Human cellular differences in cAMP--CREB signaling correlate with light-dependent melatonin suppression and bipolar disorder.

Various lines of evidence suggest a mechanistic role for altered cAMP-CREB (cAMP response element - binding protein) signaling in depressive and affective disorders. However, the establishment and validation of human inter-individual differences in this and other major signaling pathways has proven difficult. Here, we describe a novel lentiviral methodology to investigate signaling variation over long periods of time directly in human primary fibroblasts. On a cellular level, this method showed surprisingly large inter-individual differences in three major signaling pathways in human subjects that nevertheless correlated with cellular measures of genome-wide transcription and drug toxicity. We next validated this method by establishing a likely role for cAMP-mediated signaling in a human neuroendocrine response to light - the light-dependent suppression of the circadian hormone melatonin - that shows wide inter-individual differences of unknown origin in vivo. Finally, we show an overall greater magnitude of cellular CREB signaling in individuals with bipolar disorder, suggesting a possible role for this signaling pathway in susceptibility to mental disease. Overall, our results suggest that genetic differences in major signaling pathways can be reliably detected with sensitive viral-based reporter profiling, and that these differences can be conserved across tissues and be predictive of physiology and disease susceptibility.

The biological clock modulates the human cortisol response in a multiplicative fashion.

Human cortisol levels follow a clear circadian rhythm. We investigated the contribution of alternation of sleep and wakefulness and the circadian clock, using forced desynchrony. Cortisol levels were best described by a multiplication of a circadian and a wake-time component. The human cortisol response is modulated by circadian phase. Exposure to stress at an unnatural phase, as in shift work, is predicted to result in abnormal cortisol levels. Health of shift workers may therefore improve when stress is reduced at times when the clock produces high stress sensitivity.

Short-wavelength attenuated polychromatic white light during work at night: limited melatonin suppression without substantial decline of alertness.

Exposure to light at night increases alertness, but light at night (especially short-wavelength light) also disrupts nocturnal physiology. Such disruption is thought to underlie medical problems for which shiftworkers have increased risk. In 33 male subjects we investigated whether short-wavelength attenuated polychromatic white light (<530 nm filtered out) at night preserves dim light melatonin levels and whether it induces similar skin temperature, alertness, and performance levels as under full-spectrum light. All 33 subjects participated in random order during three nights (at least 1 wk apart) either under dim light (3 lux), short-wavelength attenuated polychromatic white light (193 lux), or full-spectrum light (256 lux). Hourly saliva samples for melatonin analysis were collected along with continuous measurements of skin temperature. Subjective sleepiness and activation were assessed via repeated questionnaires and performance was assessed by the accuracy and speed of an addition task. Our results show that short-wavelength attenuated polychromatic white light only marginally (6%) suppressed salivary melatonin. Average distal-to-proximal skin temperature gradient (DPG) and its pattern over time remained similar under short-wavelength attenuated polychromatic white light compared with dim light. Subjects performed equally well on an addition task under short-wavelength attenuated polychromatic white light compared with full-spectrum light. Although subjective ratings of activation were lower under short-wavelength attenuated polychromatic white light compared with full-spectrum light, subjective sleepiness was not increased. Short-wavelength attenuated polychromatic white light at night has some advantages over bright light. It hardly suppresses melatonin concentrations, whereas performance is similar to the bright light condition. Yet, alertness is slightly reduced as compared with bright light, and DPG shows similarity to the dim light condition, which is a physiological sign of reduced alertness. Short-wavelength attenuated polychromatic white light might therefore not be advisable in work settings that require high levels of alertness.

Effects of artificial dawn on subjective ratings of sleep inertia and dim light melatonin onset.

The timing of work and social requirements has a negative impact on performance and well-being of a significant proportion of the population in our modern society due to a phenomenon known as social jetlag. During workdays, in the early morning, late chronotypes, in particular, suffer from a combination of a nonoptimal circadian phase and sleep deprivation. Sleep inertia, a transient period of lowered arousal after awakening, therefore, becomes more severe. In the present home study, the authors tested whether the use of an alarm clock with artificial dawn could reduce complaints of sleep inertia in people having difficulties in waking up early. The authors also examined whether these improvements were accompanied by a shift in the melatonin rhythm. Two studies were performed: Study 1: three conditions (0, 50, and 250 lux) and Study 2: two conditions (0 lux and self-selected dawn-light intensity). Each condition lasted 2 weeks. In both studies, the use of the artificial dawn resulted in a significant reduction of sleep inertia complaints. However, no significant shift in the onset of melatonin was observed after 2 weeks of using the artificial dawn of 250 lux or 50 lux compared to the control condition. A multilevel analysis revealed that only the presence of the artificial dawn, rather than shift in the dim light melatonin onset or timing of sleep offset, is related to the observed reduction of sleep inertia complaints. Mechanisms other than shift of circadian rhythms are needed to explain the positive results on sleep inertia of waking up with a dawn signal.

Effects of artificial dawn on sleep inertia, skin temperature, and the awakening cortisol response.

The effect of artificial dawn during the last 30 min of sleep on subsequent dissipation of sleep inertia was investigated, including possible involvement of cortisol and thermoregulatory processes. Sixteen healthy subjects who reported difficulty with waking up participated in random order in a control and an artificial dawn night. Sleep inertia severity was measured by subjective ratings of sleepiness and activation, and by performance on an addition and a reaction time task measured at 1, 15, 30, 45, 60, and 90 min after waking up at habitual wake up time at workdays. At all intervals, saliva samples were collected for cortisol analysis. Sleep electroencephalogram was recorded during the 30 min prior to waking up; core body temperature and skin temperatures were recorded continuously until 90 min after waking up. Subjective sleepiness was significantly decreased and subjective activation increased after waking up in the artificial dawn condition as compared with control, in which lights were turned on at waking up. These effects can be explained by effects of artificial dawn on skin temperature and amount of wakefulness during the 30 min prior to the alarm. Artificial dawn accelerated the decline in skin temperature and in the distal-to-proximal skin temperature gradient after getting up. No significant effects of artificial dawn on performance, core body temperature, and cortisol were found. These results suggest that the physiology underlying the positive effects of artificial dawn on the dissipation of sleep inertia involves light sleep and an accelerated skin temperature decline after awakening.