Melanopsin has been proposed as an important photoreceptive molecule for the mammalian circadian system. Its importance in this role was tested in melanopsin knockout mice. These mice entrained to a light/dark cycle, phase-shifted after a light pulse, and increased circadian period when light intensity increased. Induction of the immediate-early gene c-fos was observed after a nighttime light pulse in both wild-type and knockout mice. However, the magnitude of these behavioral responses in knockout mice was 40% lower than in wild-type mice. Although melanopsin is not essential for the circadian clock to receive photic input, it contributes significantly to the magnitude of photic responses.

In situations where the accumulation of internal heat limits physical performance, enhanced heat extraction from the body should improve performance capacity. The combined application of local subatmospheric pressure (35-45 mmHg) to an entire hand (to increase blood volume) and a heat sink (18-22 degrees C) to the palmar surface were used to draw heat out of the circulating blood. Subjects walked uphill (5.63 km/h) on a treadmill in a 40 degree C environment. Slopes of the treadmill were held constant during paired experimental trials (with and without the device). Heat extraction attenuated the rate of esophageal temperature rise during exercise (2.1 +/- 0.4 degrees and 2.9 +/- 0.5 degrees C/h, mean +/- SE, with and without the device, respectively; n = 8) and increased exercise duration (46.1 +/- 3.4 and 32.3 +/- 1.7 min with and without the device, respectively; n = 18). Hand cooling alone had little effect on exercise duration (34.1 +/- 3.0, 38.0 +/- 3.5, and 57.0 +/- 6.4 min, for control, cooling only, and cooling, and subatmospheric pressure, respectively; n = 6). In a longer term study, nine subjects participated in two or four trials per week for 8 wk. The individual workloads (treadmill slope) were varied weekly. Use of the device had a beneficial effect on exercise endurance at all workloads, but the benefit proportionally decreased at higher workloads. It is concluded that heat can be efficiently removed from the body by using the described technology and that such treatment can provide a substantial performance benefit in thermally stressful conditions.

Light can induce arrhythmia in circadian systems by several weeks of constant light or by a brief light stimulus given at the transition point of the phase response curve. In the present study, a novel light treatment consisting of phase advance and phase delay photic stimuli given on 2 successive nights was used to induce circadian arrhythmia in the Siberian hamster ( Phodopus sungorus). We therefore investigated whether loss of rhythms in behavior was due to arrhythmia within the suprachiasmatic nucleus (SCN). SCN tissue samples were obtained at 6 time points across 24 h in constant darkness from entrained and arrhythmic hamsters, and per1, per2 , bmal1, and cry1 mRNA were measured by quantitative RT-PCR. The light treatment eliminated circadian expression of clock genes within the SCN, and the overall expression of these genes was reduced by 18% to 40% of entrained values. Arrhythmia in per1, per2, and bmal1 was due to reductions in the amplitudes of their oscillations. We suggest that these data are compatible with an amplitude suppression model in which light induces singularity in the molecular circadian pacemaker.

Light is the primary sensory stimulus that synchronizes or entrains the internal circadian rhythms of animals to the solar day. In mammals photic entrainment of the circadian pacemaker residing in the suprachiasmatic nuclei is due to the fact that light at certain times of day can phase shift the pacemaker. In this study we show that the circadian system of mice can integrate extremely brief, repeated photic stimuli to produce large phase shifts. A train of 2-ms light pulses delivered as one pulse every 5 or 60 s, with a total light duration of 120 ms, can cause phase shifts of several hours that endure for weeks. Single 2-ms pulses of light were ineffective. Thus these data reveal a property of the mammalian circadian clock: it can integrate and store latent sensory information in such a way that a series of extremely brief photic stimuli, each too small to cause a phase shift individually, together can cause a large and long-lasting change in behavior.

We investigated whether glucocorticoids [i.e., corticosterone (Cort) in rats] released during sleep deprivation (SD) affect regional brain glycogen stores in 34-day-old Long-Evans rats. Adrenalectomized (with Cort replacement; Adxϩ) and intact animals were sleep deprived for 6 h beginning at lights on and then immediately killed by microwave irradiation. Brain and liver glycogen and glucose and plasma glucose levels were measured. After SD in intact animals, glycogen levels decreased in the cerebellum and hippocampus but not in the cortex or brain stem. By contrast, glycogen levels in the cortex of Adxϩ rats increased by 43% (P Ͻ 0.001) after SD, while other regions were unaffected. Also in Adxϩ animals, glucose levels were decreased by an average of 28% throughout the brain after SD. Intact sleep-deprived rats had elevations of circulating Cort, blood, and liver glucose that were absent in intact control and Adxϩ animals. Different responses between brain structures after SD may be due to regional variability in metabolic rate or glycogen metabolism. Our findings suggest that the elevated glucocorticoid secretion during SD causes brain glycogenolysis in response to energy demands. sleep homeostasis; corticosterone; blood glucose; liver glycogen and glucose; glycogen metabolism THE DRIVE TO SLEEP is tightly regulated. Homeostatic sleep regulation increases subsequent sleep intensity and/or duration after periods of wakefulness. One physiological marker of homeostasis is reflected in the proportional relationship between the intensity of EEG slow-wave activity (SWA; in the delta power range 0.5-4.0 Hz) during non-rapid eye movement (NREM) sleep and the amount of prior wakefulness (5, 12). There is evidence that this homeostatic regulation is mediated by adenosine (reviewed in Refs. 3, 34). The release of adenosine is thought to modulate SWA intensity as a function of sleep need in response to decreases in metabolic supply (3). According to this hypothesis, a progressive depletion of glycogen stores during wakefulness causes transient decreases in cellular energy charge, resulting in increased adenosine. The function of sleep, therefore, would be to replenish brain glycogen stores during NREM sleep when glycogen synthesis would prevail.Glycogen stores, the largest energy reserve in the brain, are regulated by glycogen phosphorylase and glycogen synthase. Increased levels of cAMP activate glycogenolysis and inhibit glycogen synthesis. Increased neuronal activity enhances glycogen turnover (reviewed in Ref. 48), whereas reduced activity increases glycogen levels (8,23,28,41). Excitatory neurotransmitters such as norepinephrine, serotonin, and histamine, released maximally during waking hours, potentiate glycogenolysis. In the brain, glycogen can be mobilized locally and rapidly in response to energy deficits (reviewed in Ref. 11) and normal physiological conditions (e.g., sensory stimulation; Refs. 27, 43).Recent studies have explored the relationship between brain glycogen and sleep by measuring glycogen (14,16,25...