of clock genes remains unclear. We therefore investigated the temporal expression profiles of clock genes in the peripheral tissues of mice fed for 8 h during either the daytime (DF) or the nighttime (NF) for one week to determine the involvement of feeding cycle-dependent endogenous insulin rhythms in the circadian regulation of peripheral clocks. The phase of circulating insulin fluctuations was reversed in DF compared with NF mice, although those of circulating corticosterone fluctuations and nocturnal locomotor activity were identical between these mice. The reversed feeding cycle affected the circadian phases of Per1 and Per2 gene expression in the liver and not in heart, lung, white adipose and skeletal muscle tissues. On the other hand, injected exogenous insulin significantly induced Akt phosphorylation in the heart and skeletal muscle as well as the liver, and significantly induced Per1 and Per2 gene expression in all examined tissues. These findings suggest that feeding cycles and feeding cycle-dependent endogenous insulin fluctuations are not dominant entrainment signals for peripheral clocks other than the liver, although exogenous insulin might reset peripheral oscillators in mammals.

Objectives Caloric sweeteners such as sugar and honey are replaced in thousands of food products by noncaloric artificial sweeteners (NASs). The aim of the present study was to determine the effects of chronic NAS intake on circadian sleep regulation. Methods Circadian rhythms of sleep and locomotor activity were evaluated in mice after consumption of drinking water containing 0.1% (w/v) saccharin for 2 wk. Results The intake of saccharin ad libitum significantly reduced wakefulness and increased non–rapid eye movement sleep during the first half of the active (dark) phase, whereas wakefulness was significantly increased at the start of the sleep phase. Saccharin consumption obviously reduced spontaneous activity during the first half of the dark period. Conclusions The findings suggest that NASs disturb the circadian sleep-wake cycle and cause behavioral inactivity in mice.