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Several observational, cross-sectional, and longitudinal studies as well as a few well-controlled experimental studies have examined the impact of sleep loss on children's daytime functioning. The emerging results indicate that sleep plays a critical role in various aspects of daytime functioning in children, including cognitive and emotional functioning. Furthermore, studies indicate that daytime functioning may be impaired by even small amounts of sleep restriction in children., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Study Objectives: Chronic sleep restriction (CSR) impairs sustained attention in humans, as commonly assessed with the psychomotor vigilance task (PVT). To further investigate the mechanisms underlying performance deficits during CSR, we examined the effect of CSR on performance on a rat version of PVT (rPVT)., Design: Adult male rats were trained on a rPVT that required them to press a bar when they detected irregularly presented, brief light stimuli, and were then tested during CSR. CSR consisted of 100 or 148 h of continuous cycles of 3-h sleep deprivation (using slowly rotating wheels) alternating with a 1-h sleep opportunity (3/1 protocol)., Measurements and Results: After 28 h of CSR, the latency of correct responses and the percentages of lapses and omissions increased, whereas the percentage of correct responses decreased. Over 52-148 h of CSR, all performance measures showed partial or nearly complete recovery, and were at baseline levels on the first or second day after CSR. There were large interindividual differences in the magnitude of performance impairment during CSR, suggesting differential vulnerability to the effects of sleep loss. Wheel-running controls showed no changes in performance., Conclusions: A 28-h period of the 3/1 chronic sleep restriction (CSR) protocol disrupted performance on a sustained attention task in rats, as sleep deprivation does in humans. Performance improved after longer periods of CSR, suggesting allostatic adaptation, contrary to some reports of progressive deterioration in psychomotor vigilance task performance during CSR in humans. However, as observed in humans, there were individual differences among rats in the vulnerability of their attention performance to CSR., (© 2015 Associated Professional Sleep Societies, LLC.)

There is extensive evidence that sleep restriction alters endocrine function in healthy young men, increasing afternoon cortisol levels and modifying levels of other hormones that regulate metabolism. Recent studies have confirmed these effects in young women, but have not investigated whether menstrual cycle phase influences these responses. The effects on cortisol levels of limiting sleep to 3h for one night were assessed in two groups of women at different points in their menstrual cycles: mid-follicular and mid-luteal. Eighteen healthy, young women, not taking oral contraceptives (age: 21.8±0.53; BMI: 22.5±0.58 [mean±SEM]), were studied. Baseline sleep durations, eating habits and menstrual cycles were monitored. Salivary samples were collected at six times of day (08:00, 08:30, 11:00, 14:00, 17:00, 20:00) during two consecutive days: first after a 10h overnight sleep opportunity (Baseline) and then after a night with a 3h sleep opportunity (Post-sleep restriction). All were awakened at the same time of day. Women in the follicular phase showed a significant decrease (p=0.004) in their cortisol awakening responses (CAR) after sleep restriction and a sustained elevation in afternoon/evening cortisol levels (p=0.008), as has been reported for men. Women in the luteal phase showed neither a depressed CAR, nor an increase in afternoon/evening cortisol levels. Secondary analyses examined the impact of sleep restriction on self-reported hunger and mood. Menstrual cycle phase dramatically altered the cortisol responses of healthy, young women to a single night of sleep restriction, implicating effects of spontaneous changes in endocrine status on adrenal responses to sleep loss., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

To study sleep responses to chronic sleep restriction (CSR) and time-of-day influences on these responses, we developed a rat model of CSR that takes into account the polyphasic sleep patterns in rats. Adult male rats underwent cycles of 3 h of sleep deprivation (SD) and 1 h of sleep opportunity (SO) continuously for 4 days, beginning at the onset of the 12-h light phase ("3/1" protocol). Electroencephalogram (EEG) and electromyogram (EMG) recordings were made before, during, and after CSR. During CSR, total sleep time was reduced by ∼60% from baseline levels. Both rapid eye movement sleep (REMS) and non-rapid eye movement sleep (NREMS) during SO periods increased initially relative to baseline and remained elevated for the rest of the CSR period. In contrast, NREMS EEG delta power (a measure of sleep intensity) increased initially, but then declined gradually, in parallel with increases in high-frequency power in the NREMS EEG. The amplitude of daily rhythms in NREMS and REMS amounts was maintained during SO periods, whereas that of NREMS delta power was reduced. Compensatory responses during the 2-day post-CSR recovery period were either modest or negative and gated by time of day. NREMS, REMS, and EEG delta power lost during CSR were not recovered by the end of the second recovery day. Thus the "3/1" CSR protocol triggered both homeostatic responses (increased sleep amounts and intensity during SOs) and allostatic responses (gradual decline in sleep intensity during SOs and muted or negative post-CSR sleep recovery), and both responses were modulated by time of day.

Long-term (>48 h) sleep deprivation (SD) reduces adult rat hippocampal cell proliferation and neurogenesis, yet reported effects of short-term (<24 h) SD are inconsistent. We systematically assessed the effects of various durations of SD on adult rat hippocampal cell proliferation. Rats were sleep-deprived for 6, 12, 24, 36 or 48 h and injected with 5-bromo-2'-deoxyuridine (BrdU) 2 h before the end of SD. Immunolabeling for BrdU in the hippocampal subgranular zone increased significantly after 12 h SD but tended to decrease after 48 h SD relative to respective Controls. Surprisingly, SD did not alter immunolabeling for Ki67 protein (Ki67) or proliferating cell nuclear antigen (PCNA), two intrinsic cell proliferation markers. SD did not affect BrdU or Ki67 labeling in the subventricular zone, nor did it affect serum corticosterone levels. Because immunoreactivity for Ki67 and PCNA can identify cells in all phases of the ∼25 h cell cycle in adult rat hippocampus, whereas BrdU labels only cells in S-phase (∼9.5 h), this discrepancy suggests that 12 h SD might have affected cell cycle dynamics. A separate group of rats were injected with BrdU 10 h before the end of 12 h SD, which would allow some time for labeled cells to divide; the results were consistent with an acceleration of the timing of hippocampal progenitor cell division during 12 h SD. These results suggest that short-term (12 h) SD transiently produces more hippocampal progenitor cells via cell cycle acceleration, and confirm the importance of using multiple cell cycle markers or BrdU injection paradigms to assess potential changes in cell proliferation., (Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.)

Sleep restriction alters hormone patterns and appetite in men, but less is known about effects on women. We assessed effects of overnight sleep restriction on cortisol and leptin levels and on appetite in young women. Participants' baseline sleep duration and eating habits were monitored for a week before the study. Salivary cortisol and leptin were sampled from fifteen healthy women (aged 18-25) during two consecutive days: first after a 10h overnight sleep opportunity (Baseline day) and then after a night including only 3h sleep (Post sleep-restriction day). Participants also completed appetite questionnaires on both days. Sleep restriction significantly reduced morning cortisol levels (p=0.02), elevated morning leptin levels (p=0.04), elevated afternoon/evening cortisol area under the curve values (p=0.008), and slowed the decline in cortisol concentration during the day (p=0.04). Hunger and craving scores did not differ significantly between days. A single night of restricted sleep affected cortisol rhythms and morning leptin levels in young women., ((c) 2010 Elsevier Inc. All rights reserved.)

Background: Partial or total overnight sleep deprivation produces immediate mood improvement in about 50% of patients with depression, but not in healthy controls. Our objectives were to compare the neurochemical changes that accompanied partial overnight sleep deprivation in healthy and depressed participants, and to compare baseline neurochemical profiles and overnight neurochemical changes between those depressed participants who did and did not respond to sleep loss with mood improvement., Methods: We studied 2 brain regions (left dorsal prefrontal area and pons) in 12 women with unipolar depression and in 15 healthy women using proton magnetic resonance spectroscopy acquired at 1.5 T. The scans took place at baseline and 24 hours later after a night with sleep restricted to a maximum of 2.5 hours (22:30-01:00). We assessed 3 neurochemical signals (referenced to internal water): N-acetylaspartate (NAA), choline compounds (Cho) and creatine-plus-phosphocreatine (tCr)., Results: In both groups combined, sleep restriction caused a 20.1% decrease in pontine tCr (F(1-16) = 5.07, p = 0.039, Cohen's d = 0.54) and an 11.3% increase in prefrontal Cho (F(1-21) = 5.24, p = 0.033, Cohen's d = 0.46). Follow-up tests revealed that prefrontal Cho increases were significant only among depressed participants (17.9% increase, t(9) = -3.35, p = 0.008, Cohen's d = 1.06). Five depressed patients showed at least 30% improvement in mood, whereas 6 showed no change or worsening in mood after sleep restriction. Baseline pontine Cho levels distinguished subsequent responders from nonresponders to sleep restriction among depressed participants (z = 2.61, p = 0.008)., Limitations: A limitation of this study is the relatively small sample size., Conclusion: Sleep restriction altered levels of pontine tCr and prefrontal Cho in both groups combined, suggesting effects on phospholipid and creatine metabolism. Baseline levels of pontine Cho were linked to subsequent mood responses to sleep loss, suggesting a role for pontine phospholipid metabolism in mood effects of sleep restriction.

Study Objectives: Women undergo hormonal changes both naturally during their lives and as a result of sex hormone treatments. The objective of this study was to gain more knowledge about how these hormones affect sleep and responses to sleep loss., Design: Rats were ovariectomized and implanted subcutaneously with Silastic capsules containing oil vehicle, 17 beta-estradiol and/or progesterone. After 2 weeks, sleep/wake states were recorded during a 24-h baseline period, 6 h of total sleep deprivation induced by gentle handling during the light phase, and an 18-h recovery period., Measurements and Results: At baseline and particularly in the dark phase, ovariectomized rats treated with estradiol or estradiol plus progesterone spent more time awake at the expense of non-rapid eye movement sleep (NREMS) and/or REMS, whereas those given progesterone alone spent less time in REMS than ovariectomized rats receiving no hormones. Following sleep deprivation, all rats showed rebound increases in NREMS and REMS, but the relative increase in REMS was larger in females receiving hormones, especially high estradiol. In contrast, the normal increase in NREMS EEG delta power (an index of NREMS intensity) during recovery was attenuated by all hormone treatments., Conclusions: Estradiol promotes arousal in the active phase in sleep-satiated rats, but after sleep loss, both estradiol and progesterone selectively facilitate REMS rebound while reducing NREMS intensity. These results indicate that effects of ovarian hormones on recovery sleep differ from those on spontaneous sleep. The hormonal modulation of recovery sleep architecture may affect recovery of sleep related functions after sleep loss.

Women recover from sleep deprivation more efficiently than men, but the mechanism for this difference is unknown. Effects of estrogen on sleep suggest that it could play a role, but the brain targets on which estrogen may act to have this effect have not been identified. Sleep deprivation increases levels of the immediate-early gene protein c-Fos in selected brain regions, but it is unknown whether estrogen modulates this response. We investigated the influence of different levels of exogenous estradiol on the c-Fos response to sleep deprivation in ovariectomized female rats. Female rats were treated with low or high levels of estradiol (mimicking diestrous and proestrous levels, respectively) delivered via subcutaneous silastic tubes. Control ovariectomized females and sham-operated males were implanted with tubes filled with cholesterol. One week after surgery, half of the rats underwent a 3 h period of sleep deprivation during the light phase in a motorized Wahmann activity wheel that rotated constantly at a slow speed, while half were confined to fixed wheels. Immediately after sleep deprivation, animals were killed and their brains processed to detect c-Fos using immunohistochemistry. Sleep deprivation increased the number of c-Fos positive cells in a number of brain areas, including the caudate putamen, medial preoptic area, perifornical hypothalamus, and anterior paraventricular thalamic nucleus. Other areas, including the suprachiasmatic nucleus, posterior paraventricular hypothalamic nucleus, posterior paraventricular thalamic nucleus, arcuate nucleus, and central amygdala, did not respond to 3 h sleep deprivation with a significant increase in c-Fos levels. Levels of c-Fos induced in the selected brain regions by sleep deprivation were not modulated by estrogen levels, nor by sex.

To understand how female sex hormones influence homeostatic mechanisms of sleep, we studied the effects of estradiol (E(2)) replacement on c-Fos immunoreactivity in sleep/wake-regulatory brain areas after sleep deprivation (SD) in ovariectomized rats. Adult rats were ovariectomized and implanted subcutaneously with capsules containing 17beta-E(2) (10.5 microg; to mimic diestrous E(2) levels) or oil. After 2 wk, animals with E(2) capsules received a single subcutaneous injection of 17beta-E(2) (10 microg/kg; to achieve proestrous E(2) levels) or oil; control animals with oil capsules received an oil injection. Twenty-four hours later, animals were either left undisturbed or sleep deprived by "gentle handling" for 6 h during the early light phase, and killed. E(2) treatment increased serum E(2) levels and uterus weights dose dependently, while attenuating body weight gain. Regardless of hormonal conditions, SD increased c-Fos immunoreactivity in all four arousal-promoting areas and four limbic and neuroendocrine nuclei studied, whereas it decreased c-Fos labeling in the sleep-promoting ventrolateral preoptic nucleus (VLPO). Low and high E(2) treatments enhanced the SD-induced c-Fos immunoreactivity in the laterodorsal subnucleus of the bed nucleus of stria terminalis and the tuberomammillary nucleus, and in orexin-containing hypothalamic neurons, with no effect on the basal forebrain and locus coeruleus. The high E(2) treatment decreased c-Fos labeling in the VLPO under nondeprived conditions. These results indicate that E(2) replacement modulates SD-induced or spontaneous c-Fos expression in sleep/wake-regulatory and limbic forebrain nuclei. These modulatory effects of E(2) replacement on neuronal activity may be, in part, responsible for E(2)'s influence on sleep/wake behavior.

Expression of the immediate-early genes (IEGs) c-fos and junB in the rat brain was studied in response to sleep deprivation (SD) starting at four time points during the light phase of a 12:12 light:dark cycle. Animals were confined to slowly rotating wheels for 3 or 6 h in order to prevent sleep. The numbers of c-Fos- and JunB-immunoreactive cells were assessed in seven brain regions previously reported to respond to SD with increased c-fos expression (medial preoptic area (MPA), cortex, anterior and posterior paraventricular thalamic nuclei, amygdala, caudate-putamen, and laterodorsal tegmental nucleus). While c-Fos was induced by SD in all regions studied, there were differences in levels of induction depending on the duration of deprivation and on the timing of the deprivation period during the light phase. The most robust induction occurred in most regions in response to 3-h deprivation periods beginning 3 h into the light phase. A similarly timed peak of induction was observed in the MPA and cortex after 6 h of SD. In two regions, the posterior paraventricular thalamic nucleus and amygdala, 6 h of deprivation induced greater c-Fos immunoreactivity than did 3 h of deprivation, collapsed across all phases tested. Increased JunB immunoreactivity in response to either duration of deprivation was more limited and was significant only in the MPA, cortex, caudate-putamen and amygdala. c-Fos and JunB immunoreactivity in the paraventricular hypothalamic nucleus was low and similar in control and deprived animals. These results indicate that both duration of prior wakefulness and time of day influence the extent of IEG expression differentially in brain regions responsive to SD. The results also suggest that the posterior paraventricular thalamic nucleus and amygdala might be primarily responsive to length of wakefulness (sleep drive), while the MPA and anterior paraventricular thalamic nucleus might integrate input related to both homeostatic sleep drive and circadian clock influences on sleep regulation.

Deurveilher S, Cumyn EM, Peers T, Rusak B, Semba K. Estradiol replacement enhances sleep deprivation-induced c-Fos immunoreactivity in forebrain arousal regions of ovariectomized rats. Am J Physiol Regul Integr Comp Physiol 295: RI 328-RI 340, 2008. First published August 27, 2008; doi: 10.1 152/ajpregu.90576.2008.-To understand how female sex hormones influence homeostatic mechanisms of sleep, we studied the effects of estradiol (E[sub2]) replacement on c-Fos immunoreactivity in sleep! wake-regulatory brain areas after sleep deprivation (SD) in ovariectomized rats. Adult rats were ovariectomized and implanted subcutaneously with capsules containing 1713-E[sub2] (10.5 μg; to mimic diestrous E[sub2] levels) or oil. After 2 wk, animals with E[sub2] capsules received a single subcutaneous injection of 17β-E[sub2] (10 μg/kg; to achieve proestrous E[sub2] levels) or oil; control animals with oil capsules received an oil injection. Twenty-four hours later, animals were either left undisturbed or sleep deprived by "gentle handling" for 6 h during the early light phase, and killed. E[sub2] treatment increased serum E[sub2] levels and uterus weights dose dependently, while attenuating body weight gain. Regardless of hormonal conditions, SD increased c-Fos immunoreactivity in all four arousalpromoting areas and four limbic and neuroendocrine nuclei studied, whereas it decreased c-Fos labeling in the sleep-promoting ventrolateral preoptic nucleus (VLPO). Low and high E[sub2] treatments enhanced the SD-induced c-Fos immunoreactivity in the laterodorsal subnucleus of the bed nucleus of stria terminalis and the tuberomammillary nucleus, and in orexin-containing hypothalamic neurons, with no effect on the basal forebrain and locus coeruleus. The high E[sub2] treatment decreased c-Fos labeling in the VLPO under nondeprived conditions. These results indicate that E[sub2] replacement modulates SD-induced or spontaneous c-Fos expression in sleep!wake-regulatory and limbic forebrain nuclei. These modulatory effects of E[sub2] replacement on neuronal activity may be, in part, responsible for E[sub2]'s influence on sleep!wake behavior. [ABSTRACT FROM AUTHOR]