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Sample records for altered sleep homeostasis

  1. Altered Sleep Homeostasis in Rev-erbα Knockout Mice

    PubMed Central

    Mang, Géraldine M.; La Spada, Francesco; Emmenegger, Yann; Chappuis, Sylvie; Ripperger, Jürgen A.; Albrecht, Urs; Franken, Paul

    2016-01-01

    Study Objectives: The nuclear receptor REV-ERBα is a potent, constitutive transcriptional repressor critical for the regulation of key circadian and metabolic genes. Recently, REV-ERBα's involvement in learning, neurogenesis, mood, and dopamine turnover was demonstrated suggesting a specific role in central nervous system functioning. We have previously shown that the brain expression of several core clock genes, including Rev-erbα, is modulated by sleep loss. We here test the consequences of a loss of REV-ERBα on the homeostatic regulation of sleep. Methods: EEG/EMG signals were recorded in Rev-erbα knockout (KO) mice and their wild type (WT) littermates during baseline, sleep deprivation, and recovery. Cortical gene expression measurements after sleep deprivation were contrasted to baseline. Results: Although baseline sleep/wake duration was remarkably similar, KO mice showed an advance of the sleep/wake distribution relative to the light-dark cycle. After sleep onset in baseline and after sleep deprivation, both EEG delta power (1–4 Hz) and sleep consolidation were reduced in KO mice indicating a slower increase of homeostatic sleep need during wakefulness. This slower increase might relate to the smaller increase in theta and gamma power observed in the waking EEG prior to sleep onset under both conditions. Indeed, the increased theta activity during wakefulness predicted delta power in subsequent NREM sleep. Lack of Rev-erbα increased Bmal1, Npas2, Clock, and Fabp7 expression, confirming the direct regulation of these genes by REV-ERBα also in the brain. Conclusions: Our results add further proof to the notion that clock genes are involved in sleep homeostasis. Because accumulating evidence directly links REV-ERBα to dopamine signaling the altered homeostatic regulation of sleep reported here are discussed in that context. Citation: Mang GM, La Spada F, Emmenegger Y, Chappuis S, Ripperger JA, Albrecht U, Franken P. Altered sleep homeostasis in Rev

  2. Alcohol disrupts sleep homeostasis.

    PubMed

    Thakkar, Mahesh M; Sharma, Rishi; Sahota, Pradeep

    2015-06-01

    Alcohol is a potent somnogen and one of the most commonly used "over the counter" sleep aids. In healthy non-alcoholics, acute alcohol decreases sleep latency, consolidates and increases the quality (delta power) and quantity of NREM sleep during the first half of the night. However, sleep is disrupted during the second half. Alcoholics, both during drinking periods and during abstinences, suffer from a multitude of sleep disruptions manifested by profound insomnia, excessive daytime sleepiness, and altered sleep architecture. Furthermore, subjective and objective indicators of sleep disturbances are predictors of relapse. Finally, within the USA, it is estimated that societal costs of alcohol-related sleep disorders exceeds $18 billion. Thus, although alcohol-associated sleep problems have significant economic and clinical consequences, very little is known about how and where alcohol acts to affect sleep. In this review, we have described our attempts to unravel the mechanism of alcohol-induced sleep disruptions. We have conducted a series of experiments using two different species, rats and mice, as animal models. We performed microdialysis, immunohistochemical, pharmacological, sleep deprivation and lesion studies which suggest that the sleep-promoting effects of alcohol may be mediated via alcohol's action on the mediators of sleep homeostasis: adenosine (AD) and the wake-promoting cholinergic neurons of the basal forebrain (BF). Alcohol, via its action on AD uptake, increases extracellular AD resulting in the inhibition of BF wake-promoting neurons. Since binge alcohol consumption is a highly prevalent pattern of alcohol consumption and disrupts sleep, we examined the effects of binge drinking on sleep-wakefulness. Our results suggest that disrupted sleep homeostasis may be the primary cause of sleep disruption observed following binge drinking. Finally, we have also shown that sleep disruptions observed during acute withdrawal, are caused due to impaired

  3. Alcohol disrupts sleep homeostasis

    PubMed Central

    Thakkar, Mahesh M.; Sharma, Rishi; Sahota, Pradeep

    2014-01-01

    Alcohol is a potent somnogen and one of the most commonly used “over the counter” sleep aids. In healthy non-alcoholics, acute alcohol decreases sleep latency, consolidates and increases the quality (delta power) and quantity of NREM sleep during the first half of the night. However, sleep is disrupted during the second half. Alcoholics, both during drinking periods and during abstinences, suffer from a multitude of sleep disruptions manifested by profound insomnia, excessive daytime sleepiness, and altered sleep architecture. Furthermore, subjective and objective indicators of sleep disturbances are predictors of relapse. Finally, within the USA, it is estimated that societal costs of alcohol-related sleep disorders exceeds $18 billion. Thus, although alcohol-associated sleep problems have significant economic and clinical consequences, very little is known about how and where alcohol acts to affect sleep. In this review, we have described our attempts to understand how and where alcohol acts to affect sleep. We have conducted a series of experiments using two different species, rats and mice, as animal models, and a combination of multi-disciplinary experimental methodologies to examine and understand anatomical and cellular substrates mediating the effects of acute and chronic alcohol exposure on sleep-wakefulness. The results of our studies suggest that the sleep-promoting effects of alcohol may be mediated via alcohol’s action on the mediators of sleep homeostasis: adenosine (AD) and the wake-promoting cholinergic neurons of the basal forebrain (BF). Alcohol, via its action on AD uptake, increases extracellular AD resulting in the inhibition of BF wake-promoting neurons. Lesions of the BF cholinergic neurons or blockade of AD A1 receptors results in attenuation of alcohol-induced sleep promotion, suggesting that AD and BF cholinergic neurons are critical for sleep-promoting effects of alcohol. Since binge alcohol consumption is a highly prevalent pattern

  4. Sustained Sleep Fragmentation Induces Sleep Homeostasis in Mice

    PubMed Central

    Baud, Maxime O.; Magistretti, Pierre J.; Petit, Jean-Marie

    2015-01-01

    Study Objectives: Sleep fragmentation (SF) is an integral feature of sleep apnea and other prevalent sleep disorders. Although the effect of repetitive arousals on cognitive performance is well documented, the effects of long-term SF on electroencephalography (EEG) and molecular markers of sleep homeostasis remain poorly investigated. To address this question, we developed a mouse model of chronic SF and characterized its effect on EEG spectral frequencies and the expression of genes previously linked to sleep homeostasis including clock genes, heat shock proteins, and plasticity-related genes. Design: N/A. Setting: Animal sleep research laboratory. Participants : Sixty-six C57BL6/J adult mice. Interventions: Instrumental sleep disruption at a rate of 60/h during 14 days Measurements and Results: Locomotor activity and EEG were recorded during 14 days of SF followed by recovery for 2 days. Despite a dramatic number of arousals and decreased sleep bout duration, SF minimally reduced total quantity of sleep and did not significantly alter its circadian distribution. Spectral analysis during SF revealed a homeostatic drive for slow wave activity (SWA; 1–4 Hz) and other frequencies as well (4–40 Hz). Recordings during recovery revealed slow wave sleep consolidation and a transient rebound in SWA, and paradoxical sleep duration. The expression of selected genes was not induced following chronic SF. Conclusions: Chronic sleep fragmentation (SF) increased sleep pressure confirming that altered quality with preserved quantity triggers core sleep homeostasis mechanisms. However, it did not induce the expression of genes induced by sleep loss, suggesting that these molecular pathways are not sustainably activated in chronic diseases involving SF. Citation: Baud MO, Magistretti PJ, Petit JM. Sustained sleep fragmentation induces sleep homeostasis in mice. SLEEP 2015;38(4):567–579. PMID:25325477

  5. Role of corticosterone on sleep homeostasis induced by REM sleep deprivation in rats.

    PubMed

    Machado, Ricardo Borges; Tufik, Sergio; Suchecki, Deborah

    2013-01-01

    Sleep is regulated by humoral and homeostatic processes. If on one hand chronic elevation of stress hormones impair sleep, on the other hand, rapid eye movement (REM) sleep deprivation induces elevation of glucocorticoids and time of REM sleep during the recovery period. In the present study we sought to examine whether manipulations of corticosterone levels during REM sleep deprivation would alter the subsequent sleep rebound. Adult male Wistar rats were fit with electrodes for sleep monitoring and submitted to four days of REM sleep deprivation under repeated corticosterone or metyrapone (an inhibitor of corticosterone synthesis) administration. Sleep parameters were continuously recorded throughout the sleep deprivation period and during 3 days of sleep recovery. Plasma levels of adrenocorticotropic hormone and corticosterone were also evaluated. Metyrapone treatment prevented the elevation of corticosterone plasma levels induced by REM sleep deprivation, whereas corticosterone administration to REM sleep-deprived rats resulted in lower corticosterone levels than in non-sleep deprived rats. Nonetheless, both corticosterone and metyrapone administration led to several alterations on sleep homeostasis, including reductions in the amount of non-REM and REM sleep during the recovery period, although corticosterone increased delta activity (1.0-4.0 Hz) during REM sleep deprivation. Metyrapone treatment of REM sleep-deprived rats reduced the number of REM sleep episodes. In conclusion, reduction of corticosterone levels during REM sleep deprivation resulted in impairment of sleep rebound, suggesting that physiological elevation of corticosterone levels resulting from REM sleep deprivation is necessary for plentiful recovery of sleep after this stressful event.

  6. Electrophysiological correlates of sleep homeostasis in freely behaving rats

    PubMed Central

    Vyazovskiy, Vladyslav V.; Cirelli, Chiara; Tononi, Giulio

    2011-01-01

    The electrical activity of the brain does not only reflect the current level of arousal, ongoing behavior or involvement in a specific task, but is also influenced by what kind of activity, and how much sleep and waking occurred before. The best marker of sleep-wake history is the electroencephalogram (EEG) spectral power in slow frequencies (slow-wave activity, 0.5–4 Hz, SWA) during sleep, which is high after extended wakefulness and low after consolidated sleep. While sleep homeostasis has been well characterized in various species and experimental paradigms, the specific mechanisms underlying homeostatic changes in brain activity or their functional significance remain poorly understood. However, several recent studies in humans, rats and computer simulations shed light on the cortical mechanisms underlying sleep regulation. First, it was found that the homeostatic changes in SWA can be fully accounted for by the variations in amplitude and slope of EEG slow waves, which are in turn determined by the efficacy of cortico-cortical connectivity. Specifically, the slopes of sleep slow waves were steeper in early sleep compared to late sleep. Second, the slope of cortical evoked potentials, which is an established marker of synaptic strength, was steeper after waking and decreased after sleep. Furthermore, cortical long-term potentiation (LTP) was partially occluded if it was induced after a period of waking, but it could again be fully expressed after sleep. Finally, multiunit activity recordings during sleep revealed that cortical neurons fired more synchronously after waking, and less so after a period of consolidated sleep. The decline of all these electrophysiological measures - the slopes of slow waves and evoked potentials and neuronal synchrony – during sleep correlated with the decline of the traditional marker of sleep homeostasis, EEG SWA. Taken together, these data suggest that homeostatic changes in sleep EEG are the result of altered neuronal firing

  7. Sleep Homeostasis in Infant Rats

    PubMed Central

    Blumberg, Mark S.; Middlemis-Brown, Jessica E.; Johnson, Eric D.

    2008-01-01

    Homeostatic regulation is a defining characteristic of sleep but has rarely been examined in infants. This study presents an automated method of sleep deprivation in which 5-day-old rats were shocked whenever the nuchal muscle became atonic. The intensity of shock was always set at the minimal level required to maintain arousal. Deprived pups exhibited rapid increases in sleep pressure, as evidenced by increased attempts to enter sleep and subsequent increases in sensory threshold; this increased sensory threshold was not due to sensory adaptation of peripheral receptors. In addition, myoclonic twitching was suppressed during the 30-min deprivation period, leading to rebound twitching during recovery sleep. These results provide the earliest demonstration of the homeostatic regulation of sleep in an altricial mammal. PMID:15598134

  8. Identification of Neurons with a Privileged Role in Sleep Homeostasis in Drosophila melanogaster.

    PubMed

    Seidner, Glen; Robinson, James E; Wu, Meilin; Worden, Kurtresha; Masek, Pavel; Roberts, Stephen W; Keene, Alex C; Joiner, William J

    2015-11-16

    Sleep is thought to be controlled by two main processes: a circadian clock that primarily regulates sleep timing and a homeostatic mechanism that detects and responds to sleep need. Whereas abundant experimental evidence suggests that sleep need increases with time spent awake, the contributions of different brain arousal systems have not been assessed independently of each other to determine whether certain neural circuits, rather than waking per se, selectively contribute to sleep homeostasis. Using the fruit fly, Drosophila melanogaster, we found that sustained thermogenetic activation of three independent neurotransmitter systems promoted nighttime wakefulness. However, only sleep deprivation resulting from activation of cholinergic neurons was sufficient to elicit subsequent homeostatic recovery sleep, as assessed by multiple behavioral criteria. In contrast, sleep deprivation resulting from activation of octopaminergic neurons suppressed homeostatic recovery sleep, indicating that wakefulness can be dissociated from accrual of sleep need. Neurons that promote sleep homeostasis were found to innervate the central brain and motor control regions of the thoracic ganglion. Blocking activity of these neurons suppressed recovery sleep but did not alter baseline sleep, further differentiating between neural control of sleep homeostasis and daily fluctuations in the sleep/wake cycle. Importantly, selective activation of wake-promoting neurons without engaging the sleep homeostat impaired subsequent short-term memory, thus providing evidence that neural circuits that regulate sleep homeostasis are important for behavioral plasticity. Together, our data suggest a neural circuit model involving distinct populations of wake-promoting neurons, some of which are involved in homeostatic control of sleep and cognition.

  9. A role for clock genes in sleep homeostasis.

    PubMed

    Franken, Paul

    2013-10-01

    The timing and quality of both sleep and wakefulness are thought to be regulated by the interaction of two processes. One of these two processes keeps track of the prior sleep-wake history and controls the homeostatic need for sleep while the other sets the time-of-day that sleep preferably occurs. The molecular pathways underlying the latter, circadian process have been studied in detail and their key role in physiological time-keeping has been well established. Analyses of sleep in mice and flies lacking core circadian clock gene proteins have demonstrated, however, that besides disrupting circadian rhythms, also sleep homeostatic processes were affected. Subsequent studies revealed that sleep loss alters both the mRNA levels and the specific DNA-binding of the key circadian transcriptional regulators to their target sequences in the mouse brain. The fact that sleep loss impinges on the very core of the molecular circadian circuitry might explain why both inadequate sleep and disrupted circadian rhythms can similarly lead to metabolic pathology. The evidence for a role for clock genes in sleep homeostasis will be reviewed here.

  10. Do placebos alter sleep?

    PubMed

    Adam, K; Adamson, L; Brezinová, V; Oswald, I

    1976-01-24

    Deliberate suggestion that an inert capsule was a sleeping pill was found not to influence subjective ratings of sleep quality or anxiety or the electrophysiologically recorded features of sleep in 10 volunteers aged 41-62 years. PMID:1247770

  11. Do placebos alter sleep?

    PubMed

    Adam, K; Adamson, L; Brezinová, V; Oswald, I

    1976-01-24

    Deliberate suggestion that an inert capsule was a sleeping pill was found not to influence subjective ratings of sleep quality or anxiety or the electrophysiologically recorded features of sleep in 10 volunteers aged 41-62 years.

  12. Neuronal Machinery of Sleep Homeostasis in Drosophila

    PubMed Central

    Donlea, Jeffrey M.; Pimentel, Diogo; Miesenböck, Gero

    2014-01-01

    Summary Sleep is under homeostatic control, but the mechanisms that sense sleep need and correct sleep deficits remain unknown. Here, we report that sleep-promoting neurons with projections to the dorsal fan-shaped body (FB) form the output arm of Drosophila’s sleep homeostat. Homeostatic sleep control requires the Rho-GTPase-activating protein encoded by the crossveinless-c (cv-c) gene in order to transduce sleep pressure into increased electrical excitability of dorsal FB neurons. cv-c mutants exhibit decreased sleep time, diminished sleep rebound, and memory deficits comparable to those after sleep loss. Targeted ablation and rescue of Cv-c in sleep-control neurons of the dorsal FB impair and restore, respectively, normal sleep patterns. Sleep deprivation increases the excitability of dorsal FB neurons, but this homeostatic adjustment is disrupted in short-sleeping cv-c mutants. Sleep pressure thus shifts the input-output function of sleep-promoting neurons toward heightened activity by modulating ion channel function in a mechanism dependent on Cv-c. PMID:24559676

  13. Chronic sleep disturbance impairs glucose homeostasis in rats.

    PubMed

    Barf, R Paulien; Meerlo, Peter; Scheurink, Anton J W

    2010-01-01

    Epidemiological studies have shown an association between short or disrupted sleep and an increased risk for metabolic disorders. To assess a possible causal relationship, we examined the effects of experimental sleep disturbance on glucose regulation in Wistar rats under controlled laboratory conditions. Three groups of animals were used: a sleep restriction group (RS), a group subjected to moderate sleep disturbance without restriction of sleep time (DS), and a home cage control group. To establish changes in glucose regulation, animals were subjected to intravenous glucose tolerance tests (IVGTTs) before and after 1 or 8 days of sleep restriction or disturbance. Data show that both RS and DS reduce body weight without affecting food intake and also lead to hyperglycemia and decreased insulin levels during an IVGTT. Acute sleep disturbance also caused hyperglycemia during an IVGTT, yet, without affecting the insulin response. In conclusion, both moderate and severe disturbances of sleep markedly affect glucose homeostasis and body weight control. PMID:20339560

  14. Behavioral and electrophysiological correlates of sleep and sleep homeostasis.

    PubMed

    Deboer, Tom

    2015-01-01

    The definition of what sleep is depends on the method that is applied to record sleep. Behavioral and (electro)-physiological measures of sleep clearly overlap in mammals and birds , but it is often unclear how these two relate in other vertebrates and invertebrates. Homeostatic regulation of sleep, where the amount of sleep depends on the amount of previous waking, can be observed in physiology and behavior in all animals this was tested in. In mammals and birds, sleep is generally subdivided into two states, non-rapid eye movement (NREM) sleep and REM sleep. In mammals the combination of behavioral sleep and the changes in the slow-wave range of the NREM sleep electroencephalogram (EEG) can explain and predict the occurrence and depth of sleep in great detail. For REM sleep this is far less clear. Finally, the discovery that slow-waves in the NREM sleep EEG are influenced locally on the cortex depending on prior waking behavior is an interesting new development that asks for an adaptation of the concept of homeostatic regulation of sleep. Incorporating local sleep into models of sleep regulation is needed to obtain a comprehensive picture.

  15. Synaptic Homeostasis and Restructuring across the Sleep-Wake Cycle

    PubMed Central

    Rennó-Costa, César; Santos, Sharlene; Dias, Gabriella; Guerreiro, Ana M. G.; Tort, Adriano B. L.; Neto, Adrião D.; Ribeiro, Sidarta

    2015-01-01

    Sleep is critical for hippocampus-dependent memory consolidation. However, the underlying mechanisms of synaptic plasticity are poorly understood. The central controversy is on whether long-term potentiation (LTP) takes a role during sleep and which would be its specific effect on memory. To address this question, we used immunohistochemistry to measure phosphorylation of Ca2+/calmodulin-dependent protein kinase II (pCaMKIIα) in the rat hippocampus immediately after specific sleep-wake states were interrupted. Control animals not exposed to novel objects during waking (WK) showed stable pCaMKIIα levels across the sleep-wake cycle, but animals exposed to novel objects showed a decrease during subsequent slow-wave sleep (SWS) followed by a rebound during rapid-eye-movement sleep (REM). The levels of pCaMKIIα during REM were proportional to cortical spindles near SWS/REM transitions. Based on these results, we modeled sleep-dependent LTP on a network of fully connected excitatory neurons fed with spikes recorded from the rat hippocampus across WK, SWS and REM. Sleep without LTP orderly rescaled synaptic weights to a narrow range of intermediate values. In contrast, LTP triggered near the SWS/REM transition led to marked swaps in synaptic weight ranking. To better understand the interaction between rescaling and restructuring during sleep, we implemented synaptic homeostasis and embossing in a detailed hippocampal-cortical model with both excitatory and inhibitory neurons. Synaptic homeostasis was implemented by weakening potentiation and strengthening depression, while synaptic embossing was simulated by evoking LTP on selected synapses. We observed that synaptic homeostasis facilitates controlled synaptic restructuring. The results imply a mechanism for a cognitive synergy between SWS and REM, and suggest that LTP at the SWS/REM transition critically influences the effect of sleep: Its lack determines synaptic homeostasis, its presence causes synaptic

  16. Synaptic Homeostasis and Restructuring across the Sleep-Wake Cycle.

    PubMed

    Blanco, Wilfredo; Pereira, Catia M; Cota, Vinicius R; Souza, Annie C; Rennó-Costa, César; Santos, Sharlene; Dias, Gabriella; Guerreiro, Ana M G; Tort, Adriano B L; Neto, Adrião D; Ribeiro, Sidarta

    2015-05-01

    Sleep is critical for hippocampus-dependent memory consolidation. However, the underlying mechanisms of synaptic plasticity are poorly understood. The central controversy is on whether long-term potentiation (LTP) takes a role during sleep and which would be its specific effect on memory. To address this question, we used immunohistochemistry to measure phosphorylation of Ca2+/calmodulin-dependent protein kinase II (pCaMKIIα) in the rat hippocampus immediately after specific sleep-wake states were interrupted. Control animals not exposed to novel objects during waking (WK) showed stable pCaMKIIα levels across the sleep-wake cycle, but animals exposed to novel objects showed a decrease during subsequent slow-wave sleep (SWS) followed by a rebound during rapid-eye-movement sleep (REM). The levels of pCaMKIIα during REM were proportional to cortical spindles near SWS/REM transitions. Based on these results, we modeled sleep-dependent LTP on a network of fully connected excitatory neurons fed with spikes recorded from the rat hippocampus across WK, SWS and REM. Sleep without LTP orderly rescaled synaptic weights to a narrow range of intermediate values. In contrast, LTP triggered near the SWS/REM transition led to marked swaps in synaptic weight ranking. To better understand the interaction between rescaling and restructuring during sleep, we implemented synaptic homeostasis and embossing in a detailed hippocampal-cortical model with both excitatory and inhibitory neurons. Synaptic homeostasis was implemented by weakening potentiation and strengthening depression, while synaptic embossing was simulated by evoking LTP on selected synapses. We observed that synaptic homeostasis facilitates controlled synaptic restructuring. The results imply a mechanism for a cognitive synergy between SWS and REM, and suggest that LTP at the SWS/REM transition critically influences the effect of sleep: Its lack determines synaptic homeostasis, its presence causes synaptic

  17. Synaptic Homeostasis and Restructuring across the Sleep-Wake Cycle.

    PubMed

    Blanco, Wilfredo; Pereira, Catia M; Cota, Vinicius R; Souza, Annie C; Rennó-Costa, César; Santos, Sharlene; Dias, Gabriella; Guerreiro, Ana M G; Tort, Adriano B L; Neto, Adrião D; Ribeiro, Sidarta

    2015-05-01

    Sleep is critical for hippocampus-dependent memory consolidation. However, the underlying mechanisms of synaptic plasticity are poorly understood. The central controversy is on whether long-term potentiation (LTP) takes a role during sleep and which would be its specific effect on memory. To address this question, we used immunohistochemistry to measure phosphorylation of Ca2+/calmodulin-dependent protein kinase II (pCaMKIIα) in the rat hippocampus immediately after specific sleep-wake states were interrupted. Control animals not exposed to novel objects during waking (WK) showed stable pCaMKIIα levels across the sleep-wake cycle, but animals exposed to novel objects showed a decrease during subsequent slow-wave sleep (SWS) followed by a rebound during rapid-eye-movement sleep (REM). The levels of pCaMKIIα during REM were proportional to cortical spindles near SWS/REM transitions. Based on these results, we modeled sleep-dependent LTP on a network of fully connected excitatory neurons fed with spikes recorded from the rat hippocampus across WK, SWS and REM. Sleep without LTP orderly rescaled synaptic weights to a narrow range of intermediate values. In contrast, LTP triggered near the SWS/REM transition led to marked swaps in synaptic weight ranking. To better understand the interaction between rescaling and restructuring during sleep, we implemented synaptic homeostasis and embossing in a detailed hippocampal-cortical model with both excitatory and inhibitory neurons. Synaptic homeostasis was implemented by weakening potentiation and strengthening depression, while synaptic embossing was simulated by evoking LTP on selected synapses. We observed that synaptic homeostasis facilitates controlled synaptic restructuring. The results imply a mechanism for a cognitive synergy between SWS and REM, and suggest that LTP at the SWS/REM transition critically influences the effect of sleep: Its lack determines synaptic homeostasis, its presence causes synaptic

  18. Maternal Ube3a Loss Disrupts Sleep Homeostasis But Leaves Circadian Rhythmicity Largely Intact

    PubMed Central

    Ehlen, J. Christopher; Jones, Kelly A.; Pinckney, Lennisha; Gray, Cloe L.; Burette, Susan; Weinberg, Richard J.; Evans, Jennifer A.; Brager, Allison J.; Zylka, Mark J.

    2015-01-01

    Individuals with Angelman syndrome (AS) suffer sleep disturbances that severely impair quality of life. Whether these disturbances arise from sleep or circadian clock dysfunction is currently unknown. Here, we explored the mechanistic basis for these sleep disorders in a mouse model of Angelman syndrome (Ube3am−/p+ mice). Genetic deletion of the maternal Ube3a allele practically eliminates UBE3A protein from the brain of Ube3am−/p+ mice, because the paternal allele is epigenetically silenced in most neurons. However, we found that UBE3A protein was present in many neurons of the suprachiasmatic nucleus—the site of the mammalian circadian clock—indicating that Ube3a can be expressed from both parental alleles in this brain region in adult mice. We found that while Ube3am−/p+ mice maintained relatively normal circadian rhythms of behavior and light-resetting, these mice exhibited consolidated locomotor activity and skipped the timed rest period (siesta) present in wild-type (Ube3am+/p+) mice. Electroencephalographic analysis revealed that alterations in sleep regulation were responsible for these overt changes in activity. Specifically, Ube3am−/p+ mice have a markedly reduced capacity to accumulate sleep pressure, both during their active period and in response to forced sleep deprivation. Thus, our data indicate that the siesta is governed by sleep pressure, and that Ube3a is an important regulator of sleep homeostasis. These preclinical findings suggest that therapeutic interventions that target mechanisms of sleep homeostasis may improve sleep quality in individuals with AS. SIGNIFICANCE STATEMENT Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by loss of expression of the maternal copy of the UBE3A gene. Individuals with AS have severe sleep dysfunction that affects their cognition and presents challenges to their caregivers. Unfortunately, current treatment strategies have limited efficacy due to a poor understanding of the

  19. Repeated Sleep Restriction in Adolescent Rats Altered Sleep Patterns and Impaired Spatial Learning/Memory Ability

    PubMed Central

    Yang, Su-Rong; Sun, Hui; Huang, Zhi-Li; Yao, Ming-Hui; Qu, Wei-Min

    2012-01-01

    Study Objectives: To investigate possible differences in the effect of repeated sleep restriction (RSR) during adolescence and adulthood on sleep homeostasis and spatial learning and memory ability. Design: The authors examined electroencephalograms of rats as they were subjected to 4-h daily sleep deprivation that continued for 7 consecutive days and assessed the spatial learning and memory by Morris water maze test (WMT). Participants: Adolescent and adult rats. Measurements and Results: Adolescent rats exhibited a similar amount of rapid eye movement (REM) and nonrapid eye movement (NREM) sleep with higher slow wave activity (SWA, 0.5-4 Hz) and fewer episodes and conversions with prolonged durations, indicating they have better sleep quality than adult rats. After RSR, adult rats showed strong rebound of REM sleep by 31% on sleep deprivation day 1; this value was 37% on sleep deprivation day 7 in adolescents compared with 20-h baseline level. On sleep deprivation day 7, SWA in adult and adolescent rats increased by 47% and 33%, and such elevation lasted for 5 h and 7 h, respectively. Furthermore, the authors investigated the effects of 4-h daily sleep deprivation immediately after the water maze training sessions on spatial cognitive performance. Adolescent rats sleep-restricted for 7 days traveled a longer distance to find the hidden platform during the acquisition training and had fewer numbers of platform crossings in the probe trial than those in the control group, something that did not occur in the sleep-deprived adult rats. Conclusions: Repeated sleep restriction (RSR) altered sleep profiles and mildly impaired spatial learning and memory capability in adolescent rats. Citation: Yang SR; Sun H; Huang ZL; Yao MH; Qu WM. Repeated sleep restriction in adolescent rats altered sleep patterns and impaired spatial learning/memory ability. SLEEP 2012;35(6):849-859. PMID:22654204

  20. REM sleep homeostasis in the absence of REM sleep: Effects of antidepressants.

    PubMed

    McCarthy, Andrew; Wafford, Keith; Shanks, Elaine; Ligocki, Marcin; Edgar, Dale M; Dijk, Derk-Jan

    2016-09-01

    Most antidepressants suppress rapid eye movement (REM) sleep, which is thought to be important to brain function, yet the resulting REM sleep restriction is well tolerated. This study investigated the impact of antidepressants with different mechanisms of action, such as selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCA), on the regulation of REM sleep in rats. REM sleep was first demonstrated to be homeostatically regulated using 5, 8 and 10 h of REM-sleep specific restriction through EEG-triggered arousals, with an average of 91 ± 10% of lost REM sleep recovered following a 26-29 -hour recovery period. Acute treatment with the antidepressants paroxetine, citalopram and imipramine inhibited REM sleep by 84 ± 8, 84 ± 8 and 69 ± 9% respectively relative to vehicle control. The pharmacologically-induced REM sleep deficits by paroxetine and citalopram were not fully recovered, whereas, after imipramine the REM sleep deficit was fully compensated. Given the marked difference between REM sleep recovery following the administration of paroxetine, citalopram, imipramine and REM sleep restriction, the homeostatic response was further examined by pairing REM sleep specific restriction with the three antidepressants. Surprisingly, the physiologically-induced REM sleep deficits incurred prior to suppression of REM sleep by all antidepressants was consistently recovered. The data indicate that REM sleep homeostasis remains operative following subsequent treatment with antidepressants and is unaffected by additional pharmacological inhibition of REM sleep. PMID:27150557

  1. REM sleep homeostasis in the absence of REM sleep: Effects of antidepressants.

    PubMed

    McCarthy, Andrew; Wafford, Keith; Shanks, Elaine; Ligocki, Marcin; Edgar, Dale M; Dijk, Derk-Jan

    2016-09-01

    Most antidepressants suppress rapid eye movement (REM) sleep, which is thought to be important to brain function, yet the resulting REM sleep restriction is well tolerated. This study investigated the impact of antidepressants with different mechanisms of action, such as selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCA), on the regulation of REM sleep in rats. REM sleep was first demonstrated to be homeostatically regulated using 5, 8 and 10 h of REM-sleep specific restriction through EEG-triggered arousals, with an average of 91 ± 10% of lost REM sleep recovered following a 26-29 -hour recovery period. Acute treatment with the antidepressants paroxetine, citalopram and imipramine inhibited REM sleep by 84 ± 8, 84 ± 8 and 69 ± 9% respectively relative to vehicle control. The pharmacologically-induced REM sleep deficits by paroxetine and citalopram were not fully recovered, whereas, after imipramine the REM sleep deficit was fully compensated. Given the marked difference between REM sleep recovery following the administration of paroxetine, citalopram, imipramine and REM sleep restriction, the homeostatic response was further examined by pairing REM sleep specific restriction with the three antidepressants. Surprisingly, the physiologically-induced REM sleep deficits incurred prior to suppression of REM sleep by all antidepressants was consistently recovered. The data indicate that REM sleep homeostasis remains operative following subsequent treatment with antidepressants and is unaffected by additional pharmacological inhibition of REM sleep.

  2. Ketone body metabolism and sleep homeostasis in mice.

    PubMed

    Chikahisa, Sachiko; Shimizu, Noriyuki; Shiuchi, Tetsuya; Séi, Hiroyoshi

    2014-04-01

    A link has been established between energy metabolism and sleep homeostasis. The ketone bodies acetoacetate and β-hydroxybutyrate, generated from the breakdown of fatty acids, are major metabolic fuels for the brain under conditions of low glucose availability. Ketogenesis is modulated by the activity of peroxisome proliferator-activated receptor alpha (PPARα), and treatment with a PPAR activator has been shown to induce a marked increase in plasma acetoacetate and decreased β-hydroxybutyrate in mice, accompanied by increased slow-wave activity during non-rapid eye movement (NREM) sleep. The present study investigated the role of ketone bodies in sleep regulation. Six-hour sleep deprivation increased plasma ketone bodies and their ratio (acetoacetate/β-hydroxybutyrate) in 10-week-old male mice. Moreover, sleep deprivation increased mRNA expression of ketogenic genes such as PPARα and 3-hydroxy-3-methylglutarate-CoA synthase 2 in the brain and decreased ketolytic enzymes such as succinyl-CoA: 3-oxoacid CoA transferase. In addition, central injection of acetoacetate, but not β-hydroxybutyrate, markedly increased slow-wave activity during NREM sleep and suppressed glutamate release. Central metabolism of ketone bodies, especially acetoacetate, appears to play a role in the regulation of sleep homeostasis.

  3. Synaptic plasticity in sleep: learning, homeostasis, and disease

    PubMed Central

    Wang, Gordon; Grone, Brian; Colas, Damien; Appelbaum, Lior; Mourrain, Philippe

    2012-01-01

    Sleep is a fundamental and evolutionarily conserved aspect of animal life. Recent studies have shed light on the role of sleep in synaptic plasticity. Demonstrations of memory replay and synapse homeostasis suggest that one essential role of sleep is in the consolidation and optimization of synaptic circuits to retain salient memory traces despite the noise of daily experience. Here, we review this recent evidence, and suggest that sleep creates a heightened state of plasticity, which may be essential for this optimization. Furthermore, we discuss how sleep deficits seen in diseases such as Alzheimer’s disease and autism spectrum disorders might not just reflect underlying circuit malfunction, but could also play a direct role in the progression of those disorders. PMID:21840068

  4. Sleep and sleep homeostasis in constant darkness in the rat.

    PubMed

    Deboer, Tom; de Boer, Tom

    2009-09-01

    According to the two-process model of sleep regulation, a homeostatic Process S increases during waking and decreases during sleep. The time course of Process S can be derived on the basis of changes in vigilance states and changes in electroencephalogram slow-wave activity (SWA, activity below 4 Hz) during non-rapid eye movement (NREM) sleep. In most mouse strains, an optimal fit between S and SWA was achieved with one increasing (active during waking and REM sleep) and one decreasing time constant (active during NREM sleep) for Process S. However, in the rat, systematic deviations in the light and dark periods were observed, which were resolved by introducing different decreasing time constants between the light and dark periods. The present study shows that this difference between the rest (light) and active (dark) phases remains, and may even be larger, after animals are adapted to constant dark conditions for at least a week. In addition, the data show that the build-up rate of SWA at the onset of a NREM sleep episode is slow compared with the increase rate under light-dark conditions, and that this build-up rate changes with the circadian phase. The slow build-up rate introduces a systematic error between the simulation of Process S and SWA in NREM sleep. The circadian modulation of the build-up rate may, together with circadian changes in NREM sleep episode duration, be the source of the necessity of introducing a difference in the decreasing time constant between the rest and active phases.

  5. Local sleep homeostasis in the avian brain: convergence of sleep function in mammals and birds?

    PubMed

    Lesku, John A; Vyssotski, Alexei L; Martinez-Gonzalez, Dolores; Wilzeck, Christiane; Rattenborg, Niels C

    2011-08-22

    The function of the brain activity that defines slow wave sleep (SWS) and rapid eye movement (REM) sleep in mammals is unknown. During SWS, the level of electroencephalogram slow wave activity (SWA or 0.5-4.5 Hz power density) increases and decreases as a function of prior time spent awake and asleep, respectively. Such dynamics occur in response to waking brain use, as SWA increases locally in brain regions used more extensively during prior wakefulness. Thus, SWA is thought to reflect homeostatically regulated processes potentially tied to maintaining optimal brain functioning. Interestingly, birds also engage in SWS and REM sleep, a similarity that arose via convergent evolution, as sleeping reptiles and amphibians do not show similar brain activity. Although birds deprived of sleep show global increases in SWA during subsequent sleep, it is unclear whether avian sleep is likewise regulated locally. Here, we provide, to our knowledge, the first electrophysiological evidence for local sleep homeostasis in the avian brain. After staying awake watching David Attenborough's The Life of Birds with only one eye, SWA and the slope of slow waves (a purported marker of synaptic strength) increased only in the hyperpallium--a primary visual processing region--neurologically connected to the stimulated eye. Asymmetries were specific to the hyperpallium, as the non-visual mesopallium showed a symmetric increase in SWA and wave slope. Thus, hypotheses for the function of mammalian SWS that rely on local sleep homeostasis may apply also to birds.

  6. Behavioral Sleep-Wake Homeostasis and EEG Delta Power Are Decoupled By Chronic Sleep Restriction in the Rat

    PubMed Central

    Stephenson, Richard; Caron, Aimee M.; Famina, Svetlana

    2015-01-01

    Study Objectives: Chronic sleep restriction (CSR) is prevalent in society and is linked to adverse consequences that might be ameliorated by acclimation of homeostatic drive. This study was designed to test the hypothesis that the sleep-wake homeostat will acclimatize to CSR. DESIGN: A four-parameter model of proportional control was used to quantify sleep homeostasis with and without recourse to a sleep intensity function. Setting: Animal laboratory, rodent walking-wheel apparatus. Subjects: Male Sprague-Dawley rats. Interventions: Acute total sleep deprivation (TSD, 1 day × 18 or 24 h, N = 12), CSR (10 days × 18 h TSD, N = 6, or 5 days × 20 h TSD, N = 5). Measurements and Results: Behavioral rebounds were consistent with model predictions for proportional control of cumulative times in wake, nonrapid eye movement sleep (NREM) and rapid eye movement sleep (REM). Delta (Δ) energy homeostasis was secondary to behavioral homeostasis; a biphasic NREM Δ power rebound contributed to the dynamics (rapid response) but not to the magnitude of the rebound in Δ energy. REM behavioral homeostasis was little affected by CSR. NREM behavioral homeostasis was attenuated in proportion to cumulative NREM deficit, whereas the biphasic NREM Δ power rebound was only slightly suppressed, indicating decoupled regulatory mechanisms following CSR. Conclusions: We conclude that sleep homeostasis is achieved through behavioral regulation, that the nonrapid eye movement sleep behavioral homeostat is susceptible to attenuation during chronic sleep restriction and that the concept of sleep intensity is not essential in a model of sleep-wake regulation. Citation: Stephenson R, Caron AM, Famina S. Behavioral sleep-wake homeostasis and EEG delta power are decoupled by chronic sleep restriction in the rat. SLEEP 2015;38(5):685–697. PMID:25669184

  7. Sleep Homeostasis and Cortical Synchronization: I. Modeling the Effects of Synaptic Strength on Sleep Slow Waves

    PubMed Central

    Esser, Steve K.; Hill, Sean L.; Tononi, Giulio

    2007-01-01

    Study Objectives: Sleep slow-wave activity (SWA, electroencephalogram [EEG] power between 0.5 and 4.0 Hz) is homeostatically regulated, increasing with wakefulness and declining with sleep. Sleep SWA is thought to reflect sleep need, but the mechanisms of its homeostatic regulation remain unknown. Based on a recent hypothesis, we sought to determine whether a decrease in cortical synaptic strength can account for changes in sleep SWA. Design: A large-scale computer model of the sleeping thalamocortical system was used to reproduce in detail the cortical slow oscillations underlying EEG slow waves. Setting: N/A. Patients or Participants: N/A. Interventions: Simulated reductions in the strength of corticocortical synapses. Measurements and Results: Decreased synaptic strength led to (1) decreased single cell membrane potential oscillations and reduced network synchronization, (2) decreased rate of neural recruitment and decruitment, and (3) emergence of local clusters of synchronized activity. These changes were reflected in the local EEG as (1) decreased incidence of high-amplitude slow waves, (2) decreased wave slope, and (3) increased number of multipeak waves. Spectral analysis confirmed that these changes were associated with a decrease in SWA. Conclusions: A decrease in cortical synaptic strength is sufficient to account for changes in sleep SWA and is accompanied by characteristic changes in slow-wave parameters. Experimental results from rat cortical depth recordings and human high-density EEG show similar changes in slow-wave parameters with decreasing SWA, suggesting that the underlying mechanism may indeed be a net decrease in synaptic strength. Citation: Esser SK; Hill SL; Tononi G. Sleep homeostasis and cortical synchronization: I. Modeling the effects of synaptic strength on sleep slow waves. SLEEP 2007;30(12):1617-1630. PMID:18246972

  8. Independent Effects of γ-Aminobutyric Acid Transaminase (GABAT) on Metabolic and Sleep Homeostasis.

    PubMed

    Maguire, Sarah E; Rhoades, Seth; Chen, Wen-Feng; Sengupta, Arjun; Yue, Zhifeng; Lim, Jason C; Mitchell, Claire H; Weljie, Aalim M; Sehgal, Amita

    2015-08-14

    Breakdown of the major sleep-promoting neurotransmitter, γ-aminobutyric acid (GABA), in the GABA shunt generates catabolites that may enter the tricarboxylic acid cycle, but it is unknown whether catabolic by-products of the GABA shunt actually support metabolic homeostasis. In Drosophila, the loss of the specific enzyme that degrades GABA, GABA transaminase (GABAT), increases sleep, and we show here that it also affects metabolism such that flies lacking GABAT fail to survive on carbohydrate media. Expression of GABAT in neurons or glia rescues this phenotype, indicating a general metabolic function for this enzyme in the brain. As GABA degradation produces two catabolic products, glutamate and succinic semialdehyde, we sought to determine which was responsible for the metabolic phenotype. Through genetic and pharmacological experiments, we determined that glutamate, rather than succinic semialdehyde, accounts for the metabolic phenotype of gabat mutants. This is supported by biochemical measurements of catabolites in wild-type and mutant animals. Using in vitro labeling assays, we found that inhibition of GABAT affects energetic pathways. Interestingly, we also observed that gaba mutants display a general disruption in bioenergetics as measured by altered levels of tricarboxylic acid cycle intermediates, NAD(+)/NADH, and ATP levels. Finally, we report that the effects of GABAT on sleep do not depend upon glutamate, indicating that GABAT regulates metabolic and sleep homeostasis through independent mechanisms. These data indicate a role of the GABA shunt in the development of metabolic risk and suggest that neurological disorders caused by altered glutamate or GABA may be associated with metabolic disruption.

  9. Avian sleep homeostasis: convergent evolution of complex brains, cognition and sleep functions in mammals and birds.

    PubMed

    Rattenborg, Niels C; Martinez-Gonzalez, Dolores; Lesku, John A

    2009-03-01

    Birds are the only taxonomic group other than mammals that exhibit high-amplitude slow-waves in the electroencephalogram (EEG) during sleep. This defining feature of slow-wave sleep (SWS) apparently evolved independently in mammals and birds, as reptiles do not exhibit similar EEG activity during sleep. In mammals, the level of slow-wave activity (SWA) (low-frequency spectral power density) during SWS increases and decreases as a function of prior time spent awake and asleep, respectively, and therefore reflects homeostatically regulated sleep processes potentially tied to the function of SWS. Although birds also exhibit SWS, previous sleep deprivation studies in birds did not detect a compensatory increase in SWS-related SWA during recovery, as observed in similarly sleep-deprived mammals. This suggested that, unlike mammalian SWS, avian SWS is not homeostatically regulated, and therefore might serve a different function. However, we recently demonstrated that SWA during SWS increases in pigeons following short-term sleep deprivation. Herein we summarize research on avian sleep homeostasis, and cast our evidence for this phenomenon within the context of theories for the function of SWS in mammals. We propose that the convergent evolution of homeostatically regulated SWS in mammals and birds was directly linked to the convergent evolution of large, heavily interconnected brains capable of performing complex cognitive processes in each group. Specifically, as has been proposed for mammals, the interconnectivity that forms the basis of complex cognition in birds may also instantiate slow, synchronous network oscillations during SWS that in turn maintain interconnectivity and cognition at an optimal level.

  10. Chronic Sleep Restriction Disrupts Sleep Homeostasis and Behavioral Sensitivity to Alcohol by Reducing the Extracellular Accumulation of Adenosine

    PubMed Central

    Clasadonte, Jerome; McIver, Sally R.; Schmitt, Luke I.; Halassa, Michael M.

    2014-01-01

    Sleep impairments are comorbid with a variety of neurological and psychiatric disorders including depression, epilepsy, and alcohol abuse. Despite the prevalence of these disorders, the cellular mechanisms underlying the interaction between sleep disruption and behavior remain poorly understood. In this study, the impact of chronic sleep loss on sleep homeostasis was examined in C57BL/6J mice following 3 d of sleep restriction. The electroencephalographic power of slow-wave activity (SWA; 0.5–4 Hz) in nonrapid eye movement (NREM) sleep and adenosine tone were measured during and after sleep restriction, and following subsequent acute sleep deprivation. During the first day of sleep restriction, SWA and adenosine tone increased, indicating a homeostatic response to sleep loss. On subsequent days, SWA declined, and this was accompanied by a corresponding reduction in adenosine tone caused by a loss of one source of extracellular adenosine. Furthermore, the response to acute sleep deprivation (6 h) was significantly attenuated in sleep-restricted mice. These effects were long-lasting with reduced SWA and adenosine tone persisting for at least 2 weeks. To investigate the behavioral consequences of chronic sleep restriction, sensitivity to the motor-impairing effects of alcohol was also examined. Sleep-restricted mice were significantly less sensitive to alcohol when tested 24 h after sleep restriction, an effect that persisted for 4 weeks. Intracerebroventricular infusion of an adenosine A1 receptor antagonist produced a similar decrease in sensitivity to alcohol. These results suggest that chronic sleep restriction induces a sustained impairment in adenosine-regulated sleep homeostasis and consequentially impacts the response to alcohol. PMID:24478367

  11. Cold Exposure and Sleep in the Rat: REM Sleep Homeostasis and Body Size

    PubMed Central

    Amici, Roberto; Cerri, Matteo; Ocampo-Garcés, Adrian; Baracchi, Francesca; Dentico, Daniela; Jones, Christine Ann; Luppi, Marco; Perez, Emanuele; Parmeggiani, Pier Luigi; Zamboni, Giovanni

    2008-01-01

    Study Objectives: Exposure to low ambient temperature (Ta) depresses REM sleep (REMS) occurrence. In this study, both short and long-term homeostatic aspects of REMS regulation were analyzed during cold exposure and during subsequent recovery at Ta 24°C. Design: EEG activity, hypothalamic temperature, and motor activity were studied during a 24-h exposure to Tas ranging from 10°C to −10°C and for 4 days during recovery. Setting: Laboratory of Physiological Regulation during the Wake-Sleep Cycle, Department of Human and General Physiology, Alma Mater Studiorum-University of Bologna. Subjects: 24 male albino rats. Interventions: Animals were implanted with electrodes for EEG recording and a thermistor to measure hypothalamic temperature. Measurements and Results: REMS occurrence decreased proportionally with cold exposure, but a fast compensatory REMS rebound occurred during the first day of recovery when the previous loss went beyond a “fast rebound” threshold corresponding to 22% of the daily REMS need. A slow REMS rebound apparently allowed the animals to fully restore the previous REMS loss during the following 3 days of recovery. Conclusion: Comparing the present data on rats with data from earlier studies on cats and humans, it appears that small mammals have less tolerance for REMS loss than large ones. In small mammals, this low tolerance may be responsible on a short-term basis for the shorter wake-sleep cycle, and on long-term basis, for the higher percentage of REMS that is quickly recovered following REMS deprivation. Citation: Amici R; Cerri M; Ocampo-Garcés A; Baracchi F; Dentico D; Jones CA; Luppi M; Perez E; Parmeggiani PL; Zamboni G. Cold exposure and sleep in the rat: REM sleep homeostasis and body size. SLEEP 2008;31(5):708–715. PMID:18517040

  12. The Perilipin Homologue, Lipid Storage Droplet 2, Regulates Sleep Homeostasis and Prevents Learning Impairments Following Sleep Loss

    PubMed Central

    Thimgan, Matthew S.; Suzuki, Yasuko; Seugnet, Laurent; Gottschalk, Laura; Shaw, Paul J.

    2010-01-01

    Extended periods of waking result in physiological impairments in humans, rats, and flies. Sleep homeostasis, the increase in sleep observed following sleep loss, is believed to counter the negative effects of prolonged waking by restoring vital biological processes that are degraded during sleep deprivation. Sleep homeostasis, as with other behaviors, is influenced by both genes and environment. We report here that during periods of starvation, flies remain spontaneously awake but, in contrast to sleep deprivation, do not accrue any of the negative consequences of prolonged waking. Specifically, the homeostatic response and learning impairments that are a characteristic of sleep loss are not observed following prolonged waking induced by starvation. Recently, two genes, brummer (bmm) and Lipid storage droplet 2 (Lsd2), have been shown to modulate the response to starvation. bmm mutants have excess fat and are resistant to starvation, whereas Lsd2 mutants are lean and sensitive to starvation. Thus, we hypothesized that bmm and Lsd2 may play a role in sleep regulation. Indeed, bmm mutant flies display a large homeostatic response following sleep deprivation. In contrast, Lsd2 mutant flies, which phenocopy aspects of starvation as measured by low triglyceride stores, do not exhibit a homeostatic response following sleep loss. Importantly, Lsd2 mutant flies are not learning impaired after sleep deprivation. These results provide the first genetic evidence, to our knowledge, that lipid metabolism plays an important role in regulating the homeostatic response and can protect against neuronal impairments induced by prolonged waking. PMID:20824166

  13. Sleep and the Price of Plasticity: From Synaptic and Cellular Homeostasis to Memory Consolidation and Integration

    PubMed Central

    Tononi, Giulio; Cirelli, Chiara

    2014-01-01

    Summary Sleep is universal, tightly regulated, and its loss impairs cognition. But why does the brain need to disconnect from the environment for hours every day? The synaptic homeostasis hypothesis (SHY) proposes that sleep is the price the brain pays for plasticity. During a waking episode, learning statistical regularities about the current environment requires strengthening connections throughout the brain. This increases cellular needs for energy and supplies, decreases signal-to-noise ratios, and saturates learning. During sleep, spontaneous activity renormalizes net synaptic strength and restores cellular homeostasis. Activity-dependent down-selection of synapses can also explain the benefits of sleep on memory acquisition, consolidation, and integration. This happens through the off-line, comprehensive sampling of statistical regularities incorporated in neuronal circuits over a lifetime. This review considers the rationale and evidence for SHY and points to open issues related to sleep and plasticity. PMID:24411729

  14. HYPOTHALAMIC OREXINE SYSTEM ACCELERATES REGULATION OF SLEEP HOMEOSTASIS AND SLEEP-WAKEFULNESS CYCLE RECOVERY FROM BARBITURATE ANESTHESIA-INDUCED ARTIFICIAL SLEEP.

    PubMed

    Nachkebia, N; Maglakelidze, N; Chijavadze, E; Chkhartishvili, E; Babilodze, M

    2015-12-01

    The work was aimed for the ascertainment of following question - whether Orexin-containing neurons of dorsal and lateral hypothalamus and brain Orexinergic system in general are those cellular targets which can accelerate recovery of disturbed sleep homeostasis and restoration of sleep-wakefulness cycle behavioral states from barbiturate anesthesia-induced artificial sleep. Investigation was carried out on 18 wild type white rats (weight 200-250gr). Different doses of Nembutal Sodium were used for the initiation of deep anesthesia. 30 min after barbiturate anesthesia induced artificial sleep serial electrical stimulations of dorsal or lateral hypothalamus were started. Stimulation period lasted for 1 hour with the 5 min intervals between subsequent stimulations applied by turn to the left and right side hypothalamic parts. EEG registration of cortical and hippocampal electrical activity was started 10 min after intra-peritoneal administration of Nembutal Sodium and continued continuously during 72 hour. According to obtained new evidences, serial electrical stimulations of dorsal and lateral hypothalamic Orexin-containing neurons significantly accelerate recovery of wakefulness, sleep homeostasis, disturbed because of barbiturate anesthesia induced artificial sleep and different behavioral states of sleep-wakefulness cycle. Hypothalamic Orexin-containing neurons can be considered as the cellular targets for regulating of sleep homeostasis through the acceleration of recovery of wakefulness, and SWC in general, from barbiturate anesthesia-induced deep sleep. PMID:26719553

  15. Network Homeostasis and State Dynamics of Neocortical Sleep.

    PubMed

    Watson, Brendon O; Levenstein, Daniel; Greene, J Palmer; Gelinas, Jennifer N; Buzsáki, György

    2016-05-18

    Sleep exerts many effects on mammalian forebrain networks, including homeostatic effects on both synaptic strengths and firing rates. We used large-scale recordings to examine the activity of neurons in the frontal cortex of rats and first observed that the distribution of pyramidal cell firing rates was wide and strongly skewed toward high firing rates. Moreover, neurons from different parts of that distribution were differentially modulated by sleep substates. Periods of nonREM sleep reduced the activity of high firing rate neurons and tended to upregulate firing of slow-firing neurons. By contrast, the effect of REM was to reduce firing rates across the entire rate spectrum. Microarousals, interspersed within nonREM epochs, increased firing rates of slow-firing neurons. The net result of sleep was to homogenize the firing rate distribution. These findings are at variance with current homeostatic models and provide a novel view of sleep in adjusting network excitability.

  16. Altered sleep composition after traumatic brain injury does not affect declarative sleep-dependent memory consolidation

    PubMed Central

    Mantua, Janna; Mahan, Keenan M.; Henry, Owen S.; Spencer, Rebecca M. C.

    2015-01-01

    Individuals with a history of traumatic brain injury (TBI) often report sleep disturbances, which may be caused by changes in sleep architecture or reduced sleep quality (greater time awake after sleep onset, poorer sleep efficiency, and sleep stage proportion alterations). Sleep is beneficial for memory formation, and herein we examine whether altered sleep physiology following TBI has deleterious effects on sleep-dependent declarative memory consolidation. Participants learned a list of word pairs in the morning or evening, and recall was assessed 12-h later, following an interval awake or with overnight sleep. Young adult participants (18–22 years) were assigned to one of four experimental groups: TBI Sleep (n = 14), TBI Wake (n = 12), non-TBI Sleep (n = 15), non-TBI Wake (n = 15). Each TBI participant was >1 year post-injury. Sleep physiology was measured with polysomnography. Memory consolidation was assessed by comparing change in word-pair recall over 12-h intersession intervals. The TBI group spent a significantly greater proportion of the night in SWS than the non-TBI group at the expense of NREM1. The TBI group also had marginally lower EEG delta power during SWS in the central region. Intersession changes in recall were greater for intervals with sleep than without sleep in both groups. However, despite abnormal sleep stage proportions for individuals with a TBI history, there was no difference in the intersession change in recall following sleep for the TBI and non-TBI groups. In both Sleep groups combined, there was a positive correlation between Intersession Change and the proportion of the night in NREM2 + SWS. Overall, sleep composition is altered following TBI but such deficits do not yield insufficiencies in sleep-dependent memory consolidation. PMID:26097451

  17. Sleep as spatiotemporal integration of biological processes that evolved to periodically reinforce neurodynamic and metabolic homeostasis: The 2m3d paradigm of sleep.

    PubMed

    Mader, Edward Claro; Mader, Annie Cielo Llave

    2016-08-15

    Sleep continues to perplex scientists and researchers. Despite decades of sleep research, we still lack a clear understanding of the biological functions and evolution of sleep. In this review, we will examine sleep from a functional and phylogenetic perspective and describe some important conceptual gaps in understanding sleep. Classical theories of the biology and evolution of sleep emphasize sensory activation, energy balance, and metabolic homeostasis. Advances in electrophysiology, functional neuroimaging, and neuroplasticity allow us to view sleep within the framework of neural dynamics. With this paradigm shift, we have come to realize the importance of neurodynamic homeostasis in shaping the biology of sleep. Evidently, animals sleep to achieve neurodynamic and metabolic homeostasis. We are not aware of any framework for understanding sleep where neurodynamic, metabolic, homeostatic, chronophasic, and afferent variables are all taken into account. This motivated us to propose the two-mode three-drive (2m3d) paradigm of sleep. In the 2m3d paradigm, local neurodynamic/metabolic (N/M) processes switch between two modes-m0 and m1-in response to three drives-afferent, chronophasic, and homeostatic. The spatiotemporal integration of local m0/m1 operations gives rise to the global states of sleep and wakefulness. As a framework of evolution, the 2m3d paradigm allows us to view sleep as a robust adaptive strategy that evolved so animals can periodically reinforce neurodynamic and metabolic homeostasis while remaining sensitive to their internal and external environment.

  18. Update of sleep alterations in depression

    PubMed Central

    Medina, Andrés Barrera; Lechuga, DeboraYoaly Arana; Escandón, Oscar Sánchez; Moctezuma, Javier Velázquez

    2014-01-01

    Sleep disturbances in depression are up to 70%. Patients frequently have difficulty in falling asleep, frequent awakenings during the night and non-restorative sleep. Sleep abnormalities in depression are mainly characterized by increased rapid eye movement (REM) sleep and reduced slow wave sleep. Among the mechanisms of sleep disturbances in depression are hyperactivation of the hypothalamic-pituitary-adrenal axis, CLOCK gene polymorphism and primary sleep disorders. The habenula is a structure regulating the activities of monoaminergic neurons in the brain. The hyperactivation of the habenula has also been implicated, together with sleep disturbances, in depression. The presence of depression in primary sleep disorders is common. Sleep disturbances treatment include pharmacotherapy or Cognitive Behavioral Therapy. PMID:26483922

  19. Osteopontin Deficiency Alters Biliary Homeostasis and Protects against Gallstone Formation.

    PubMed

    Lin, Jing; Shao, Wei-Qing; Chen, Zong-You; Zhu, Wen-Wei; Lu, Lu; Cai, Duan; Qin, Lun-Xiu; Jia, Hu-Liang; Lu, Ming; Chen, Jin-Hong

    2016-01-01

    The precipitation of excess biliary cholesterol as solid crystals is a prerequisite for cholesterol gallstone formation, which occurs due to disturbed biliary homeostasis. Biliary homeostasis is regulated by an elaborate network of genes in hepatocytes. If unmanaged, the cholesterol crystals will aggregate, fuse and form gallstones. We have previously observed that the levels of osteopontin (OPN) in bile and gallbladder were reduced in gallstone patients. However, the role and mechanism for hepatic OPN in cholesterol gallstone formation is undetermined. In this study, we found that the expression of hepatic OPN was increased in gallstone patients compared with gallstone-free counterparts. Then, we observed that OPN-deficient mice were less vulnerable to cholesterol gallstone formation than wild type mice. Further mechanistic studies revealed that this protective effect was associated with alterations of bile composition and was caused by the increased hepatic CYP7A1 expression and the reduced expression of hepatic SHP, ATP8B1, SR-B1 and SREBP-2. Finally, the correlations between the expression of hepatic OPN and the expression of these hepatic genes were validated in gallstone patients. Taken together, our findings reveal that hepatic OPN contributes to cholesterol gallstone formation by regulating biliary metabolism and might be developed as a therapeutic target for gallstone treatments. PMID:27484115

  20. Osteopontin Deficiency Alters Biliary Homeostasis and Protects against Gallstone Formation

    PubMed Central

    Lin, Jing; Shao, Wei-qing; Chen, Zong-you; Zhu, Wen-wei; Lu, Lu; Cai, Duan; Qin, Lun-xiu; Jia, Hu-liang; Lu, Ming; Chen, Jin-hong

    2016-01-01

    The precipitation of excess biliary cholesterol as solid crystals is a prerequisite for cholesterol gallstone formation, which occurs due to disturbed biliary homeostasis. Biliary homeostasis is regulated by an elaborate network of genes in hepatocytes. If unmanaged, the cholesterol crystals will aggregate, fuse and form gallstones. We have previously observed that the levels of osteopontin (OPN) in bile and gallbladder were reduced in gallstone patients. However, the role and mechanism for hepatic OPN in cholesterol gallstone formation is undetermined. In this study, we found that the expression of hepatic OPN was increased in gallstone patients compared with gallstone-free counterparts. Then, we observed that OPN-deficient mice were less vulnerable to cholesterol gallstone formation than wild type mice. Further mechanistic studies revealed that this protective effect was associated with alterations of bile composition and was caused by the increased hepatic CYP7A1 expression and the reduced expression of hepatic SHP, ATP8B1, SR-B1 and SREBP-2. Finally, the correlations between the expression of hepatic OPN and the expression of these hepatic genes were validated in gallstone patients. Taken together, our findings reveal that hepatic OPN contributes to cholesterol gallstone formation by regulating biliary metabolism and might be developed as a therapeutic target for gallstone treatments. PMID:27484115

  1. Astrocytic modulation of sleep homeostasis and cognitive consequences of sleep loss

    PubMed Central

    Halassa, Michael M.; Florian, Cedrick; Fellin, Tommaso; Munoz, James R.; Lee, So-Young; Abel, Ted; Haydon, Philip G.; Frank, Marcos G.

    2009-01-01

    Astrocytes modulate neuronal activity by releasing chemical transmitters via a process termed gliotransmission. The role of this process in the control of behavior is unknown. Since one outcome of SNARE-dependent gliotransmission is the regulation of extracellular adenosine and because adenosine promotes sleep, we genetically inhibited the release of gliotransmitters and asked if astrocytes play an unsuspected role in sleep regulation. Inhibiting gliotransmission attenuated the accumulation of sleep pressure, assessed by measuring the slow wave activity of the EEG during NREM sleep and prevented cognitive deficits associated with sleep loss. Since the sleep-suppressing effects of the A1 receptor antagonist CPT were prevented following inhibition of gliotransmission and because intracerebroventricular delivery of CPT to wildtype mice mimicked the transgenic phenotype we conclude that astrocytes modulate the accumulation of sleep pressure and its cognitive consequences through a pathway involving A1 receptors. PMID:19186164

  2. Daytime melatonin infusions induce sleep in pigeons without altering subsequent amounts of nocturnal sleep.

    PubMed

    Mintz, E M; Phillips, N H; Berger, R J

    1998-12-18

    Daily infusions of melatonin restore sleep suppressed by continuous bright light in pigeons. To test whether melatonin could also induce sleep in pigeons on a 12:12 h light-dark cycle (LD), pigeons received 12-h intravenous melatonin infusions during the day. Melatonin induced sleep during the day, increased EEG slow wave activity, and decreased body temperature and locomotor activity. None of these variables were altered during the night following infusions. The induction of extended daytime sleep by melatonin infusions indicates that melatonin is a principal factor in the regulation of sleep in pigeons.

  3. Relevance of the metabotropic glutamate receptor (mGluR5) in the regulation of NREM-REM sleep cycle and homeostasis: evidence from mGluR5 (-/-) mice.

    PubMed

    Ahnaou, A; Raeymaekers, L; Steckler, T; Drinkenbrug, W H I M

    2015-04-01

    Sleep is a homeostatically regulated behavior and sleep loss evokes a proportional increase in sleep time and delta slow wave activity. Glutamate and pharmacological modulation of the metabotropic glutamate receptors (mGluR) signaling have been implicated in the organization of vigilance states. Here, the role of the mGluR5 on homeostatic regulation of sleep-wake cycle and electroencephalographic (EEG) activity was examined in mGluR5 (-/-) mice. We first characterized the sleep-wake EEG phenotype in mGluR5 (-/-) and wild-type (WT) littermates mice by continuous recording for 72h of EEG, body temperature (BT) and locomotor activity (LMA). Next, we investigated the influence of sleep deprivation on the recovery sleep and EEG slow wave activity (1-4Hz) during NREM sleep to assess whether mGluR5 deletion affects the sleep homeostasis process. Like the control animals, mGluR5 (-/-) mice exhibited a clear-cut circadian sleep-wake architecture, however they showed reduced REM sleep time during the light phase with shorter REM sleep bouts and reduced state transitions in the NREM sleep-REM sleep cycle during the first and last 24h of the spontaneous 72h recording period. In addition, mGluR5 (-/-) mice had decreased slow EEG delta power during NREM sleep and enhanced LMA associated with elevated BT during the dark phase. Moreover, mGluR5 (-/-) mice exhibited reduced slow wave activity and sleep drive after sleep deprivation, indicating altered sleep homeostatic processes. The findings strongly indicate that mGluR5 is involved in shaping the stability of NREM sleep-REM sleep state transitions, NREM slow wave activity and homeostatic response to sleep loss.

  4. Hallucinations, sleep fragmentation, and altered dream phenomena in Parkinson's disease.

    PubMed

    Pappert, E J; Goetz, C G; Niederman, F G; Raman, R; Leurgans, S

    1999-01-01

    In a series of consecutively randomized outpatients who had Parkinson's disease (PD), we examined the association of three behaviors: sleep fragmentation, altered dream phenomena, and hallucinations/illusions. Using a log-linear model methodology, we tested the independence of each behavior. Sixty-two percent of the subjects had sleep fragmentation, 48% had altered dream phenomena, and 26% had hallucinations/illusions. Eighty-two percent of the patients with hallucinations/illusions experienced some form of sleep disorder. The three phenomena were not independent. The interaction between sleep fragmentation and altered dream phenomena was strongly statistically significant. Likewise, a significant interaction existed between altered dream phenomena and hallucinations/illusions. No interaction occurred between sleep fragmentation and hallucinations/illusions. Sleep fragmentation, altered dream phenomena, and hallucinations/illusions in PD should be considered distinct but often overlapping behaviors. The close association between altered dream phenomena and hallucinations suggests that therapeutic interventions aimed at diminishing dream-related activities may have a specific positive impact on hallucinatory behavior.

  5. Altered Sleep Stage Transitions of REM Sleep: A Novel and Stable Biomarker of Narcolepsy

    PubMed Central

    Liu, Yaping; Zhang, Jihui; Lam, Venny; Ho, Crover Kwok Wah; Zhou, Junying; Li, Shirley Xin; Lam, Siu Ping; Yu, Mandy Wai Man; Tang, Xiangdong; Wing, Yun-Kwok

    2015-01-01

    Objectives: To determine the diagnostic values, longitudinal stability, and HLA association of the sleep stage transitions in narcolepsy. Methods: To compare the baseline differences in the sleep stage transition to REM sleep among 35 patients with type 1 narcolepsy, 39 patients with type 2 narcolepsy, 26 unaffected relatives, and 159 non-narcoleptic sleep patient controls, followed by a reassessment at a mean duration of 37.4 months. Results: The highest prevalence of altered transition from stage non-N2/N3 to stage R in multiple sleep latency test (MSLT) and nocturnal polysomnography (NPSG) was found in patients with type 1 narcolepsy (92.0% and 57.1%), followed by patients with type 2 narcolepsy (69.4% and 12.8%), unaffected relatives (46.2% and 0%), and controls (39.3% and 1.3%). Individual sleep variables had varied sensitivity and specificity in diagnosing narcolepsy. By incorporating a combination of sleep variables, the decision tree analysis improved the sensitivity to 94.3% and 82.1% and enhanced specificity to 82.4% and 83% for the diagnosis of type 1 and type 2 narcolepsy, respectively. There was a significant association of DBQ1*0602 with the altered sleep stage transition (OR = 16.0, 95% CI: 1.7–149.8, p = 0.015). The persistence of the altered sleep stage transition in both MSLT and NPSG was high for both type 1 (90.5% and 64.7%) and type 2 narcolepsy (92.3% and 100%), respectively. Conclusions: Altered sleep stage transition is a significant and stable marker of narcolepsy, which suggests a vulnerable wake-sleep dysregulation trait in narcolepsy. Altered sleep stage transition has a significant diagnostic value in the differential diagnosis of hypersomnias, especially when combined with other diagnostic sleep variables in decision tree analysis. Citation: Liu Y, Zhang J, Lam V, Ho CK, Zhou J, Li SX, Lam SP, Yu MW, Tang X, Wing YK. Altered sleep stage transitions of REM sleep: a novel and stable biomarker of narcolepsy. J Clin Sleep Med 2015

  6. Musculoskeletal Sensitization and Sleep: Chronic Muscle Pain Fragments Sleep of Mice without Altering Its Duration

    PubMed Central

    Sutton, Blair C.; Opp, Mark R.

    2014-01-01

    Study Objectives: Musculoskeletal pain in humans is often associated with poor sleep quality. We used a model in which mechanical hypersensitivity was induced by injection of acidified saline into muscle to study the impact of musculoskeletal sensitization on sleep of mice. Design: A one month pre-clinical study was designed to determine the impact of musculoskeletal sensitization on sleep of C57BL/6J mice. Methods: We instrumented mice with telemeters to record the electroencephalogram (EEG) and body temperature. We used an established model of musculoskeletal sensitization in which mechanical hypersensitivity was induced using two unilateral injections of acidified saline (pH 4.0). The injections were given into the gastrocnemius muscle and spaced five days apart. EEG and body temperature recordings started prior to injections (baseline) and continued for three weeks after musculoskeletal sensitization was induced by the second injection. Mechanical hypersensitivity was assessed using von Frey filaments at baseline (before any injections) and on days 1, 3, 7, 14, and 21 after the second injection. Results: Mice injected with acidified saline developed bilateral mechanical hypersensitivity at the hind paws as measured by von Frey testing and as compared to control mice and baseline data. Sleep during the light period was fragmented in experimental mice injected with acidified saline, and EEG spectra altered. Musculoskeletal sensitization did not alter the duration of time spent in wakefulness, non-rapid eye movement sleep, or rapid eye movement sleep. Conclusions: Musculoskeletal sensitization in this model results in a distinct sleep phenotype in which sleep is fragmented during the light period, but the overall duration of sleep is not changed. This study suggests the consequences of musculoskeletal pain include sleep disruption, an observation that has been made in the clinical literature but has yet to be studied using preclinical models. Citation: Sutton BC

  7. Sepsis-induced alterations in sleep of rats.

    PubMed

    Baracchi, Francesca; Ingiosi, Ashley M; Raymond, Richard M; Opp, Mark R

    2011-11-01

    Sepsis is a systemic immune response to infection that may result in multiple organ failure and death. Polymicrobial infections remain a serious clinical problem, and in the hospital, sepsis is the number-one noncardiac killer. Although the central nervous system may be one of the first systems affected, relatively little effort has been made to determine the impact of sepsis on the brain. In this study, we used the cecal ligation and puncture (CLP) model to determine the extent to which sepsis alters sleep, the EEG, and brain temperature (Tbr) of rats. Sepsis increases the amount of time rats spend in non-rapid eye movement sleep (NREMS) during the dark period, but not during the light period. Rapid eye movements sleep (REMS) of septic rats is suppressed for about 24 h following CLP surgery, after which REMS increases during dark periods for at least three nights. The EEG is dramatically altered shortly after sepsis induction, as evidenced by reductions in slow-frequency components. Furthermore, sleep is fragmented, indicating that the quality of sleep is diminished. Effects on sleep, the EEG, and Tbr persist for at least 84 h after sepsis induction, the duration of our recording period. Immunohistochemical assays focused on brain stem mechanisms responsible for alterations in REMS, as little information is available concerning infection-induced suppression of this sleep stage. Our immunohistochemical data suggest that REMS suppression after sepsis onset may be mediated, in part, by the brain stem GABAergic system. This study demonstrates for the first time that sleep and EEG patterns are altered during CLP-induced sepsis. These data suggest that the EEG may serve as a biomarker for sepsis onset. These data also contribute to our knowledge of potential mechanisms, whereby infections alter sleep and other central nervous system functions.

  8. Neuronal Firing Rate Homeostasis Is Inhibited by Sleep and Promoted by Wake.

    PubMed

    Hengen, Keith B; Torrado Pacheco, Alejandro; McGregor, James N; Van Hooser, Stephen D; Turrigiano, Gina G

    2016-03-24

    Homeostatic mechanisms stabilize neural circuit function by keeping firing rates within a set-point range, but whether this process is gated by brain state is unknown. Here, we monitored firing rate homeostasis in individual visual cortical neurons in freely behaving rats as they cycled between sleep and wake states. When neuronal firing rates were perturbed by visual deprivation, they gradually returned to a precise, cell-autonomous set point during periods of active wake, with lengthening of the wake period enhancing firing rate rebound. Unexpectedly, this resetting of neuronal firing was suppressed during sleep. This raises the possibility that memory consolidation or other sleep-dependent processes are vulnerable to interference from homeostatic plasticity mechanisms. PAPERCLIP. PMID:26997481

  9. Neuronal Firing Rate Homeostasis Is Inhibited by Sleep and Promoted by Wake.

    PubMed

    Hengen, Keith B; Torrado Pacheco, Alejandro; McGregor, James N; Van Hooser, Stephen D; Turrigiano, Gina G

    2016-03-24

    Homeostatic mechanisms stabilize neural circuit function by keeping firing rates within a set-point range, but whether this process is gated by brain state is unknown. Here, we monitored firing rate homeostasis in individual visual cortical neurons in freely behaving rats as they cycled between sleep and wake states. When neuronal firing rates were perturbed by visual deprivation, they gradually returned to a precise, cell-autonomous set point during periods of active wake, with lengthening of the wake period enhancing firing rate rebound. Unexpectedly, this resetting of neuronal firing was suppressed during sleep. This raises the possibility that memory consolidation or other sleep-dependent processes are vulnerable to interference from homeostatic plasticity mechanisms. PAPERCLIP.

  10. Dopaminergic role in regulating neurophysiological markers of sleep homeostasis in humans.

    PubMed

    Holst, Sebastian C; Bersagliere, Alessia; Bachmann, Valérie; Berger, Wolfgang; Achermann, Peter; Landolt, Hans-Peter

    2014-01-01

    While dopamine affects fundamental brain processes such as movement control, emotional responses, addiction, and pain, the roles for this neurotransmitter in regulating wakefulness and sleep are incompletely understood. Genetically modified animal models with reduced dopamine clearance exhibit hypersensitivity to caffeine, reduced-responsiveness to modafinil, and increased homeostatic response to prolonged wakefulness when compared with wild-type animals. Here we studied sleep-wake regulation in humans and combined pharmacogenetic and neurophysiologic methods to analyze the effects of the 3'-UTR variable-number-tandem-repeat polymorphism of the gene (DAT1, SLC6A3) encoding dopamine transporter (DAT). Previous research demonstrated that healthy homozygous 10-repeat (10R/10R) allele carriers of this genetic variant have reduced striatal DAT protein expression when compared with 9-repeat (9R) allele carriers. Objective and subjective estimates of caffeine sensitivity were higher in 10R allele homozygotes than in carriers of the 9R allele. Moreover, caffeine and modafinil affected wakefulness-induced changes in functional bands (delta, sigma, beta) of rhythmic brain activity in wakefulness and sleep in a DAT1 genotype-dependent manner. Finally, the sleep deprivation-induced increase in well established neurophysiologic markers of sleep homeostasis, including slow-wave sleep, electroencephalographic slow-wave activity (0.5-4.5 Hz), and number of low-frequency (0.5-2.0 Hz) oscillations in non-rapid-eye-movement sleep, was significantly larger in the 10R/10R genotype than in the 9R allele carriers of DAT1. Together, the data suggest that the dopamine transporter contributes to homeostatic sleep-wake regulation in humans.

  11. Impact of sleep and sleep loss on glucose homeostasis and appetite regulation

    PubMed Central

    Knutson, Kristen L

    2007-01-01

    Synopsis Over the past 30 years there has been an increase in the prevalence of obesity and diabetes, both of which can have serious consequences for longevity and quality of life. Sleep durations may have also decreased over this time period. This chapter reviews laboratory and epidemiologic evidence for an association between sleep loss and impairments in glucose metabolism and appetite regulation, which could increase the risk of diabetes or weight gain. PMID:18516218

  12. Disturbed dreaming and sleep quality: altered sleep architecture in subjects with frequent nightmares.

    PubMed

    Simor, Péter; Horváth, Klára; Gombos, Ferenc; Takács, Krisztina P; Bódizs, Róbert

    2012-12-01

    Nightmares are intense, emotionally negative mental experiences that usually occur during late-night sleep and result in abrupt awakenings. Questionnaire-based studies have shown that nightmares are related to impaired sleep quality; however, the polysomnographic profile of nightmare subjects has been only scarcely investigated. We investigated the sleep architecture of 17 individuals with frequent nightmares and 23 control subjects based on polysomnographic recordings of a second night spent in the laboratory after an adaptation night. Nightmare subjects in comparison with control subjects were characterized by impaired sleep architecture, as reflected by reduced sleep efficiency, increased wakefulness, a reduced amount of slow wave sleep, and increased nocturnal awakenings, especially from Stage 2 sleep. While these differences were independent of the effects of waking psychopathology, nightmare subjects also exhibited longer durations of REM sleep that was mediated by heightened negative affect. Our results support that nightmares are related to altered sleep architecture, showing impaired sleep continuity and emotion-related increase in REM propensity.

  13. Sleep and Metabolism: An Overview

    PubMed Central

    Sharma, Sunil; Kavuru, Mani

    2010-01-01

    Sleep and its disorders are increasingly becoming important in our sleep deprived society. Sleep is intricately connected to various hormonal and metabolic processes in the body and is important in maintaining metabolic homeostasis. Research shows that sleep deprivation and sleep disorders may have profound metabolic and cardiovascular implications. Sleep deprivation, sleep disordered breathing, and circadian misalignment are believed to cause metabolic dysregulation through myriad pathways involving sympathetic overstimulation, hormonal imbalance, and subclinical inflammation. This paper reviews sleep and metabolism, and how sleep deprivation and sleep disorders may be altering human metabolism. PMID:20811596

  14. Increased Automaticity and Altered Temporal Preparation Following Sleep Deprivation

    PubMed Central

    Kong, Danyang; Asplund, Christopher L.; Ling, Aiqing; Chee, Michael W.L.

    2015-01-01

    participants also rely more on automatic processes. Citation: Kong D, Asplund CL, Ling A, Chee MWL. Increased automaticity and altered temporal preparation following sleep deprivation. SLEEP 2015;38(8):1219–1227. PMID:25845689

  15. Influence of serial electrical stimulations of perifornical and posterior hypothalamic orexin-containing neurons on regulation of sleep homeostasis and sleep-wakefulness cycle recovery from experimental comatose state and anesthesia-induced deep sleep.

    PubMed

    Chijavadze, E; Chkhartishvili, E; Babilodze, M; Maglakelidze, N; Nachkebia, N

    2013-11-01

    The work was aimed for the ascertainment of following question - whether Orexin-containing neurons of dorsal and lateral hypothalamic, and brain Orexinergic system in general, are those cellular targets which can speed up recovery of disturbed sleep homeostasis and accelerate restoration of sleep-wakefulness cycle phases during some pathological conditions - experimental comatose state and/or deep anesthesia-induced sleep. Study was carried out on white rats. Modeling of experimental comatose state was made by midbrain cytotoxic lesions at intra-collicular level.Animals were under artificial respiration and special care. Different doses of Sodium Ethaminal were used for deep anesthesia. 30 min after comatose state and/or deep anesthesia induced sleep serial electrical stimulations of posterior and/or perifornical hypothalamus were started. Stimulation period lasted for 1 hour with the 5 min intervals between subsequent stimulations applied by turn to the left and right side hypothalamic parts.EEG registration of cortical and hippocampal electrical activity was started immediately after experimental comatose state and deep anesthesia induced sleep and continued continuously during 72 hour. According to obtained new evidences, serial electrical stimulations of posterior and perifornical hypothalamic Orexin-containing neurons significantly accelerate recovery of sleep homeostasis, disturbed because of comatose state and/or deep anesthesia induced sleep. Speed up recovery of sleep homeostasis was manifested in acceleration of coming out from comatose state and deep anesthesia induced sleep and significant early restoration of sleep-wakefulness cycle behavioral states.

  16. Alterations in sleep architecture in response to experimental sleep curtailment are associated with signs of positive energy balance.

    PubMed

    Shechter, Ari; O'Keeffe, Majella; Roberts, Amy L; Zammit, Gary K; RoyChoudhury, Arindam; St-Onge, Marie-Pierre

    2012-11-01

    Sleep reduction is associated with increased energy intake and weight gain, though few studies have explored the relationship between sleep architecture and energy balance measures in the context of experimental sleep restriction. Fourteen males and 13 females (body mass index: 22-26 kg/m(2)) participated in a crossover sleep curtailment study. Participants were studied under two sleep conditions: short (4 h/night; 0100-0500 h) and habitual (9 h/night; 2200-0700 h), for 5 nights each. Sleep was polysomnographically recorded nightly. Outcome measures included resting metabolic rate (RMR), feelings of appetite-satiety, and ad libitum food intake. Short sleep resulted in reductions in stage 2 sleep and rapid eye movement (REM) sleep duration (P < 0.001), as well as decreased percentage of stage 2 sleep and REM sleep and increased slow wave sleep (SWS) percentage (P < 0.05). Linear mixed model analysis demonstrated a positive association between stage 2 sleep duration and RMR (P = 0.051). Inverse associations were observed between REM sleep duration and hunger (P = 0.031) and between stage 2 sleep duration and appetite for sweet (P = 0.015) and salty (P = 0.046) foods. Stage 2 sleep percentage was inversely related to energy consumed (P = 0.024). Stage 2 sleep (P = 0.005), SWS (P = 0.008), and REM sleep (P = 0.048) percentages were inversely related to fat intake, and SWS (P = 0.040) and REM sleep (P = 0.050) were inversely related to carbohydrate intake. This study demonstrates that changes in sleep architecture are associated with markers of positive energy balance and indicate a means by which exposure to short sleep duration and/or an altered sleep architecture profile may lead to excess weight gain over time.

  17. Sleep deprivation alters choice strategy without altering uncertainty or loss aversion preferences.

    PubMed

    Mullette-Gillman, O'Dhaniel A; Kurnianingsih, Yoanna A; Liu, Jean C J

    2015-01-01

    Sleep deprivation alters decision making; however, it is unclear what specific cognitive processes are modified to drive altered choices. In this manuscript, we examined how one night of total sleep deprivation (TSD) alters economic decision making. We specifically examined changes in uncertainty preferences dissociably from changes in the strategy with which participants engage with presented choice information. With high test-retest reliability, we show that TSD does not alter uncertainty preferences or loss aversion. Rather, TSD alters the information the participants rely upon to make their choices. Utilizing a choice strategy metric which contrasts the influence of maximizing and satisficing information on choice behavior, we find that TSD alters the relative reliance on maximizing information and satisficing information, in the gains domain. This alteration is the result of participants both decreasing their reliance on cognitively-complex maximizing information and a concomitant increase in the use of readily-available satisficing information. TSD did not result in a decrease in overall information use in either domain. These results show that sleep deprivation alters decision making by altering the informational strategies that participants employ, without altering their preferences.

  18. Sleep deprivation alters choice strategy without altering uncertainty or loss aversion preferences

    PubMed Central

    Mullette-Gillman, O'Dhaniel A.; Kurnianingsih, Yoanna A.; Liu, Jean C. J.

    2015-01-01

    Sleep deprivation alters decision making; however, it is unclear what specific cognitive processes are modified to drive altered choices. In this manuscript, we examined how one night of total sleep deprivation (TSD) alters economic decision making. We specifically examined changes in uncertainty preferences dissociably from changes in the strategy with which participants engage with presented choice information. With high test-retest reliability, we show that TSD does not alter uncertainty preferences or loss aversion. Rather, TSD alters the information the participants rely upon to make their choices. Utilizing a choice strategy metric which contrasts the influence of maximizing and satisficing information on choice behavior, we find that TSD alters the relative reliance on maximizing information and satisficing information, in the gains domain. This alteration is the result of participants both decreasing their reliance on cognitively-complex maximizing information and a concomitant increase in the use of readily-available satisficing information. TSD did not result in a decrease in overall information use in either domain. These results show that sleep deprivation alters decision making by altering the informational strategies that participants employ, without altering their preferences. PMID:26500479

  19. Short-term homeostasis of REM sleep assessed in an intermittent REM sleep deprivation protocol in the rat.

    PubMed

    Ocampo-Garcés, Adrián; Vivaldi, Ennio A

    2002-03-01

    An intermittent rapid eye movement (REM) sleep deprivation protocol was applied to determine whether an increase in REM sleep propensity occurs throughout an interval without REM sleep comparable with the spontaneous sleep cycle of the rat. Seven chronically implanted rats under a 12 : 12 light-dark schedule were subjected to an intermittent REM sleep deprivation protocol that started at hour 6 after lights-on and lasted for 3 h. It consisted of six instances of a 10-min REM sleep permission window alternating with a 20-min REM sleep deprivation window. REM sleep increased throughout the protocol, so that total REM sleep in the two REM sleep permission windows of the third hour became comparable with that expected in the corresponding baseline hour. Attempted REM sleep transitions were already increased in the second deprivation window. Attempted transitions to REM sleep were more frequent in the second than in the first half of any 20-min deprivation window. From one deprivation window to the next, transitions to REM sleep changed in correspondence to the amount of REM sleep in the permission window in-between. Our results suggest that: (i) REM sleep pressure increases throughout a time segment similar in duration to a spontaneous interval without REM sleep; (ii) it diminishes during REM sleep occurrence; and (iii) that drop is proportional to the intervening amount of REM sleep. These results are consistent with a homeostatic REM sleep regulatory mechanism that operates in the time scale of spontaneous sleep cycle.

  20. ABILITY OF THE MALE RAT PUBERTAL ASSAY TO DETECT ENVIRONMENTAL CHEMICALS THAT ALTER THYROID HORMONE HOMEOSTASIS

    EPA Science Inventory

    ABILITY OF THE MALE RAT PUBERTAL ASSAY TO DETECT ENVIRONMENTAL CHEMICALS THAT ALTER THYROID HORMONE HOMEOSTASIS

    Stoker, Tammy E.1; Laws, Susan C.1; Ferrell, Janet M.1; Cooper, Ralph L.1.

    Endocrinology Branch, RTD, NHEERL, ORD, U.S. EPA, RTP, NC, 27711.

    The...

  1. TRICLOSAN AND ENDOCRINE DISRUPTION: EVIDENCE FOR ALTERATIONS IN THYROID HORMONE HOMEOSTASIS.

    EPA Science Inventory

    Impact Statement: Triclosan (5-chloro-2-(2,4-dichlorophenoxy)phenol) is a chlorinated phenolic antibacterial compound found as an active ingredient in many personal care and household products. Recent studies suggest that triclosan may alter thyroid hormone (TH) homeostasis via ...

  2. Neuroendocrine alterations in the exercising human: implications for energy homeostasis.

    PubMed

    Fuqua, John S; Rogol, Alan D

    2013-07-01

    Complex mechanisms exist in the human to defend against adverse effects of negative energy balance. These include alterations of hormone secretion affecting the growth hormone/insulin-like growth factor system, the adrenal axis, and the reproductive system, particularly in females. Energy deficits are least partially offset by neuroendocrine mechanisms regulating appetite and satiety. The complex feedback mechanisms reporting peripheral fat and energy stores to the central nervous system involve secretion of the peptide hormones leptin and ghrelin, which act centrally on neurons in the arcuate nucleus and anteroventral periventricular area. In addition to appetite regulation, these hormones exert influences on spatially and functionally-related mechanisms regulating reproductive function, such as the kisspeptin-gonadotropin releasing hormone system. Negative energy balance often occurs partially as a result of strenuous and repetitive physical exercise. Exercise stress leads to increased cortisol secretion, but this action is mediated through the induced negative energy balance. In healthy adults with energy deficits, this exercise-induced stress appears to be more important than pure psychological stress in impairing reproductive function. Estrogen deficiency resulting from negative energy balance has important adverse effects on bone density as well as bone microarchitecture, and it may also adversely affect markers of cardiovascular disease. PMID:23415825

  3. Altered Lipid Homeostasis in Sertoli Cells Stressed by Mild Hyperthermia

    PubMed Central

    Vallés, Ana S.; Aveldaño, Marta I.; Furland, Natalia E.

    2014-01-01

    Spermatogenesis is known to be vulnerable to temperature. Exposures of rat testis to moderate hyperthermia result in loss of germ cells with survival of Sertoli cells (SC). Because SC provide structural and metabolic support to germ cells, our aim was to test the hypothesis that these exposures affect SC functions, thus contributing to germ cell damage. In vivo, regularly repeated exposures (one of 15 min per day, once a day during 5 days) of rat testes to 43°C led to accumulation of neutral lipids. This SC-specific lipid function took 1–2 weeks after the last of these exposures to be maximal. In cultured SC, similar daily exposures for 15 min to 43°C resulted in significant increase in triacylglycerol levels and accumulation of lipid droplets. After incubations with [3H]arachidonate, the labeling of cardiolipin decreased more than that of other lipid classes. Another specifically mitochondrial lipid metabolic function, fatty acid oxidation, also declined. These lipid changes suggested that temperature affects SC mitochondrial physiology, which was confirmed by significantly increased degrees of membrane depolarization and ROS production. This concurred with reduced expression of two SC-specific proteins, transferrin, and Wilms' Tumor 1 protein, markers of SC secretion and differentiation functions, respectively, and with an intense SC cytoskeletal perturbation, evident by loss of microtubule network (α-tubulin) and microfilament (f-actin) organization. Albeit temporary and potentially reversible, hyperthermia-induced SC structural and metabolic alterations may be long-lasting and/or extensive enough to respond for the decreased survival of the germ cells they normally foster. PMID:24690895

  4. Nuclear DISC1 regulates CRE-mediated gene transcription and sleep homeostasis in the fruit fly.

    PubMed

    Sawamura, N; Ando, T; Maruyama, Y; Fujimuro, M; Mochizuki, H; Honjo, K; Shimoda, M; Toda, H; Sawamura-Yamamoto, T; Makuch, L A; Hayashi, A; Ishizuka, K; Cascella, N G; Kamiya, A; Ishida, N; Tomoda, T; Hai, T; Furukubo-Tokunaga, K; Sawa, A

    2008-12-01

    Disrupted-in-schizophrenia-1 (DISC1) is one of major susceptibility factors for a wide range of mental illnesses, including schizophrenia, bipolar disorder, major depression and autism spectrum conditions. DISC1 is located in several subcellular domains, such as the centrosome and the nucleus, and interacts with various proteins, including NudE-like (NUDEL/NDEL1) and activating transcription factor 4 (ATF4)/CREB2. Nevertheless, a role for DISC1 in vivo remains to be elucidated. Therefore, we have generated a Drosophila model for examining normal functions of DISC1 in living organisms. DISC1 transgenic flies with preferential accumulation of exogenous human DISC1 in the nucleus display disturbance in sleep homeostasis, which has been reportedly associated with CREB signaling/CRE-mediated gene transcription. Thus, in mammalian cells, we characterized nuclear DISC1, and identified a subset of nuclear DISC1 that colocalizes with the promyelocytic leukemia (PML) bodies, a nuclear compartment for gene transcription. Furthermore, we identified three functional cis-elements that regulate the nuclear localization of DISC1. We also report that DISC1 interacts with ATF4/CREB2 and a corepressor N-CoR, modulating CRE-mediated gene transcription. PMID:18762802

  5. A human sleep homeostasis phenotype in mice expressing a primate-specific PER3 variable-number tandem-repeat coding-region polymorphism.

    PubMed

    Hasan, Sibah; van der Veen, Daan R; Winsky-Sommerer, Raphaelle; Hogben, Alexandra; Laing, Emma E; Koentgen, Frank; Dijk, Derk-Jan; Archer, Simon N

    2014-06-01

    In humans, a primate-specific variable-number tandem-repeat (VNTR) polymorphism (4 or 5 repeats 54 nt in length) in the circadian gene PER3 is associated with differences in sleep timing and homeostatic responses to sleep loss. We investigated the effects of this polymorphism on circadian rhythmicity and sleep homeostasis by introducing the polymorphism into mice and assessing circadian and sleep parameters at baseline and during and after 12 h of sleep deprivation (SD). Microarray analysis was used to measure hypothalamic and cortical gene expression. Circadian behavior and sleep were normal at baseline. The response to SD of 2 electrophysiological markers of sleep homeostasis, electroencephalography (EEG) θ power during wakefulness and δ power during sleep, were greater in the Per3(5/5) mice. During recovery, the Per3(5/5) mice fully compensated for the SD-induced deficit in δ power, but the Per3(4/4) and wild-type mice did not. Sleep homeostasis-related transcripts (e.g., Homer1, Ptgs2, and Kcna2) were differentially expressed between the humanized mice, but circadian clock genes were not. These data are in accordance with the hypothesis derived from human data that the PER3 VNTR polymorphism modifies the sleep homeostatic response without significantly influencing circadian parameters.

  6. Effects of sleep deprivation on sleep homeostasis and restoration during methadone-maintenance: a [31] P MRS brain imaging study

    PubMed Central

    Trksak, George H.; Jensen, J. Eric; Plante, David T.; Penetar, David M.; Tartarini, Wendy L.; Maywalt, Melissa A.; Brendel, Michael; Dorsey, Cynthia M.; Renshaw, Perry F.; Lukas, Scott E.

    2009-01-01

    SUMMARY Insomnia afflicts many individuals, but particularly those in chronic methadone treatment. Studies examining sleep deprivation (SD) have begun to identify sleep restoration processes involving brain bioenergetics. The technique [31]P magnetic resonance spectroscopy (MRS) can measure brain changes in the high-energy phosphates: alpha-, beta-, and gamma-nucleoside triphosphate (NTP). In the present study, 21 methadone-maintained (MM) and 16 control participants underwent baseline (BL), SD (40 wakeful hrs), recovery1 (RE1), and recovery2 (RE2) study nights. Polysomnographic sleep was recorded each night and [31]P MRS brain scanning conducted each morning using a 4T MR scanner (dual-tuned proton/phosphorus headcoil). Interestingly, increases in total sleep time (TST) and sleep efficiency index (SEI) commonly associated with RE sleep were not apparent in MM participants. Analysis of methadone treatment duration revealed that the lack of RE sleep increases in TST and SEI were primarily exhibited by short-term MM participants (methadone<12 months), while RE sleep in long-term MM (methadone>12 months) participants was more comparable to control participants. Slow wave sleep increased during RE1, but there was no difference between MM and control participants. Spectral power analysis revealed that compared to control participants; MM participants had greater delta, theta, and alpha spectral power during BL and RE sleep. [31]P MRS revealed that elevations in brain beta-NTP (a direct measure of ATP) following RE sleep were greater in MM compared to control participants. Results suggest that differences in sleep and brain chemistry during RE in MM participants may be reflective of a disruption in homeostatic sleep function. PMID:19775835

  7. Exaggerated Nighttime Sleep and Defective Sleep Homeostasis in a Drosophila Knock-In Model of Human Epilepsy

    PubMed Central

    Petruccelli, Emily; Lansdon, Patrick; Kitamoto, Toshihiro

    2015-01-01

    Despite an established link between epilepsy and sleep behavior, it remains unclear how specific epileptogenic mutations affect sleep and subsequently influence seizure susceptibility. Recently, Sun et al. (2012) created a fly knock-in model of human generalized epilepsy with febrile seizures plus (GEFS+), a wide-spectrum disorder characterized by fever-associated seizing in childhood and lifelong affliction. GEFS+ flies carry a disease-causing mutation in their voltage-gated sodium channel (VGSC) gene and display semidominant heat-induced seizing, likely due to reduced GABAergic inhibitory activity at high temperature. Here, we show that at room temperature the GEFS+ mutation dominantly modifies sleep, with mutants exhibiting rapid sleep onset at dusk and increased nighttime sleep as compared to controls. These characteristics of GEFS+ sleep were observed regardless of sex, mating status, and genetic background. GEFS+ mutant sleep phenotypes were more resistant to pharmacologic reduction of GABA transmission by carbamazepine (CBZ) than controls, and were mitigated by reducing GABAA receptor expression specifically in wake-promoting pigment dispersing factor (PDF) neurons. These findings are consistent with increased GABAergic transmission to PDF neurons being mainly responsible for the enhanced nighttime sleep of GEFS+ mutants. Additionally, analyses under other light conditions suggested that the GEFS+ mutation led to reduced buffering of behavioral responses to light on and off stimuli, which contributed to characteristic GEFS+ sleep phenotypes. We further found that GEFS+ mutants had normal circadian rhythms in free-running dark conditions. Interestingly, the mutants lacked a homeostatic rebound following mechanical sleep deprivation, and whereas deprivation treatment increased heat-induced seizure susceptibility in control flies, it unexpectedly reduced seizure activity in GEFS+ mutants. Our study has revealed the sleep architecture of a Drosophila VGSC mutant

  8. Exaggerated Nighttime Sleep and Defective Sleep Homeostasis in a Drosophila Knock-In Model of Human Epilepsy.

    PubMed

    Petruccelli, Emily; Lansdon, Patrick; Kitamoto, Toshihiro

    2015-01-01

    Despite an established link between epilepsy and sleep behavior, it remains unclear how specific epileptogenic mutations affect sleep and subsequently influence seizure susceptibility. Recently, Sun et al. (2012) created a fly knock-in model of human generalized epilepsy with febrile seizures plus (GEFS+), a wide-spectrum disorder characterized by fever-associated seizing in childhood and lifelong affliction. GEFS+ flies carry a disease-causing mutation in their voltage-gated sodium channel (VGSC) gene and display semidominant heat-induced seizing, likely due to reduced GABAergic inhibitory activity at high temperature. Here, we show that at room temperature the GEFS+ mutation dominantly modifies sleep, with mutants exhibiting rapid sleep onset at dusk and increased nighttime sleep as compared to controls. These characteristics of GEFS+ sleep were observed regardless of sex, mating status, and genetic background. GEFS+ mutant sleep phenotypes were more resistant to pharmacologic reduction of GABA transmission by carbamazepine (CBZ) than controls, and were mitigated by reducing GABAA receptor expression specifically in wake-promoting pigment dispersing factor (PDF) neurons. These findings are consistent with increased GABAergic transmission to PDF neurons being mainly responsible for the enhanced nighttime sleep of GEFS+ mutants. Additionally, analyses under other light conditions suggested that the GEFS+ mutation led to reduced buffering of behavioral responses to light on and off stimuli, which contributed to characteristic GEFS+ sleep phenotypes. We further found that GEFS+ mutants had normal circadian rhythms in free-running dark conditions. Interestingly, the mutants lacked a homeostatic rebound following mechanical sleep deprivation, and whereas deprivation treatment increased heat-induced seizure susceptibility in control flies, it unexpectedly reduced seizure activity in GEFS+ mutants. Our study has revealed the sleep architecture of a Drosophila VGSC mutant

  9. Sleep restriction alters the hypothalamic-pituitary-adrenal response to stress

    NASA Technical Reports Server (NTRS)

    Meerlo, P.; Koehl, M.; van der Borght, K.; Turek, F. W.

    2002-01-01

    Chronic sleep restriction is an increasing problem in many countries and may have many, as yet unknown, consequences for health and well being. Studies in both humans and rats suggest that sleep deprivation may activate the hypothalamic-pituitary-adrenal (HPA) axis, one of the main neuroendocrine stress systems. However, few attempts have been made to examine how sleep loss affects the HPA axis response to subsequent stressors. Furthermore, most studies applied short-lasting total sleep deprivation and not restriction of sleep over a longer period of time, as often occurs in human society. Using the rat as our model species, we investigated: (i) the HPA axis activity during and after sleep deprivation and (ii) the effect of sleep loss on the subsequent HPA response to a novel stressor. In one experiment, rats were subjected to 48 h of sleep deprivation by placing them in slowly rotating wheels. Control rats were placed in nonrotating wheels. In a second experiment, rats were subjected to an 8-day sleep restriction protocol allowing 4 h of sleep each day. To test the effects of sleep loss on subsequent stress reactivity, rats were subjected to a 30-min restraint stress. Blood samples were taken at several time points and analysed for adrenocorticotropic hormone (ACTH) and corticosterone. The results show that ACTH and corticosterone concentrations were elevated during sleep deprivation but returned to baseline within 4 h of recovery. After 1 day of sleep restriction, the ACTH and corticosterone response to restraint stress did not differ between control and sleep deprived rats. However, after 48 h of total sleep deprivation and after 8 days of restricted sleep, the ACTH response to restraint was significantly reduced whereas the corticosterone response was unaffected. These results show that sleep loss not only is a mild activator of the HPA axis itself, but also affects the subsequent response to stress. Alterations in HPA axis regulation may gradually appear under

  10. A biobehavioral framework for examining altered sleep-wake patterns in homeless women.

    PubMed

    Davis, J E; Shuler, P A

    2000-03-01

    The interactions among psychosocial and environmental stressors and the hypothalamus-pituitary-adrenal-ovarian-immune axes may provide a framework for examining altered sleep-wake patterns in women. Based on this biobehavioral framework, homeless women represent a subgroup of the female population who have many lifestyle factors that might make them vulnerable to sleep disturbances. This article presents a study designed to investigate the self-reported sleep patterns and lifestyle factors associated with the sleep of 50 homeless women, 18-44 years of age, residing in the downtown area of Los Angeles. Results indicated that almost half of the women slept six or less hours a day and had a day/night sleep pattern. A majority of the women reported restless sleep. Drinking beer, using cocaine, anxiety, depression, loneliness, and concerns about safety and money were factors significantly related to altered sleep patterns. PMID:10839059

  11. Sleep

    MedlinePlus

    ... sleep deprivation? What are sleep myths? What are sleep disorders? Can certain diseases/conditions disrupt sleep? What is ... sleep deprivation? What are sleep myths? What are sleep disorders? Can certain diseases/conditions disrupt sleep? What is ...

  12. Sleep variability in adolescence is associated with altered brain development.

    PubMed

    Telzer, Eva H; Goldenberg, Diane; Fuligni, Andrew J; Lieberman, Matthew D; Gálvan, Adriana

    2015-08-01

    Despite the known importance of sleep for brain development, and the sharp increase in poor sleep during adolescence, we know relatively little about how sleep impacts the developing brain. We present the first longitudinal study to examine how sleep during adolescence is associated with white matter integrity. We find that greater variability in sleep duration one year prior to a DTI scan is associated with lower white matter integrity above and beyond the effects of sleep duration, and variability in bedtime, whereas sleep variability a few months prior to the scan is not associated with white matter integrity. Thus, variability in sleep duration during adolescence may have long-term impairments on the developing brain. White matter integrity should be increasing during adolescence, and so sleep variability is directly at odds with normative developmental trends.

  13. Heparanase Overexpression Reduces Hepcidin Expression, Affects Iron Homeostasis and Alters the Response to Inflammation

    PubMed Central

    Asperti, Michela; Stuemler, Tanja; Poli, Maura; Gryzik, Magdalena; Lifshitz, Lena; Meyron-Holtz, Esther G.; Vlodavsky, Israel

    2016-01-01

    Hepcidin is the key regulator of systemic iron availability that acts by controlling the degradation of the iron exporter ferroportin. It is expressed mainly in the liver and regulated by iron, inflammation, erythropoiesis and hypoxia. The various agents that control its expression act mainly via the BMP6/SMAD signaling pathway. Among them are exogenous heparins, which are strong hepcidin repressors with a mechanism of action not fully understood but that may involve the competition with the structurally similar endogenous Heparan Sulfates (HS). To verify this hypothesis, we analyzed how the overexpression of heparanase, the HS degrading enzyme, modified hepcidin expression and iron homeostasis in hepatic cell lines and in transgenic mice. The results showed that transient and stable overexpression of heparanase in HepG2 cells caused a reduction of hepcidin expression and of SMAD5 phosphorylation. Interestingly, the clones showed also altered level of TfR1 and ferritin, indices of a modified iron homeostasis. The heparanase transgenic mice showed a low level of liver hepcidin, an increase of serum and liver iron with a decrease in spleen iron content. The hepcidin expression remained surprisingly low even after treatment with the inflammatory LPS. The finding that modification of HS structure mediated by heparanase overexpression affects hepcidin expression and iron homeostasis supports the hypothesis that HS participate in the mechanisms controlling hepcidin expression. PMID:27711215

  14. TCPTP-deficiency in muscle does not alter insulin signalling and glucose homeostasis

    PubMed Central

    Loh, Kim; Merry, Troy L.; Galic, Sandra; Wu, Ben J.; Watt, Matthew J.; Zhang, Sheng; Zhang, Zhong-Yin; Neel, Benjamin G.; Tiganis, Tony

    2013-01-01

    Aims/Hypothesis Insulin activates the insulin receptor (IR) protein tyrosine kinase and downstream phosphatidylinositol-3-kinase (PI3K)/Akt signalling in muscle to promote glucose uptake. The IR can serve as a substrate for the protein tyrosine phosphatases (PTP) 1B and TCPTP, which share a striking 74% sequence identity in their catalytic domains. PTP1B is a validated therapeutic target for the alleviation of insulin resistance in type 2 diabetes. PTP1B dephosphorylates the IR in liver and muscle to regulate glucose homeostasis, whereas TCPTP regulates IR signalling and gluconeogenesis in the liver. In this study we have assessed for the first time the role of TCPTP in the regulation of IR signalling in muscle. Methods We generated muscle-specific TCPTP-deficient (MCK-Cre;Ptpn2lox/lox) mice and assessed the impact on glucose homeostasis and muscle IR signalling in chow versus high fat fed mice. Results Blood glucose and insulin levels, insulin and glucose tolerances and insulininduced muscle IR activation and downstream PI3K/Akt signalling remained unaltered in chow fed MCK-Cre;Ptpn2lox/lox versus Ptpn2lox/lox mice. In addition, body weight, adiposity, energy expenditure, insulin sensitivity and glucose homeostasis were not altered in high fat fed MCK-Cre;Ptpn2lox/lox versus Ptpn2lox/lox mice. Conclusions These results indicate that TCPTP deficiency in muscle has no effect on insulin signalling and glucose homeostasis and does not prevent the development of high fat diet-induced insulin resistance. Thus, despite their high degree of sequence identity, PTP1B and TCPTP differentially contribute to IR regulation in muscle. Our results are consistent with these two highly related PTPs having distinct contributions to IR regulation in different tissues. PMID:22124607

  15. Altered Energy Homeostasis and Resistance to Diet-Induced Obesity in KRAP-Deficient Mice

    PubMed Central

    Fujimoto, Takahiro; Miyasaka, Kyoko; Koyanagi, Midori; Tsunoda, Toshiyuki; Baba, Iwai; Doi, Keiko; Ohta, Minoru; Kato, Norihiro; Sasazuki, Takehiko; Shirasawa, Senji

    2009-01-01

    Obesity and related metabolic disorders have become leading causes of adult morbidity and mortality. KRAP (Ki-ras-induced actin-interacting protein) is a cytoskeleton-associated protein and a ubiquitous protein among tissues, originally identified as a cancer-related molecule, however, its physiological roles remain unknown. Here we demonstrate that KRAP-deficient (KRAP−/−) mice show enhanced metabolic rate, decreased adiposity, improved glucose tolerance, hypoinsulinemia and hypoleptinemia. KRAP−/− mice are also protected against high-fat diet-induced obesity and insulin resistance despite of hyperphagia. Notably, glucose uptake in the brown adipose tissue (BAT) in KRAP−/− mice is enhanced in an insulin-independent manner, suggesting that BAT is involved in altered energy homeostasis in KRAP−/− mice, although UCP (Uncoupling protein) expressions are not altered. Of interest is the down-regulation of fatty acid metabolism-related molecules, including acetyl-CoA carboxylase (ACC)-1, ACC-2 and fatty acid synthase in the liver of KRAP−/− mice, which could in part account for the metabolic phenotype in KRAP−/− mice. Thus, KRAP is a novel regulator in whole-body energy homeostasis and may be a therapeutic target in obesity and related diseases. PMID:19156225

  16. Prominent pancreatic endocrinopathy and altered control of food intake disrupt energy homeostasis in prion diseases

    USGS Publications Warehouse

    Bailey, J.D.; Berardinelli, J.G.; Rocke, T.E.; Bessen, R.A.

    2008-01-01

    Prion diseases are fatal neurodegenerative diseases that can induce endocrinopathies. The basis of altered endocrine function in prion diseases is not well understood, and the purpose of this study was to investigate the spatiotemporal relationship between energy homeostasis and prion infection in hamsters inoculated with either the 139H strain of scrapie agent, which induces preclinical weight gain, or the HY strain of transmissible mink encephalopathy (TME), which induces clinical weight loss. Temporal changes in body weight, feed, and water intake were measured as well as both non-fasted and fasted concentrations of serum glucose, insulin, glucagon, ??-ketones, and leptin. In 139H scrapie-infected hamsters, polydipsia, hyperphagia, non-fasted hyperinsulinemia with hyperglycemia, and fasted hyperleptinemia were found at preclinical stages and are consistent with an anabolic syndrome that has similarities to type II diabetes mellitus and/or metabolic syndrome X. In HY TME-infected hamsters, hypodipsia, hypersecretion of glucagon (in both non-fasted and fasted states), increased fasted ??-ketones, fasted hypoglycemia, and suppressed non-fasted leptin concentrations were found while feed intake was normal. These findings suggest a severe catabolic syndrome in HY TME infection mediated by chronic increases in glucagon secretion. In both models, alterations of pancreatic endocrine function were not associated with PrPSc deposition in the pancreas. The results indicate that prominent endocrinopathy underlies alterations in body weight, pancreatic endocrine function, and intake of food. The prion-induced alterations of energy homeostasis in 139H scrapie- or HY TME-infected hamsters could occur within areas of the hypothalamus that control food satiety and/or within autonomic centers that provide neural outflow to the pancreas. ?? 2008 Society for Endocrinology.

  17. Sympathetic and Catecholaminergic Alterations in Sleep Apnea with Particular Emphasis on Children

    PubMed Central

    Hakim, Fahed; Gozal, David; Kheirandish-Gozal, Leila

    2012-01-01

    Sleep is involved in the regulation of major organ functions in the human body, and disruption of sleep potentially can elicit organ dysfunction. Obstructive sleep apnea (OSA) is the most prevalent sleep disorder of breathing in adults and children, and its manifestations reflect the interactions between intermittent hypoxia, intermittent hypercapnia, increased intra-thoracic pressure swings, and sleep fragmentation, as elicited by the episodic changes in upper airway resistance during sleep. The sympathetic nervous system is an important modulator of the cardiovascular, immune, endocrine and metabolic systems, and alterations in autonomic activity may lead to metabolic imbalance and organ dysfunction. Here we review how OSA and its constitutive components can lead to perturbation of the autonomic nervous system in general, and to altered regulation of catecholamines, both of which then playing an important role in some of the mechanisms underlying OSA-induced morbidities. PMID:22319509

  18. Altered sleep latency and arousal regulation in mice lacking norepinephrine.

    PubMed

    Hunsley, Melissa S; Palmiter, Richard D

    2004-08-01

    Latency to sleep and the amount of sensory stimulation required to awaken an animal are measures of arousal threshold, which are ultimately modulated by an arousal regulation system involving many brain areas. Among these brain areas and network connections are wake-promoting nuclei of the brainstem and their corresponding neurotransmitters, including norepinephrine (NE). In this study, we used mice that are unable to produce NE to study its role in regulating sleep latency after a variety of interventions, and to study arousal from sleep after sleep deprivation (SD). Sleep latency was measured after gentle awakening or after injections of saline, caffeine or modafinil. Sleep latency was also measured before and after partial restoration of NE pharmacologically. Arousal threshold was measured by recording the number of decibels of white noise required to wake each mouse from NREM sleep after 0, 3 and 3 + 3 h SD (3 h SD followed by < 2 min sleep, followed by an additional 3 h SD). Results showed that when mice were awakened without being touched, there were no differences in sleep latency between the genotypes. However, after an injection of saline, the control mice increased their sleep latency, whereas the NE-deficient mice did not. There were no group differences in sleep latency after treatment with either stimulant. The sleep latency difference between the genotypes was ameliorated by partial restoration of NE. The arousal threshold experiments revealed that significantly more noise was required to wake the NE-deficient mice after 3 and 3 + 3 h of SD. These findings show that mice lacking NE fall asleep more rapidly only after a mild stressor, such as an intraperitoneal injection. NE-deficient mice are also more difficult to wake up using audio stimulation after SD. The results presented here suggest that NE promotes wakefulness during transitions between sleep and wake under conditions involving mild stress and SD, but not under baseline circumstances.

  19. Regional cerebral blood flow alterations in obstructive sleep apnea.

    PubMed

    Yadav, Santosh K; Kumar, Rajesh; Macey, Paul M; Richardson, Heidi L; Wang, Danny J J; Woo, Mary A; Harper, Ronald M

    2013-10-25

    Obstructive sleep apnea (OSA) is a condition characterized by upper airway muscle atonia with continued diaphragmatic efforts, resulting in repeated airway obstructions, periods of intermittent hypoxia, large thoracic pressure changes, and substantial shifts in arterial pressure with breathing cessation and resumption. The hypoxic exposure and hemodynamic changes likely induce the structural and functional deficits found in multiple brain areas, as shown by magnetic resonance imaging (MRI) procedures. Altered cerebral blood flow (CBF) may contribute to these localized deficits; thus, we examined regional CBF, using arterial spin labeling procedures, in 11 OSA (age, 49.1±12.2 years; 7 male) and 16 control subjects (42.3±10.2 years; 6 male) with a 3.0-Tesla MRI scanner. CBF maps were calculated, normalized to a common space, and regional CBF values across the brain quantified. Lowered CBF values emerged near multiple bilateral brain sites in OSA, including the corticospinal tracts, superior cerebellar peduncles, and pontocerebellar fibers. Lateralized, decreased CBF appeared near the left inferior cerebellar peduncles, left tapetum, left dorsal fornix/stria terminalis, right medial lemniscus, right red nucleus, right midbrain, and midline pons. Regional CBF values in OSA are significantly reduced in major sensory and motor fiber systems and motor regulatory sites, especially in structures mediating motor coordination; those reductions are often lateralized. The asymmetric CBF declines in motor regulatory areas may contribute to loss of coordination between upper airway and diaphragmatic musculature, and lead to further damage in the syndrome.

  20. Analysis of the QTL for sleep homeostasis in mice: Homer1a is a likely candidate.

    PubMed

    Mackiewicz, M; Paigen, B; Naidoo, N; Pack, A I

    2008-03-14

    Electroencephalographic oscillations in the frequency range of 0.5-4 Hz, characteristic of slow-wave sleep (SWS), are often referred to as the delta oscillation or delta power. Delta power reflects sleep intensity and correlates with the homeostatic response to sleep loss. A published survey of inbred strains of mice demonstrated that the time course of accumulation of delta power varied among inbred strains, and the segregation of the rebound of delta power in BxD recombinant inbred strains identified a genomic region on chromosome 13 referred to as the delta power in SWS (or Dps1). The quantitative trait locus (QTL) contains genes that modify the accumulation of delta power after sleep deprivation. Here, we narrow the QTL using interval-specific haplotype analysis and present a comprehensive annotation of the remaining genes in the Dps1 region with sequence comparisons to identify polymorphisms within the coding and regulatory regions. We established the expression pattern of selected genes located in the Dps1 interval in sleep and wakefulness in B6 and D2 parental strains. Taken together, these steps reduced the number of potential candidate genes that may underlie the accumulation of delta power after sleep deprivation and explain the Dps1 QTL. The strongest candidate gene is Homer1a, which is supported by expression differences between sleep and wakefulness and the SNP polymorphism in the upstream regulatory regions.

  1. Loss of p53 causes mitochondrial DNA depletion and altered mitochondrial reactive oxygen species homeostasis

    PubMed Central

    Lebedeva, Maria A.; Eaton, Jana S.; Shadel, Gerald S.

    2009-01-01

    In addition to its central role in cellular stress signaling, the tumor suppressor p53 modulates mitochondrial respiration through its nuclear transcription factor activity and localizes to mitochondria where it enhances apoptosis and suppresses mitochondrial DNA (mtDNA) mutagenesis. Here we demonstrate a new conserved role for p53 in mtDNA copy number maintenance and mitochondrial reactive oxygen species (ROS) homeostasis. In mammals, mtDNA is present in thousands of copies per cell and is essential for normal development and cell function. We show that p53 null mouse and p53 knock-down human primary fibroblasts exhibit mtDNA depletion and decreased mitochondrial mass under normal culture growth conditions. This is accompanied by a reduction of the p53R2 subunit of ribonucleotide reductase mRNA and protein and of mitochondrial transcription factor A (mtTFA) at the protein level only. Finally, p53-depleted cells exhibit significant disruption of cellular ROS homeostasis, characterized by reduced mitochondrial and cellular superoxide levels and increased cellular hydrogen peroxide. Altogether, these results elucidate additional mitochondria-related functions for p53 and implicate mtDNA depletion and ROS alterations as potentially relevant to cellular transformation, cancer cell phenotypes, and the Warburg Effect. PMID:19413947

  2. Altered potassium homeostasis in cirrhosis of the liver and Crohn's disease

    SciTech Connect

    Schober, O.; Bossaller, C.

    1984-01-01

    In the course of patients (pts) with cirrhosis of the liver (Ci) and Crohn's disease (CD) frequently noticed arrhythmias of the heart, weakness and adynamic ileus suggest alterations in the potassium (K) homeostasis. It is the purpose of the study to assess the role of Na/sup +/-K/sup +/ pump mechanism in intracellular and extracellular K homeostasis. Relative total body potassium (TBK), serum potassium (K-S), and the number of red blood cell ouabain binding sites (n-ATPase) was studied in 21 pts with Ci, 31 pts with CD and in 31 controls (C), all were not on digitalis. TBK was measured by equilibrium binding of H-3-ouabain. A significant reduction in TBK was accompanied by normal serum potassium levels, whereas the number of Na-K pumps is increased. The results support the suggestion that changes in TBK may regulate the synthesis of Na-K pump molecules. Secondary hyperaldosteronism and diarrhea e.g. may be responsible for chronic potassium depletion. The need for a nutritional support is discussed.

  3. Sleep Deprivation Reveals Altered Brain Perfusion Patterns in Somnambulism

    PubMed Central

    Dang-Vu, Thien Thanh; Zadra, Antonio; Labelle, Marc-Antoine; Petit, Dominique; Soucy, Jean-Paul; Montplaisir, Jacques

    2015-01-01

    Background Despite its high prevalence, relatively little is known about the pathophysiology of somnambulism. Increasing evidence indicates that somnambulism is associated with functional abnormalities during wakefulness and that sleep deprivation constitutes an important drive that facilitates sleepwalking in predisposed patients. Here, we studied the neural mechanisms associated with somnambulism using Single Photon Emission Computed Tomography (SPECT) with 99mTc-Ethylene Cysteinate Dimer (ECD), during wakefulness and after sleep deprivation. Methods Ten adult sleepwalkers and twelve controls with normal sleep were scanned using 99mTc-ECD SPECT in morning wakefulness after a full night of sleep. Eight of the sleepwalkers and nine of the controls were also scanned during wakefulness after a night of total sleep deprivation. Between-group comparisons of regional cerebral blood flow (rCBF) were performed to characterize brain activity patterns during wakefulness in sleepwalkers. Results During wakefulness following a night of total sleep deprivation, rCBF was decreased bilaterally in the inferior temporal gyrus in sleepwalkers compared to controls. Conclusions Functional neural abnormalities can be observed during wakefulness in somnambulism, particularly after sleep deprivation and in the inferior temporal cortex. Sleep deprivation thus not only facilitates the occurrence of sleepwalking episodes, but also uncovers patterns of neural dysfunction that characterize sleepwalkers during wakefulness. PMID:26241047

  4. Altered brain iron homeostasis and dopaminergic function in Restless Legs Syndrome (Willis-Ekbom Disease).

    PubMed

    Earley, Christopher J; Connor, James; Garcia-Borreguero, Diego; Jenner, Peter; Winkelman, John; Zee, Phyllis C; Allen, Richard

    2014-11-01

    Restless legs syndrome (RLS), also known as Willis-Ekbom Disease (WED), is a sensorimotor disorder for which the exact pathophysiology remains unclear. Brain iron insufficiency and altered dopaminergic function appear to play important roles in the etiology of the disorder. This concept is based partly on extensive research studies using cerebrospinal fluid (CSF), autopsy material, and brain imaging indicating reduced regional brain iron and on the clinical efficacy of dopamine receptor agonists for alleviating RLS symptoms. Finding causal relations, linking low brain iron to altered dopaminergic function in RLS, has required however the use of animal models. These models have provided insights into how alterations in brain iron homeostasis and dopaminergic system may be involved in RLS. The results of animal models of RLS and biochemical, postmortem, and imaging studies in patients with the disease suggest that disruptions in brain iron trafficking lead to disturbances in striatal dopamine neurotransmission for at least some patients with RLS. This review examines the data supporting an iron deficiency-dopamine metabolic theory of RLS by relating the results from animal model investigations of the influence of brain iron deficiency on dopaminergic systems to data from clinical studies in patients with RLS.

  5. Alterations in calcium homeostasis and bone during actual and simulated space flight.

    PubMed

    Wronski, T J; Morey, E R

    1983-01-01

    The weightlessness experienced in space produces alterations in calcium homeostasis. Gemini, Apollo, and Skylab astronauts exhibited a negative calcium balance due primarily to hypercalciuria. In addition, the bone mineral density of the calcaneus declined by approximately 4% in Skylab crew members after 84 d of orbital flight. The negative calcium balance and loss of calcaneal bone mineral in normal adults subjected to prolonged bed rest was comparable to that observed in space. The pathogenesis of bone loss during space flight and bed rest is not well understood due to the lack of histomorphometric data. It is also uncertain whether osteoporotic changes in astronauts are corrected postflight. The observed bone loss would be reversible and of no long-term consequence if the only abnormality was an increased remodeling rate. However, altered bone cell activity would probably result in irreversible bone loss with the premature development of senile osteoporosis many years after space flight. The main skeletal defect in growing rats placed in orbit aboard Soviet Cosmos biosatellites appears to be diminished bone formation. Bone resorption was not elevated during weightlessness. Although cortical bone returned to normal postflight, the decline in trabecular bone mass was somewhat persistent. These studies established that the modeling of a growing skeleton was altered in a weightless environment, but do not necessarily imply that a remodeling imbalance occurs in adults during space flight. However, various forms of simulated space flight inhibited bone formation during both skeletal modeling and the remodeling of adult bone.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:6645871

  6. Altered Neural Responses to Sounds in Primate Primary Auditory Cortex during Slow-Wave Sleep

    PubMed Central

    Issa, Elias B.

    2011-01-01

    How sounds are processed by the brain during sleep is an important question for understanding how we perceive the sensory environment in this unique behavioral state. While human behavioral data have indicated selective impairments of sound processing during sleep, brain imaging and neurophysiology studies have reported that overall neural activity in auditory cortex during sleep is surprisingly similar to that during wakefulness. This responsiveness to external stimuli leaves open the question of how neural responses during sleep differ, if at all, from wakefulness. Using extracellular neural recordings in the primary auditory cortex of naturally sleeping common marmosets, we show that slow-wave sleep (SWS) alters neural responses in the primate auditory cortex in two specific ways. SWS reduced the sensitivity of auditory cortex such that quiet sounds elicited weak responses in SWS compared with wakefulness, while loud sounds evoked similar responses in SWS and wakefulness. Furthermore, SWS reduced the extent of sound-evoked response suppression. This pattern of alterations was not observed during rapid eye movement sleep and could not be easily explained by the presence of slow rhythms in SWS. The alteration of excitatory and inhibitory responses during SWS suggests limitations in auditory processing and provides novel insights for understanding why certain sounds are processed while others are missed during deep sleep. PMID:21414918

  7. Iron deficiency anemia in infancy is associated with altered temporal organization of sleep states in childhood.

    PubMed

    Peirano, Patricio D; Algarín, Cecilia R; Garrido, Marcelo I; Lozoff, Betsy

    2007-12-01

    The highest prevalence of iron deficiency anemia (IDA) in infancy coincides with a time of rapid changes in sleep organization. Since IDA in infancy is associated with long-lasting neurofunctional effects despite iron treatment, the normal development of sleep patterns might be affected. Night polysomnographic recordings were performed in 55 healthy 4-y-old children (former IDA = 27, nonanemic controls = 28). Both groups were followed from infancy and were similar in background characteristics. The duration of each waking episode was measured, as was the duration of each episode of nonrapid eye movement (NREM) sleep stages 1 (NREM1), 2 (NREM2), and 3-4 (SWS), and rapid eye movement (REM) sleep. The data were analyzed according to the successive thirds of the total sleep time (TST). Relative to controls, former IDA children showed: a) longer duration of REM sleep episodes in the first third and shorter in the last third; b) more REM sleep episodes in the first third and fewer in the second third; and c) shorter latency to the first REM sleep episode and shorter NREM stage 2 and SWS episodes within the first sleep cycle. The results show that early IDA is associated with long-lasting alterations in the temporal organization of sleep patterns. PMID:17957147

  8. ALTERATIONS OF FE HOMEOSTASIS IN RAT CARDIOVASCULAR DISEASE MODELS AND ITS CONTRIBUTION TO CARDIOPULMONARY TOXICITY

    EPA Science Inventory

    Introduction: Fe homeostasis can be disrupted in human cardiovascular diseases (CVD). We addressed how dysregulation of Fe homeostasis affected the pulmonary inflammation/oxidative stress response and disease progression after exposure to Libby amphibole (LA), an asbestifonn mine...

  9. Sleep disorders in Pregnancy: Glycaemic implications.

    PubMed

    Kumar, K V S Hari

    2016-09-01

    Sleep is one of the essential biorhythms of the body that helps in optimum restoration of many body functions. The sleep-wake cycle is determined by the circadian centre and is responsible for the anabolic functions in the body. Infants require about 14 to 18 hours of sleep per day, which reduces gradually to about 8 hours in adults. Urbanization and evolutionary changes have altered the sleep hygiene and shortened the sleep duration. This lead to various sleep disorders like sleep disordered breathing, insomnia and narcolepsy. Sleep disorders lead to adverse cardio-metabolic consequences, including insulin resistance and hyperglycaemia. Pregnancy poses an enormous burden on the homeostasis of the women with alteration in many physiological functions. The sleep disorders during pregnancy lead to adverse foeto-maternal outcomes with long term cardiovascular implications. In this article, I review the pathophysiology of sleep disorders during pregnancy and their glycaemic implications. PMID:27582156

  10. Sleep architecture and homeostasis in mice with partial ablation of melanin-concentrating hormone neurons.

    PubMed

    Varin, Christophe; Arthaud, Sébastien; Salvert, Denise; Gay, Nadine; Libourel, Paul-Antoine; Luppi, Pierre-Hervé; Léger, Lucienne; Fort, Patrice

    2016-02-01

    Recent reports support a key role of tuberal hypothalamic neurons secreting melanin concentrating-hormone (MCH) in the promotion of Paradoxical Sleep (PS). Controversies remain concerning their concomitant involvement in Slow-Wave Sleep (SWS). We studied the effects of their selective loss achieved by an Ataxin 3-mediated ablation strategy to decipher the contribution of MCH neurons to SWS and/or PS. Polysomnographic recordings were performed on male adult transgenic mice expressing Ataxin-3 transgene within MCH neurons (MCH(Atax)) and their wild-type littermates (MCH(WT)) bred on two genetic backgrounds (FVB/N and C57BL/6). Compared to MCH(WT) mice, MCH(Atax) mice were characterized by a significant drop in MCH mRNAs (-70%), a partial loss of MCH-immunoreactive neurons (-30%) and a marked reduction in brain density of MCH-immunoreactive fibers. Under basal condition, such MCH(Atax) mice exhibited higher PS amounts during the light period and a pronounced SWS fragmentation without any modification of SWS quantities. Moreover, SWS and PS rebounds following 4-h total sleep deprivation were quantitatively similar in MCH(Atax)vs. MCH(WT) mice. Additionally, MCH(Atax) mice were unable to consolidate SWS and increase slow-wave activity (SWA) in response to this homeostatic challenge as observed in MCH(WT) littermates. Here, we show that the partial loss of MCH neurons is sufficient to disturb the fine-tuning of sleep. Our data provided new insights into their contribution to subtle process managing SWS quality and its efficiency rather than SWS quantities, as evidenced by the deleterious impact on two powerful markers of sleep depth, i.e., SWS consolidation/fragmentation and SWA intensity under basal condition and under high sleep pressure.

  11. Protective effect of methionine supplementation on arsenic-induced alteration of glucose homeostasis.

    PubMed

    Pal, Sudipta; Chatterjee, Ajay K

    2004-05-01

    Short term exposure of arsenic produces carbohydrate depletion and hypoglycemia. Dietary deficiency of methionine causes impaired biotransformation of arsenic which has been attributed to the pathogenesis of different diseases induced by arsenic. Accordingly, the effects of methionine supplementation on the altered glucose homeostasis induced by arsenic were studied. Arsenic (as sodium arsenite) treatment (i.p) of male Wistar rats (weighing 80-100 g) at a dose of 5.55 mg kg(-1) body weight (equivalent to 35% LD50) per day for a period of 21 days caused a significant diminution in blood glucose level and fall in liver glycogen and pyruvic acid contents. The free amino acid nitrogen content of liver was elevated while that of kidney was decreased after arsenic treatment. Transaminase activities in liver and kidney were not significantly altered except that glutamate-pyruvate transaminase activity of kidney decreased significantly after arsenic treatment. Methionine supplementation reversed the above changes except decreased liver glycogen due to arsenic treatment. It may be suggested that hypoglycemia with associated decreased glycolytic activity induced by arsenic treatment at the present dose and duration can be partially counteracted by dietary methionine supplementation.

  12. Caffeine Consuming Children and Adolescents Show Altered Sleep Behavior and Deep Sleep

    PubMed Central

    Aepli, Andrina; Kurth, Salome; Tesler, Noemi; Jenni, Oskar G.; Huber, Reto

    2015-01-01

    Caffeine is the most commonly ingested psychoactive drug worldwide with increasing consumption rates among young individuals. While caffeine leads to decreased sleep quality in adults, studies investigating how caffeine consumption affects children’s and adolescents’ sleep remain scarce. We explored the effects of regular caffeine consumption on sleep behavior and the sleep electroencephalogram (EEG) in children and adolescents (10–16 years). While later habitual bedtimes (Caffeine 23:14 ± 11.4, Controls 22:17 ± 15.4) and less time in bed were found in caffeine consumers compared to the control group (Caffeine 08:10 ± 13.3, Controls 09:03 ± 16.1), morning tiredness was unaffected. Furthermore, caffeine consumers exhibited reduced sleep EEG slow-wave activity (SWA, 1–4.5 Hz) at the beginning of the night compared to controls (20% ± 9% average reduction across all electrodes and subjects). Comparable reductions were found for alpha activity (8.25–9.75 Hz). These effects, however, disappeared in the morning hours. Our findings suggest that caffeine consumption in adolescents may lead to later bedtimes and reduced SWA, a well-established marker of sleep depth. Because deep sleep is involved in recovery processes during sleep, further research is needed to understand whether a caffeine-induced loss of sleep depth interacts with neuronal network refinement processes that occur during the sensitive period of adolescent development. PMID:26501326

  13. Caffeine Consuming Children and Adolescents Show Altered Sleep Behavior and Deep Sleep.

    PubMed

    Aepli, Andrina; Kurth, Salome; Tesler, Noemi; Jenni, Oskar G; Huber, Reto

    2015-01-01

    Caffeine is the most commonly ingested psychoactive drug worldwide with increasing consumption rates among young individuals. While caffeine leads to decreased sleep quality in adults, studies investigating how caffeine consumption affects children's and adolescents' sleep remain scarce. We explored the effects of regular caffeine consumption on sleep behavior and the sleep electroencephalogram (EEG) in children and adolescents (10-16 years). While later habitual bedtimes (Caffeine 23:14 ± 11.4, Controls 22:17 ± 15.4) and less time in bed were found in caffeine consumers compared to the control group (Caffeine 08:10 ± 13.3, Controls 09:03 ± 16.1), morning tiredness was unaffected. Furthermore, caffeine consumers exhibited reduced sleep EEG slow-wave activity (SWA, 1-4.5 Hz) at the beginning of the night compared to controls (20% ± 9% average reduction across all electrodes and subjects). Comparable reductions were found for alpha activity (8.25-9.75 Hz). These effects, however, disappeared in the morning hours. Our findings suggest that caffeine consumption in adolescents may lead to later bedtimes and reduced SWA, a well-established marker of sleep depth. Because deep sleep is involved in recovery processes during sleep, further research is needed to understand whether a caffeine-induced loss of sleep depth interacts with neuronal network refinement processes that occur during the sensitive period of adolescent development. PMID:26501326

  14. Altered salience network connectivity predicts macronutrient intake after sleep deprivation

    PubMed Central

    Fang, Zhuo; Spaeth, Andrea M.; Ma, Ning; Zhu, Senhua; Hu, Siyuan; Goel, Namni; Detre, John A.; Dinges, David F.; Rao, Hengyi

    2015-01-01

    Although insufficient sleep is a well-recognized risk factor for overeating and weight gain, the neural mechanisms underlying increased caloric (particularly fat) intake after sleep deprivation remain unclear. Here we used resting-state functional magnetic resonance imaging and examined brain connectivity changes associated with macronutrient intake after one night of total sleep deprivation (TSD). Compared to the day following baseline sleep, healthy adults consumed a greater percentage of calories from fat and a lower percentage of calories from carbohydrates during the day following TSD. Subjects also exhibited increased brain connectivity in the salience network from the dorsal anterior cingulate cortex (dACC) to bilateral putamen and bilateral anterior insula (aINS) after TSD. Moreover, dACC-putamen and dACC-aINS connectivity correlated with increased fat and decreased carbohydrate intake during the day following TSD, but not during the day following baseline sleep. These findings provide a potential neural mechanism by which sleep loss leads to increased fat intake. PMID:25645575

  15. Familial Alzheimer’s disease–associated presenilin-1 alters cerebellar activity and calcium homeostasis

    PubMed Central

    Sepulveda-Falla, Diego; Barrera-Ocampo, Alvaro; Hagel, Christian; Korwitz, Anne; Vinueza-Veloz, Maria Fernanda; Zhou, Kuikui; Schonewille, Martijn; Zhou, Haibo; Velazquez-Perez, Luis; Rodriguez-Labrada, Roberto; Villegas, Andres; Ferrer, Isidro; Lopera, Francisco; Langer, Thomas; De Zeeuw, Chris I.; Glatzel, Markus

    2014-01-01

    Familial Alzheimer’s disease (FAD) is characterized by autosomal dominant heritability and early disease onset. Mutations in the gene encoding presenilin-1 (PS1) are found in approximately 80% of cases of FAD, with some of these patients presenting cerebellar damage with amyloid plaques and ataxia with unclear pathophysiology. A Colombian kindred carrying the PS1-E280A mutation is the largest known cohort of PS1-FAD patients. Here, we investigated PS1-E280A–associated cerebellar dysfunction and found that it occurs early in PS1-E208A carriers, while cerebellar signs are highly prevalent in patients with dementia. Postmortem analysis of cerebella of PS1-E280A carrier revealed greater Purkinje cell (PC) loss and more abnormal mitochondria compared with controls. In PS1-E280A tissue, ER/mitochondria tethering was impaired, Ca2+ channels IP3Rs and CACNA1A were downregulated, and Ca2+-dependent mitochondrial transport proteins MIRO1 and KIF5C were reduced. Accordingly, expression of PS1-E280A in a neuronal cell line altered ER/mitochondria tethering and transport compared with that in cells expressing wild-type PS1. In a murine model of PS1-FAD, animals exhibited mild ataxia and reduced PC simple spike activity prior to cerebellar β-amyloid deposition. Our data suggest that impaired calcium homeostasis and mitochondrial dysfunction in PS1-FAD PCs reduces their activity and contributes to motor coordination deficits prior to Aβ aggregation and dementia. We propose that PS1-E280A affects both Ca2+ homeostasis and Aβ precursor processing, leading to FAD and neurodegeneration. PMID:24569455

  16. Normal sleep homeostasis and lack of epilepsy phenotype in GABA A receptor alpha3 subunit-knockout mice.

    PubMed

    Winsky-Sommerer, R; Knapman, A; Fedele, D E; Schofield, C M; Vyazovskiy, V V; Rudolph, U; Huguenard, J R; Fritschy, J-M; Tobler, I

    2008-06-23

    Thalamo-cortical networks generate specific patterns of oscillations during distinct vigilance states and epilepsy, well characterized by electroencephalography (EEG). Oscillations depend on recurrent synaptic loops, which are controlled by GABAergic transmission. In particular, GABA A receptors containing the alpha3 subunit are expressed predominantly in cortical layer VI and thalamic reticular nucleus (nRT) and regulate the activity and firing pattern of neurons in relay nuclei. Therefore, ablation of these receptors by gene targeting might profoundly affect thalamo-cortical oscillations. Here, we investigated the role of alpha3-GABA A receptors in regulating vigilance states and seizure activity by analyzing chronic EEG recordings in alpha3 subunit-knockout (alpha3-KO) mice. The presence of postsynaptic alpha3-GABA A receptors/gephyrin clusters in the nRT and GABA A-mediated synaptic currents in acute thalamic slices was also examined. EEG spectral analysis showed no difference between genotypes during non rapid-eye movement (NREM) sleep or at waking-NREM sleep transitions. EEG power in the spindle frequency range (10-15 Hz) was significantly lower at NREM-REM sleep transitions in mutant compared with wild-type mice. Enhancement of sleep pressure by 6 h sleep deprivation did not reveal any differences in the regulation of EEG activities between genotypes. Finally, the waking EEG showed a slightly larger power in the 11-13-Hz band in alpha3-KO mice. However, neither behavior nor the waking EEG showed alterations suggestive of absence seizures. Furthermore, alpha3-KO mice did not differ in seizure susceptibility in a model of temporal lobe epilepsy. Strikingly, despite the disruption of postsynaptic gephyrin clusters, whole-cell patch clamp recordings revealed intact inhibitory synaptic transmission in the nRT of alpha3-KO mice. These findings show that the lack of alpha3-GABA(A) receptors is extensively compensated for to preserve the integrity of thalamo

  17. Altered Chondrocyte Differentiation and Extracellular Matrix Homeostasis in a Zebrafish Model for Mucolipidosis II

    PubMed Central

    Flanagan-Steet, Heather; Sias, Christina; Steet, Richard

    2009-01-01

    Mucolipidosis II (ML-II) is a pediatric disorder caused by defects in the biosynthesis of mannose 6-phosphate, the carbohydrate recognition signal responsible for targeting certain acid hydrolases to lysosomes. The mechanisms underlying the developmental defects of ML-II are largely unknown due in part to the lack of suitable animal models. To overcome these limitations, we developed a model for ML-II in zebrafish by inhibiting the expression of N-acetylglucosamine-1-phosphotransferase, the enzyme that initiates mannose 6-phosphate biosynthesis. Morphant embryos manifest craniofacial defects, impaired motility, and abnormal otolith and pectoral fin development. Decreased mannose phosphorylation of several lysosomal glycosidases was observed in morphant lysates, consistent with the reduction in phosphotransferase activity. Investigation of the craniofacial defects in the morphants uncovered striking changes in the timing and localization of both type II collagen and Sox9 expression, suggestive of an accelerated chondrocyte differentiation program. Accumulation of type II collagen was also noted within misshapen cartilage elements at later stages of development. Furthermore, we observed abnormal matrix formation and calcium deposition in morphant otoliths. Collectively, these data provide new insight into the developmental pathology of ML-II and suggest that altered production and/or homeostasis of extracellular matrix proteins are integral to the disease process. These findings highlight the potential of the zebrafish system in studying lysosomal disease pathogenesis. PMID:19834066

  18. Cohesin loss alters adult hematopoietic stem cell homeostasis, leading to myeloproliferative neoplasms

    PubMed Central

    Mullenders, Jasper; Aranda-Orgilles, Beatriz; Lhoumaud, Priscillia; Keller, Matthew; Pae, Juhee; Wang, Kun; Kayembe, Clarisse; Rocha, Pedro P.; Raviram, Ramya; Gong, Yixiao; Premsrirut, Prem K.; Tsirigos, Aristotelis; Bonneau, Richard; Skok, Jane A.; Cimmino, Luisa; Hoehn, Daniela

    2015-01-01

    The cohesin complex (consisting of Rad21, Smc1a, Smc3, and Stag2 proteins) is critically important for proper sister chromatid separation during mitosis. Mutations in the cohesin complex were recently identified in a variety of human malignancies including acute myeloid leukemia (AML). To address the potential tumor-suppressive function of cohesin in vivo, we generated a series of shRNA mouse models in which endogenous cohesin can be silenced inducibly. Notably, silencing of cohesin complex members did not have a deleterious effect on cell viability. Furthermore, knockdown of cohesin led to gain of replating capacity of mouse hematopoietic progenitor cells. However, cohesin silencing in vivo rapidly altered stem cells homeostasis and myelopoiesis. Likewise, we found widespread changes in chromatin accessibility and expression of genes involved in myelomonocytic maturation and differentiation. Finally, aged cohesin knockdown mice developed a clinical picture closely resembling myeloproliferative disorders/neoplasms (MPNs), including varying degrees of extramedullary hematopoiesis (myeloid metaplasia) and splenomegaly. Our results represent the first successful demonstration of a tumor suppressor function for the cohesin complex, while also confirming that cohesin mutations occur as an early event in leukemogenesis, facilitating the potential development of a myeloid malignancy. PMID:26438359

  19. Triphenyltin alters lipid homeostasis in females of the ramshorn snail Marisa cornuarietis.

    PubMed

    Lyssimachou, Angeliki; Navarro, Juan Carlos; Bachmann, Jean; Porte, Cinta

    2009-05-01

    Molluscs are sensitive species to the toxic effects of organotin compounds, particularly to masculinisation. Both tributyltin (TBT) and triphenyltin (TPT) have been recently shown to bind to mollusc retinoid X receptor (RXR). If RXR is involved in lipid homeostasis, exposure to TPT would have an immediate effect on endogenous lipids. To test this hypothesis, the ramshorn snail Marisa cornuarietis was exposed to environmentally relevant concentrations of TPT (30, 125, 500 ng/L as Sn) in a semi-static water regime for 7 days. Percentage of lipids and total fatty acid content decreased significantly in TPT-exposed females while the activity of peroxisomal acyl-CoA oxidase, involved in fatty acid catabolism, increased. In addition, fatty acid profiles (carbon chain length and unsaturation degree) were significantly altered in exposed females but not in males. This work highlights the ability of TPT to disrupt lipid metabolism in M. cornuarietis at environmentally realistic concentrations and the higher susceptibility of females in comparison to males.

  20. Transgenic poplar expressing the pine GS1a show alterations in nitrogen homeostasis during drought.

    PubMed

    Molina-Rueda, Juan Jesús; Kirby, Edward G

    2015-09-01

    Transgenic hybrid poplars engineered to express ectopically the heterologous pine cytosolic GS1a display a number of significant pleiotropic phenotypes including enhanced growth, enhanced nitrogen use efficiency, and resistance to drought stress. The present study was undertaken in order to assess mechanisms whereby ectopic expression of pine GS1a in transgenic poplars results in enhanced agronomic phenotypes. Microarray analysis using the Agilent Populus whole genome array has allowed identification of genes differentially expressed between wild type (WT) and GS transgenics in four tissues (sink leaves, source leaves, stems, and roots) under three growth conditions (well-watered, drought, and recovery). Analysis revealed that differentially expressed genes in functional categories related to nitrogen metabolism show a trend of significant down-regulation in GS poplars compared to the WT, including genes encoding nitrate and nitrite reductases. The down-regulation of these genes was verified using qPCR, and downstream effects were further tested using NR activity assays. Results suggest that higher glutamine levels in GS transgenics regulate nitrate uptake and reduction. Transcript levels of nitrogen-related genes in leaves, including GS/GOGAT cycle enzymes, aspartate aminotransferase, GABA shunt enzymes, photorespiration enzymes, asparagine synthetase, phenylalanine ammonia lyase, isocitrate dehydrogenase, and PII, were also assessed using qPCR revealing significant differences between GS poplars and the WT. Moreover, metabolites related to these differentially expressed genes showed alterations in levels, including higher levels of GABA, hydroxyproline, and putrescine in the GS transgenic. These alterations in nitrogen homeostasis offer insights into mechanisms accounting for drought tolerance observed in GS poplars. PMID:26113157

  1. Transgenic poplar expressing the pine GS1a show alterations in nitrogen homeostasis during drought.

    PubMed

    Molina-Rueda, Juan Jesús; Kirby, Edward G

    2015-09-01

    Transgenic hybrid poplars engineered to express ectopically the heterologous pine cytosolic GS1a display a number of significant pleiotropic phenotypes including enhanced growth, enhanced nitrogen use efficiency, and resistance to drought stress. The present study was undertaken in order to assess mechanisms whereby ectopic expression of pine GS1a in transgenic poplars results in enhanced agronomic phenotypes. Microarray analysis using the Agilent Populus whole genome array has allowed identification of genes differentially expressed between wild type (WT) and GS transgenics in four tissues (sink leaves, source leaves, stems, and roots) under three growth conditions (well-watered, drought, and recovery). Analysis revealed that differentially expressed genes in functional categories related to nitrogen metabolism show a trend of significant down-regulation in GS poplars compared to the WT, including genes encoding nitrate and nitrite reductases. The down-regulation of these genes was verified using qPCR, and downstream effects were further tested using NR activity assays. Results suggest that higher glutamine levels in GS transgenics regulate nitrate uptake and reduction. Transcript levels of nitrogen-related genes in leaves, including GS/GOGAT cycle enzymes, aspartate aminotransferase, GABA shunt enzymes, photorespiration enzymes, asparagine synthetase, phenylalanine ammonia lyase, isocitrate dehydrogenase, and PII, were also assessed using qPCR revealing significant differences between GS poplars and the WT. Moreover, metabolites related to these differentially expressed genes showed alterations in levels, including higher levels of GABA, hydroxyproline, and putrescine in the GS transgenic. These alterations in nitrogen homeostasis offer insights into mechanisms accounting for drought tolerance observed in GS poplars.

  2. Alteration of Homeostasis in Pre-osteoclasts Induced by Aggregatibacter actinomycetemcomitans CDT

    PubMed Central

    Kawamoto, Dione; Ando-Suguimoto, Ellen S.; Bueno-Silva, Bruno; DiRienzo, Joseph M.; Mayer, Marcia P. A.

    2016-01-01

    The dysbiotic microbiota associated with aggressive periodontitis includes Aggregatibacter actinomycetemcomitans, the only oral species known to produce a cytolethal distending toxin (AaCDT). Give that CDT alters the cytokine profile in monocytic cells, we aimed to test the hypothesis that CDT plays a role in bone homeostasis by affecting the differentiation of precursor cells into osteoclasts. Recombinant AaCDT was added to murine bone marrow monocytes (BMMC) in the presence or absence of RANKL and the cell viability and cytokine profile of osteoclast precursor cells were determined. Multinucleated TRAP+ cell numbers, and relative transcription of genes related to osteoclastogenesis were also evaluated. The addition of AaCDT did not lead to loss in cell viability but promoted an increase in the average number of TRAP+ cells with 1-2 nuclei in the absence or presence of RANKL (Tukey, p < 0.05). This increase was also observed for TRAP+ cells with ≥3nuclei, although this difference was not significant. Levels of TGF-β, TNF-α, and IL-6, in the supernatant fraction of cells, were higher when in AaCDT exposed cells, whereas levels of IL-1β and IL-10 were lower than controls under the same conditions. After interaction with AaCDT, transcription of the rank (encoding the receptor RANK), nfatc1 (transcription factor), and ctpK (encoding cathepsin K) genes was downregulated in pre-osteoclastic cells. The data indicated that despite the presence of RANKL and M-CSF, AaCDT may inhibit osteoclast differentiation by altering cytokine profiles and repressing transcription of genes involved in osteoclastogenesis. Therefore, the CDT may impair host defense mechanisms in periodontitis. PMID:27064424

  3. Disturbed Dreaming and the Instability of Sleep: Altered Nonrapid Eye Movement Sleep Microstructure in Individuals with Frequent Nightmares as Revealed by the Cyclic Alternating Pattern

    PubMed Central

    Simor, Péter; Bódizs, Róbert; Horváth, Klára; Ferri, Raffaele

    2013-01-01

    Study Objectives: Nightmares are disturbing mental experiences during sleep that usually result in abrupt awakenings. Frequent nightmares are associated with poor subjective sleep quality, and recent polysomnographic data suggest that nightmare sufferers exhibit impaired sleep continuity during nonrapid eye movement (NREM) sleep. Because disrupted sleep might be related to abnormal arousal processes, the goal of this study was to examine polysomnographic arousal-related activities in a group of nightmare sufferers and a healthy control group. Design: Sleep microstructure analysis was carried out by scoring the cyclic alternating pattern (CAP) in NREM sleep and the arousal index in rapid eye movement (REM) sleep on the second night of the polysomnographic examination. Setting: Hospital-based sleep research laboratory. Participants: There were 17 in the nightmare (NMs) group and 23 in the healthy control (CTLs) group. Interventions: N/A. Measurements and Results: The NMs group exhibited reduced amounts of CAP A1 subtype and increased CAP A2 and A3 subtypes, as well as longer duration of CAP A phases in comparison with CTLs. Moreover, these differences remained significant after controlling for the confounding factors of anxious and depressive symptoms. The absolute number and frequency of REM arousals did not differ significantly between the two groups. Conclusions: The results of our study indicate that NREM sleep microstructure is altered during nonsymptomatic nights of nightmares. Disrupted sleep in the NMs group seems to be related to abnormal arousal processes, specifically an imbalance in sleep-promoting and arousing mechanisms during sleep. Citation: Simor P; Bódizs R; Horváth K; Ferri R. Disturbed dreaming and the instability of sleep: altered nonrapid eye movement sleep microstructure in individuals with frequent nightmares as revealed by the cyclic alternating pattern. SLEEP 2013;36(3):413-419. PMID:23449753

  4. Abdominal Fat and Sarcopenia in Women Significantly Alter Osteoblasts Homeostasis In Vitro by a WNT/β-Catenin Dependent Mechanism

    PubMed Central

    Wannenes, Francesca; Papa, Vincenza; Greco, Emanuela A.; Fornari, Rachele; Marocco, Chiara; Di Luigi, Luigi; Donini, Lorenzo M.; Lenzi, Andrea

    2014-01-01

    Obesity and sarcopenia have been associated with mineral metabolism derangement and low bone mineral density (BMD). We investigated whether imbalance of serum factors in obese or obese sarcopenic patients could affect bone cell activity in vitro. To evaluate and characterize potential cellular and molecular changes of human osteoblasts, cells were exposed to sera of four groups of patients: (1) affected by obesity with normal BMD (O), (2) affected by obesity with low BMD (OO), (3) affected by obesity and sarcopenia (OS), and (4) affected by obesity, sarcopenia, and low BMD (OOS) as compared to subjects with normal body weight and normal BMD (CTL). Patients were previously investigated and characterized for body composition, biochemical and bone turnover markers. Then, sera of different groups of patients were used to incubate human osteoblasts and evaluate potential alterations in cell homeostasis. Exposure to OO, OS, and OOS sera significantly reduced alkaline phosphatase, osteopontin, and BMP4 expression compared to cells exposed to O and CTL, indicating a detrimental effect on osteoblast differentiation. Interestingly, sera of all groups of patients induced intracellular alteration in Wnt/β-catenin molecular pathway, as demonstrated by the significant alteration of specific target genes expression and by altered β-catenin cellular compartmentalization and GSK3β phosphorylation. In conclusion our results show for the first time that sera of obese subjects with low bone mineral density and sarcopenia significantly alter osteoblasts homeostasis in vitro, indicating potential detrimental effects of trunk fat on bone formation and skeletal homeostasis. PMID:24963291

  5. Abdominal Fat and Sarcopenia in Women Significantly Alter Osteoblasts Homeostasis In Vitro by a WNT/ β -Catenin Dependent Mechanism.

    PubMed

    Wannenes, Francesca; Papa, Vincenza; Greco, Emanuela A; Fornari, Rachele; Marocco, Chiara; Baldari, Carlo; Di Luigi, Luigi; Emerenziani, Gian Pietro; Poggiogalle, Eleonora; Guidetti, Laura; Donini, Lorenzo M; Lenzi, Andrea; Migliaccio, Silvia

    2014-01-01

    Obesity and sarcopenia have been associated with mineral metabolism derangement and low bone mineral density (BMD). We investigated whether imbalance of serum factors in obese or obese sarcopenic patients could affect bone cell activity in vitro. To evaluate and characterize potential cellular and molecular changes of human osteoblasts, cells were exposed to sera of four groups of patients: (1) affected by obesity with normal BMD (O), (2) affected by obesity with low BMD (OO), (3) affected by obesity and sarcopenia (OS), and (4) affected by obesity, sarcopenia, and low BMD (OOS) as compared to subjects with normal body weight and normal BMD (CTL). Patients were previously investigated and characterized for body composition, biochemical and bone turnover markers. Then, sera of different groups of patients were used to incubate human osteoblasts and evaluate potential alterations in cell homeostasis. Exposure to OO, OS, and OOS sera significantly reduced alkaline phosphatase, osteopontin, and BMP4 expression compared to cells exposed to O and CTL, indicating a detrimental effect on osteoblast differentiation. Interestingly, sera of all groups of patients induced intracellular alteration in Wnt/ β -catenin molecular pathway, as demonstrated by the significant alteration of specific target genes expression and by altered β -catenin cellular compartmentalization and GSK3 β phosphorylation. In conclusion our results show for the first time that sera of obese subjects with low bone mineral density and sarcopenia significantly alter osteoblasts homeostasis in vitro, indicating potential detrimental effects of trunk fat on bone formation and skeletal homeostasis. PMID:24963291

  6. Food restriction alters the diurnal distribution of sleep in rats.

    PubMed

    Roky, R; Kapás, L; Taishi, T P; Fang, J; Krueger, J M

    1999-11-01

    The purpose of the present study was to determine the effects of restricting food and water intake to the light period on sleep and brain temperature (Tbr). Sprague-Dawley male rats were anesthetized and provided with electrodes and thermistors for electroencephalographic (EEG) and Tbr recordings. Baseline recordings were performed after a 3-week recovery period. After baseline recordings, access to food and water was restricted (FWR) to the light period for 29 days. During FWR, the diurnal distribution of rapid-eye-movement sleep (REMS) and Tbr were reversed, while the distribution of non-REMS (NREMS) between the dark and light periods was attenuated. Daily food and water intake, body weight, and the diurnal distribution of EEG slow-wave activity within NREMS remained unchanged. In a separate study, sham-operated and pinealectomized rats were studied in a similar manner. The sleep responses of pinealectomized and sham-operated rats to FWR were similar. Further, FWR did not affect melatonin levels in the sham-operated rats, thereby suggesting that the pineal gland does not mediate the effects of FWR on sleep.

  7. Sleep alterations following exposure to stress predict fear-associated memory impairments in a rodent model of PTSD.

    PubMed

    Vanderheyden, William M; George, Sophie A; Urpa, Lea; Kehoe, Michaela; Liberzon, Israel; Poe, Gina R

    2015-08-01

    Sleep abnormalities, such as insomnia, nightmares, hyper-arousal, and difficulty initiating or maintaining sleep, are diagnostic criteria of posttraumatic stress disorder (PTSD). The vivid dream state, rapid eye movement (REM) sleep, has been implicated in processing emotional memories. We have hypothesized that REM sleep is maladaptive in those suffering from PTSD. However, the precise neurobiological mechanisms regulating sleep disturbances following trauma exposure are poorly understood. Using single prolonged stress (SPS), a well-validated rodent model of PTSD, we measured sleep alterations in response to stressor exposure and over a subsequent 7-day isolation period during which the PTSD-like phenotype develops. SPS resulted in acute increases in REM sleep and transition to REM sleep, and decreased waking in addition to alterations in sleep architecture. The severity of the PTSD-like phenotype was later assessed by measuring freezing levels on a fear-associated memory test. Interestingly, the change in REM sleep following SPS was significantly correlated with freezing behavior during extinction recall assessed more than a week later. Reductions in theta (4-10 Hz) and sigma (10-15 Hz) band power during transition to REM sleep also correlated with impaired fear-associated memory processing. These data reveal that changes in REM sleep, transition to REM sleep, waking, and theta and sigma power may serve as sleep biomarkers to identify individuals with increased susceptibility to PTSD following trauma exposure. PMID:26019008

  8. Sleep Alterations Following Exposure to Stress Predict Fear-Associated Memory Impairments in a Rodent Model of PTSD

    PubMed Central

    Vanderheyden, William M.; George, Sophie A.; Urpa, Lea; Kehoe, Michaela; Liberzon, Israel; Poe, Gina R.

    2015-01-01

    Sleep abnormalities such as insomnia, nightmares, hyper-arousal, and difficulty initiating or maintaining sleep, are diagnostic criteria of post-traumatic stress disorder (PTSD). The vivid dream state, rapid eye movement (REM) sleep, has been implicated in processing emotional memories. We have hypothesized that REM sleep is maladaptive in those suffering from PTSD. However, the precise neurobiological mechanisms regulating these sleep disturbances following trauma exposure are poorly understood. Using single prolonged stress (SPS), a well-validated rodent model of PTSD, we measured sleep alterations in response to stress exposure and over a subsequent 7-day isolation period during which the PTSD-like phenotype develops in rats. SPS resulted in acutely increased REM sleep, transition to REM sleep, and decreased waking in addition to alterations in sleep architecture. The severity of the PTSD-like phenotype was later assessed by measuring freezing levels on a fear-associated memory test. Interestingly, the change in REM sleep following SPS was significantly correlated with freezing behavior during extinction recall assessed more than a week later. We also report reductions in theta (4–10 Hz) and sigma (10–15 Hz) band power during transition to REM sleep which also correlated with impaired fear-associated memory processing. These data reveal that changes in REM sleep, transition to REM sleep, waking, and theta and sigma power may serve as sleep biomarkers to identify individuals with increased susceptibility to PTSD following trauma exposure. PMID:26019008

  9. CHOLINERGIC NEURONS OF THE BASAL FOREBRAIN MEDIATE BIOCHEMICAL AND ELECTROPHYSIOLOGICAL MECHANISMS UNDERLYING SLEEP HOMEOSTASIS

    PubMed Central

    Kalinchuk, Anna V.; Porkka-Heiskanen, Tarja; McCarley, Robert W.; Basheer, Radhika

    2015-01-01

    The tight coordination of biochemical and electrophysiological mechanisms underlies the homeostatic sleep pressure (HSP) produced by sleep deprivation (SD). We have reported that during SD the levels of inducible nitric oxide synthase (iNOS), extracellular nitric oxide (NO), adenosine [AD]ex, lactate [Lac]ex and pyruvate [Pyr]ex increase in the basal forebrain (BF). However, it is not clear whether all of them contribute to HSP leading to increased electroencephalogram (EEG) delta activity during non-rapid eye movement (NREM) recovery sleep (RS) following SD. Previously, we showed that NREM delta increase evident during RS depends on the presence of BF cholinergic (ChBF) neurons. Here, we investigated the role of ChBF cells in coordination of biochemical and EEG changes seen during SD and RS in the rat. Increases in low theta power (5–7Hz), but not high theta (7–9Hz), during SD correlated with the increase in NREM delta power during RS, and with the changes in nitrate/nitrite [NOx]ex and [AD]ex. Lesions of ChBF cells using IgG 192-saporin prevented increases in [NOx]ex, [AD]ex and low theta activity, during SD, but did not prevent increases in [Lac]ex and [Pyr]ex. Infusion of NO donor DETA NONOate into the saporin-treated BF failed to increase NREM RS and delta power, suggesting ChBF cells are important for mediating NO homeostatic effects. Finally, SD-induced iNOS was mostly expressed in ChBF cells, and the intensity of iNOS induction correlated with the increase in low theta activity. Together, our data indicate ChBF cells are important in regulating the biochemical and EEG mechanisms that contribute to HSP. PMID:25369989

  10. Implications of Hydrogen Sulfide in Glucose Regulation: How H2S Can Alter Glucose Homeostasis through Metabolic Hormones.

    PubMed

    Pichette, Jennifer; Gagnon, Jeffrey

    2016-01-01

    Diabetes and its comorbidities continue to be a major health problem worldwide. Understanding the precise mechanisms that control glucose homeostasis and their dysregulation during diabetes are a major research focus. Hydrogen sulfide (H2S) has emerged as an important regulator of glucose homeostasis. This is achieved through its production and action in several metabolic and hormone producing organs including the pancreas, liver, and adipose. Of importance, H2S production and signaling in these tissues are altered during both type 1 and type 2 diabetes mellitus. This review first examines how H2S is produced both endogenously and by gastrointestinal microbes, with a particular focus on the altered production that occurs during obesity and diabetes. Next, the action of H2S on the metabolic organs with key roles in glucose homeostasis, with a particular focus on insulin, is described. Recent work has also suggested that the effects of H2S on glucose homeostasis goes beyond its role in insulin secretion. Several studies have demonstrated important roles for H2S in hepatic glucose output and adipose glucose uptake. The mechanism of H2S action on these metabolic organs is described. In the final part of this review, future directions examining the roles of H2S in other metabolic and glucoregulatory hormone secreting tissues are proposed. PMID:27478532

  11. Implications of Hydrogen Sulfide in Glucose Regulation: How H2S Can Alter Glucose Homeostasis through Metabolic Hormones

    PubMed Central

    Pichette, Jennifer

    2016-01-01

    Diabetes and its comorbidities continue to be a major health problem worldwide. Understanding the precise mechanisms that control glucose homeostasis and their dysregulation during diabetes are a major research focus. Hydrogen sulfide (H2S) has emerged as an important regulator of glucose homeostasis. This is achieved through its production and action in several metabolic and hormone producing organs including the pancreas, liver, and adipose. Of importance, H2S production and signaling in these tissues are altered during both type 1 and type 2 diabetes mellitus. This review first examines how H2S is produced both endogenously and by gastrointestinal microbes, with a particular focus on the altered production that occurs during obesity and diabetes. Next, the action of H2S on the metabolic organs with key roles in glucose homeostasis, with a particular focus on insulin, is described. Recent work has also suggested that the effects of H2S on glucose homeostasis goes beyond its role in insulin secretion. Several studies have demonstrated important roles for H2S in hepatic glucose output and adipose glucose uptake. The mechanism of H2S action on these metabolic organs is described. In the final part of this review, future directions examining the roles of H2S in other metabolic and glucoregulatory hormone secreting tissues are proposed. PMID:27478532

  12. Regulation of calpain activity in rat brain with altered Ca2+ homeostasis.

    PubMed

    Averna, Monica; Stifanese, Roberto; De Tullio, Roberta; Passalacqua, Mario; Defranchi, Enrico; Salamino, Franca; Melloni, Edon; Pontremoli, Sandro

    2007-01-26

    Activation of calpain occurs as an early event in correlation with an increase in [Ca2+]i induced in rat brain upon treatment with a high salt diet for a prolonged period of time. The resulting sequential events have been monitored in the brain of normal and hypertensive rats of the Milan strain, diverging for a constitutive alteration in the level of [Ca2+]i found to be present in nerve cells of hypertensive animals. After 2 weeks of treatment, the levels of the plasma membrane Ca2+-ATPase and of native calpastatin are profoundly decreased. These degradative processes, more pronounced in the brain of hypertensive rats, are progressively and efficiently compensated in the brain of both rat strains by different incoming mechanisms. Along with calpastatin degradation, 15-kDa still-active inhibitory fragments are accumulated, capable of efficiently replacing the loss of native inhibitor molecules. A partial return to a more efficient control of Ca2+ homeostasis occurs in parallel, assured by an early increase in the expression of Ca2+-ATPase and of calpastatin, both producing, after 12 weeks of a high salt (sodium) diet, the restoration of almost original levels of the Ca2+ pump and of significant amounts of native inhibitor molecules. Thus, conservative calpastatin fragmentation, associated with an increased expression of Ca2+-ATPase and of the calpain natural inhibitor, has been demonstrated to occur in vivo in rat brain. This represents a sequential adaptive response capable of overcoming the effects of calpain activation induced by a moderate long term elevation of [Ca2+]i.

  13. Altered clot microstructure detected in obstructive sleep apnoea hypopnoea syndrome

    PubMed Central

    D׳Silva, Lindsay; Wilczynska, Maria; Lewis, Keir; Lawrence, Matthew; Hawkins, Karl; Williams, Rhodri; Stanford, Sophia; Davidson, Simon; Morris, Keith; Evans, Adrian

    2016-01-01

    Abnormal clot microstructure plays a pivotal role in the pathophysiology of thromboembolic diseases. Assessing the viscoelastic properties of clot microstructure using novel parameters, Time to Gel Point (TGP), Fractal Dimension (df) and clot elasticity (G׳GP) could explain the increased cardiovascular and thromboembolic events in patients with Obstructive Sleep Apnoea Hypopnea Syndrome (OSAHS). We wanted to compare TGP, df, and G׳GP and their diurnal variation in OSAHS and symptomatic comparators. thirty six patients attending a sleep disturbed breathing clinic with symptoms of OSAHS were recruited. TGP, df and G׳GP were measured alongside standard coagulation screening, thrombin generation assays, and platelet aggregometry at 16:00 h and immediately after an in-patient sleep study at 07:30 h. OSAHS group had significantly lower afternoon df than comparators (1.705±0.033 vs. 1.731±0.031, p<0.05). df showed diurnal variation and only in the OSAHS group, being significantly lower in the afternoon than morning (p<0.05). Diurnal changes in df correlated with 4% DR, even after controlling for BMI (r=0.37, p=0.02). The lower df in the afternoon in OSAHS suggests a partial compensatory change that may make up for other pro-clotting abnormalities/hypertension during the night. The change to the thrombotic tendency in the afternoon is biggest in severe OSAHS. df Shows promise as a new microstructural indicator for abnormal haemostasis in OSAHS. PMID:27226818

  14. Mars 520-d mission simulation reveals protracted crew hypokinesis and alterations of sleep duration and timing.

    PubMed

    Basner, Mathias; Dinges, David F; Mollicone, Daniel; Ecker, Adrian; Jones, Christopher W; Hyder, Eric C; Di Antonio, Adrian; Savelev, Igor; Kan, Kevin; Goel, Namni; Morukov, Boris V; Sutton, Jeffrey P

    2013-02-12

    The success of interplanetary human spaceflight will depend on many factors, including the behavioral activity levels, sleep, and circadian timing of crews exposed to prolonged microgravity and confinement. To address the effects of the latter, we used a high-fidelity ground simulation of a Mars mission to objectively track sleep-wake dynamics in a multinational crew of six during 520 d of confined isolation. Measurements included continuous recordings of wrist actigraphy and light exposure (4.396 million min) and weekly computer-based neurobehavioral assessments (n = 888) to identify changes in the crew's activity levels, sleep quantity and quality, sleep-wake periodicity, vigilance performance, and workload throughout the record-long 17 mo of mission confinement. Actigraphy revealed that crew sedentariness increased across the mission as evident in decreased waking movement (i.e., hypokinesis) and increased sleep and rest times. Light exposure decreased during the mission. The majority of crewmembers also experienced one or more disturbances of sleep quality, vigilance deficits, or altered sleep-wake periodicity and timing, suggesting inadequate circadian entrainment. The results point to the need to identify markers of differential vulnerability to hypokinesis and sleep-wake changes during the prolonged isolation of exploration spaceflight and the need to ensure maintenance of circadian entrainment, sleep quantity and quality, and optimal activity levels during exploration missions. Therefore, successful adaptation to such missions will require crew to transit in spacecraft and live in surface habitats that instantiate aspects of Earth's geophysical signals (appropriately timed light exposure, food intake, exercise) required for temporal organization and maintenance of human behavior.

  15. Mars 520-d mission simulation reveals protracted crew hypokinesis and alterations of sleep duration and timing.

    PubMed

    Basner, Mathias; Dinges, David F; Mollicone, Daniel; Ecker, Adrian; Jones, Christopher W; Hyder, Eric C; Di Antonio, Adrian; Savelev, Igor; Kan, Kevin; Goel, Namni; Morukov, Boris V; Sutton, Jeffrey P

    2013-02-12

    The success of interplanetary human spaceflight will depend on many factors, including the behavioral activity levels, sleep, and circadian timing of crews exposed to prolonged microgravity and confinement. To address the effects of the latter, we used a high-fidelity ground simulation of a Mars mission to objectively track sleep-wake dynamics in a multinational crew of six during 520 d of confined isolation. Measurements included continuous recordings of wrist actigraphy and light exposure (4.396 million min) and weekly computer-based neurobehavioral assessments (n = 888) to identify changes in the crew's activity levels, sleep quantity and quality, sleep-wake periodicity, vigilance performance, and workload throughout the record-long 17 mo of mission confinement. Actigraphy revealed that crew sedentariness increased across the mission as evident in decreased waking movement (i.e., hypokinesis) and increased sleep and rest times. Light exposure decreased during the mission. The majority of crewmembers also experienced one or more disturbances of sleep quality, vigilance deficits, or altered sleep-wake periodicity and timing, suggesting inadequate circadian entrainment. The results point to the need to identify markers of differential vulnerability to hypokinesis and sleep-wake changes during the prolonged isolation of exploration spaceflight and the need to ensure maintenance of circadian entrainment, sleep quantity and quality, and optimal activity levels during exploration missions. Therefore, successful adaptation to such missions will require crew to transit in spacecraft and live in surface habitats that instantiate aspects of Earth's geophysical signals (appropriately timed light exposure, food intake, exercise) required for temporal organization and maintenance of human behavior. PMID:23297197

  16. Autonomic and Renal Alterations in the Offspring of Sleep-Restricted Mothers During Late Pregnancy

    PubMed Central

    Raimundo, Joyce R S; Bergamaschi, Cassia T; Campos, Ruy R; Palma, Beatriz D; Tufik, Sergio; Gomes, Guiomar N

    2016-01-01

    OBJECTIVES: Considering that changes in the maternal environment may result in changes in progeny, the aim of this study was to investigate the influence of sleep restriction during the last week of pregnancy on renal function and autonomic responses in male descendants at an adult age. METHODS: After confirmation of pregnancy, female Wistar rats were randomly assigned to either a control or a sleep restriction group. The sleep-restricted rats were subjected to sleep restriction using the multiple platforms method for over 20 hours per day between the 14th and 20th day of pregnancy. After delivery, the litters were limited to 6 offspring that were designated as offspring from control and offspring from sleep-restricted mothers. Indirect measurements of systolic blood pressure (BPi), renal plasma flow, glomerular filtration rate, glomerular area and number of glomeruli per field were evaluated at three months of age. Direct measurements of cardiovascular function (heart rate and mean arterial pressure), cardiac sympathetic tone, cardiac parasympathetic tone, and baroreflex sensitivity were evaluated at four months of age. RESULTS: The sleep-restricted offspring presented increases in BPi, glomerular filtration rate and glomerular area compared with the control offspring. The sleep-restricted offspring also showed higher basal heart rate, increased mean arterial pressure, increased sympathetic cardiac tone, decreased parasympathetic cardiac tone and reduced baroreflex sensitivity. CONCLUSIONS: Our data suggest that reductions in sleep during the last week of pregnancy lead to alterations in cardiovascular autonomic regulation and renal morpho-functional changes in offspring, triggering increases in blood pressure. PMID:27652834

  17. Autonomic and Renal Alterations in the Offspring of Sleep-Restricted Mothers During Late Pregnancy

    PubMed Central

    Raimundo, Joyce R S; Bergamaschi, Cassia T; Campos, Ruy R; Palma, Beatriz D; Tufik, Sergio; Gomes, Guiomar N

    2016-01-01

    OBJECTIVES: Considering that changes in the maternal environment may result in changes in progeny, the aim of this study was to investigate the influence of sleep restriction during the last week of pregnancy on renal function and autonomic responses in male descendants at an adult age. METHODS: After confirmation of pregnancy, female Wistar rats were randomly assigned to either a control or a sleep restriction group. The sleep-restricted rats were subjected to sleep restriction using the multiple platforms method for over 20 hours per day between the 14th and 20th day of pregnancy. After delivery, the litters were limited to 6 offspring that were designated as offspring from control and offspring from sleep-restricted mothers. Indirect measurements of systolic blood pressure (BPi), renal plasma flow, glomerular filtration rate, glomerular area and number of glomeruli per field were evaluated at three months of age. Direct measurements of cardiovascular function (heart rate and mean arterial pressure), cardiac sympathetic tone, cardiac parasympathetic tone, and baroreflex sensitivity were evaluated at four months of age. RESULTS: The sleep-restricted offspring presented increases in BPi, glomerular filtration rate and glomerular area compared with the control offspring. The sleep-restricted offspring also showed higher basal heart rate, increased mean arterial pressure, increased sympathetic cardiac tone, decreased parasympathetic cardiac tone and reduced baroreflex sensitivity. CONCLUSIONS: Our data suggest that reductions in sleep during the last week of pregnancy lead to alterations in cardiovascular autonomic regulation and renal morpho-functional changes in offspring, triggering increases in blood pressure.

  18. Alteration of ROS homeostasis and decreased lifespan in S. cerevisiae elicited by deletion of the mitochondrial translocator FLX1.

    PubMed

    Giancaspero, Teresa Anna; Dipalo, Emilia; Miccolis, Angelica; Boles, Eckhard; Caselle, Michele; Barile, Maria

    2014-01-01

    This paper deals with the control exerted by the mitochondrial translocator FLX1, which catalyzes the movement of the redox cofactor FAD across the mitochondrial membrane, on the efficiency of ATP production, ROS homeostasis, and lifespan of S. cerevisiae. The deletion of the FLX1 gene resulted in respiration-deficient and small-colony phenotype accompanied by a significant ATP shortage and ROS unbalance in glycerol-grown cells. Moreover, the flx1Δ strain showed H2O2 hypersensitivity and decreased lifespan. The impaired biochemical phenotype found in the flx1Δ strain might be justified by an altered expression of the flavoprotein subunit of succinate dehydrogenase, a key enzyme in bioenergetics and cell regulation. A search for possible cis-acting consensus motifs in the regulatory region upstream SDH1-ORF revealed a dozen of upstream motifs that might respond to induced metabolic changes by altering the expression of Flx1p. Among these motifs, two are present in the regulatory region of genes encoding proteins involved in flavin homeostasis. This is the first evidence that the mitochondrial flavin cofactor status is involved in controlling the lifespan of yeasts, maybe by changing the cellular succinate level. This is not the only case in which the homeostasis of redox cofactors underlies complex phenotypical behaviours, as lifespan in yeasts. PMID:24895546

  19. Alteration of ROS Homeostasis and Decreased Lifespan in S. cerevisiae Elicited by Deletion of the Mitochondrial Translocator FLX1

    PubMed Central

    Giancaspero, Teresa Anna; Dipalo, Emilia; Miccolis, Angelica; Boles, Eckhard; Caselle, Michele; Barile, Maria

    2014-01-01

    This paper deals with the control exerted by the mitochondrial translocator FLX1, which catalyzes the movement of the redox cofactor FAD across the mitochondrial membrane, on the efficiency of ATP production, ROS homeostasis, and lifespan of S. cerevisiae. The deletion of the FLX1 gene resulted in respiration-deficient and small-colony phenotype accompanied by a significant ATP shortage and ROS unbalance in glycerol-grown cells. Moreover, the flx1Δ strain showed H2O2 hypersensitivity and decreased lifespan. The impaired biochemical phenotype found in the flx1Δ strain might be justified by an altered expression of the flavoprotein subunit of succinate dehydrogenase, a key enzyme in bioenergetics and cell regulation. A search for possible cis-acting consensus motifs in the regulatory region upstream SDH1-ORF revealed a dozen of upstream motifs that might respond to induced metabolic changes by altering the expression of Flx1p. Among these motifs, two are present in the regulatory region of genes encoding proteins involved in flavin homeostasis. This is the first evidence that the mitochondrial flavin cofactor status is involved in controlling the lifespan of yeasts, maybe by changing the cellular succinate level. This is not the only case in which the homeostasis of redox cofactors underlies complex phenotypical behaviours, as lifespan in yeasts. PMID:24895546

  20. Laryngeal motility alteration: A missing link between sleep apnea and vagus nerve stimulation for epilepsy.

    PubMed

    Zambrelli, Elena; Saibene, Alberto M; Furia, Francesca; Chiesa, Valentina; Vignoli, Aglaia; Pipolo, Carlotta; Felisati, Giovanni; Canevini, Maria Paola

    2016-01-01

    This study aimed to evaluate the prevalence and the relationship of sleep breathing disorders (SBDs) and laryngeal motility alterations in patients with drug-resistant epilepsy after vagus nerve stimulator (VNS) implantation. Twenty-three consecutive patients with medically refractory epilepsy underwent out-of-center sleep testing before and after VNS implantation. Eighteen eligible subjects underwent endoscopic laryngeal examination post-VNS implantation. Statistical analysis was carried out to assess an association between laryngeal motility alterations and the onset/worsening of SBDs. After VNS implantation, 11 patients showed a new-onset mild/moderate SBD. Half of the patients already affected by obstructive sleep apnea (OSA) showed worsening of SBD. All of the patients with a new-onset OSA had a laryngeal pattern with left vocal cord adduction (LVCA) during VNS stimulation. The association between VNS-induced LVCA and SBD was statistically significant. This study suggests an association between VNS and SBD, hinting to a pivotal role of laryngeal motility alterations. The relationship between SBD and VNS-induced LVCA supports the need to routinely investigate sleep respiratory and laryngeal motility patterns before and after VNS implantation.

  1. A dopamine receptor d2-type agonist attenuates the ability of stress to alter sleep in mice.

    PubMed

    Jefferson, F; Ehlen, J C; Williams, N S; Montemarano, J J; Paul, K N

    2014-11-01

    Although sleep disruptions that accompany stress reduce quality of life and deteriorate health, the mechanisms through which stress alters sleep remain obscure. Psychological stress can alter sleep in a variety of ways, but it has been shown to be particularly influential on rapid eye movement (REM) sleep. Prolactin (PRL), a sexually dimorphic, stress-sensitive hormone whose basal levels are higher in females, has somnogenic effects on REM sleep. In the current study, we examined the relationship between PRL secretion and REM sleep after restraint stress to determine whether: 1) the ability of stress to increase REM sleep is PRL-dependent, and 2) fluctuating PRL levels underlie sex differences in sleep responses to stress. Because dopamine D2 receptors in the pituitary gland are the primary regulator of PRL secretion, D2 receptor agonist, 1-[(6-allylergolin-8β-yl)-carbonyl]-1-[3-(dimethylamino) propyl]-3-ethylurea (cabergoline), was used to attenuate PRL levels in mice before 1 hour of restraint stress. Mice were implanted with electroencephalographic/electromyographic recording electrodes and received an ip injection of either 0.3-mg/kg cabergoline or vehicle before a control procedure of 1 hour of sleep deprivation by gentle handling during the light phase. Six days after the control procedure, mice received cabergoline or vehicle 15 minutes before 1 hour of restraint stress. Cabergoline blocked the ability of restraint stress to increase REM sleep amount in males but did not alter REM sleep amount after stress in females even though it reduced basal REM sleep amount in female controls. These data provide evidence that the ability for restraint stress to increase REM sleep is dependent on PRL and that sex differences in REM sleep amount may be driven by PRL.

  2. A new theoretical approach to the functional meaning of sleep and dreaming in humans based on the maintenance of 'predictive psychic homeostasis'.

    PubMed

    Agnati, Luigi F; Barlow, Peter W; Baluška, František; Tonin, Paolo; Guescini, Michele; Leo, Giuseppina; Fuxe, Kjell

    2011-11-01

    Different theories have been put forward during the last decade to explain the functional meaning of sleep and dreaming in humans. In the present paper, a new theory is presented which, while taking advantage of these earlier theories, introduces the following new and original aspects:   • Circadian rhythms relevant to various organs of the body affect the reciprocal interactions which operate to maintain constancy of the internal milieu and thereby also affect the sleep/wakefulness cycle. Particular attention is given to the constancy of natraemia and osmolarity and to the permissive role that the evolution of renal function has had for the evolution of the central nervous system and its integrative actions. • The resetting of neuro-endocrine controls at the onset of wakefulness leads to the acquisition of new information and its integration within previously stored memories. This point is dealt with in relation to Moore-Ede's proposal for the existence of a 'predictive homeostasis'. • The concept of 'psychic homeostasis' is introduced and is considered as one of the most important states since it is aimed at the well-being, or eudemonia, of the human psyche. Sleep and dreaming in humans are discussed as important functions for the maintenance of a newly proposed composite state: that of 'predictive psychic homeostasis'. On the basis of these assumptions, and in accordance with the available neurobiological data, the present paper puts forward the novel hypothesis that sleep and dreaming play important functions in humans by compensating for psychic allostatic overloads. Hence, both consolatory dreams and disturbing nightmares can be part of the vis medicatrix naturae, the natural healing power, in this case, the state of eudemonia.

  3. Larval Population Density Alters Adult Sleep in Wild-Type Drosophila melanogaster but Not in Amnesiac Mutant Flies.

    PubMed

    Chi, Michael W; Griffith, Leslie C; Vecsey, Christopher G

    2014-08-11

    Sleep has many important biological functions, but how sleep is regulated remains poorly understood. In humans, social isolation and other stressors early in life can disrupt adult sleep. In fruit flies housed at different population densities during early adulthood, social enrichment was shown to increase subsequent sleep, but it is unknown if population density during early development can also influence adult sleep. To answer this question, we maintained Drosophila larvae at a range of population densities throughout larval development, kept them isolated during early adulthood, and then tested their sleep patterns. Our findings reveal that flies that had been isolated as larvae had more fragmented sleep than those that had been raised at higher population densities. This effect was more prominent in females than in males. Larval population density did not affect sleep in female flies that were mutant for amnesiac, which has been shown to be required for normal memory consolidation, adult sleep regulation, and brain development. In contrast, larval population density effects on sleep persisted in female flies lacking the olfactory receptor or83b, suggesting that olfactory signals are not required for the effects of larval population density on adult sleep. These findings show that population density during early development can alter sleep behavior in adulthood, suggesting that genetic and/or structural changes are induced by this developmental manipulation that persist through metamorphosis.

  4. The median preoptic nucleus: front and centre for the regulation of body fluid, sodium, temperature, sleep and cardiovascular homeostasis.

    PubMed

    McKinley, M J; Yao, S T; Uschakov, A; McAllen, R M; Rundgren, M; Martelli, D

    2015-05-01

    Located in the midline anterior wall of the third cerebral ventricle (i.e. the lamina terminalis), the median preoptic nucleus (MnPO) receives a unique set of afferent neural inputs from fore-, mid- and hindbrain. These afferent connections enable it to receive neural signals related to several important aspects of homeostasis. Included in these afferent projections are (i) neural inputs from two adjacent circumventricular organs, the subfornical organ and organum vasculosum laminae terminalis, that respond to hypertonicity, circulating angiotensin II or other humoural factors, (ii) signals from cutaneous warm and cold receptors that are relayed to MnPO, respectively, via different subnuclei in the lateral parabrachial nucleus and (iii) input from the medulla associated with baroreceptor and vagal afferents. These afferent signals reach appropriate neurones within the MnPO that enable relevant neural outputs, both excitatory and inhibitory, to be activated or inhibited. The efferent neural pathways that proceed from the MnPO terminate on (i) neuroendocrine cells in the hypothalamic supraoptic and paraventricular nuclei to regulate vasopressin release, while polysynaptic pathways from MnPO to cortical sites may drive thirst and water intake, (ii) thermoregulatory pathways to the dorsomedial hypothalamic nucleus and medullary raphé to regulate shivering, brown adipose tissue and skin vasoconstriction, (iii) parvocellular neurones in the hypothalamic paraventricular nucleus that drive autonomic pathways influencing cardiovascular function. As well, (iv) other efferent pathways from the MnPO to sites in the ventrolateral pre-optic nucleus, perifornical region of the lateral hypothalamic area and midbrain influence sleep mechanisms. PMID:25753944

  5. Obesity and Altered Sleep: A Pathway to Metabolic Derangements in Children?

    PubMed Central

    Hakim, Fahed; Kheirandish-Gozal, Leila; Gozal, David

    2015-01-01

    Obstructive sleep apnea (OSA) is a frequent disorder in children and is primarily associated with adenotonsillar hypertrophy., The prominent increases in childhood overweight and obesity rates in the world even among youngest of children have translated into parallel increases in the prevalence of OSA, and such trends will undoubtedly be associated with deleterious global health outcomes and life expectancy. Even an obesity phenotype in childhood OSA, more close to the adult type, has been recently proposed. Reciprocal interactions between sleep in general, OSA, obesity, and disruptions of metabolic homeostasis have emerged in recent years. These associations have suggested the a priori involvement of complex sets of metabolic and inflammatory pathways all of which may underlie increased risk for increased orexigenic behaviors and dysfunctional satiety, hyperlipidemia, and insulin resistance that ultimately favor the emergence of metabolic syndrome. Here, we will review some of the critical evidence supporting the proposed associations between sleep disruption and the metabolism-obesity complex. In addition, we will describe the more recent evidence linking the potential interactive roles of OSA and obesity on metabolic phenotype. PMID:26072337

  6. Obesity and Altered Sleep: A Pathway to Metabolic Derangements in Children?

    PubMed

    Hakim, Fahed; Kheirandish-Gozal, Leila; Gozal, David

    2015-06-01

    Obstructive sleep apnea (OSA) is a frequent disorder in children and is primarily associated with adenotonsillar hypertrophy. The prominent increases in childhood overweight and obesity rates in the world even among youngest of children have translated into parallel increases in the prevalence of OSA, and such trends are undoubtedly associated with deleterious global health outcomes and life expectancy. Even an obesity phenotype in childhood OSA, more close to the adult type, has been recently proposed. Reciprocal interactions between sleep in general, OSA, obesity, and disruptions of metabolic homeostasis have emerged in recent years. These associations have suggested the a priori involvement of complex sets of metabolic and inflammatory pathways, all of which may underlie an increased risk for increased orexigenic behaviors and dysfunctional satiety, hyperlipidemia, and insulin resistance that ultimately favor the emergence of metabolic syndrome. Here, we review some of the critical evidence supporting the proposed associations between sleep disruption and the metabolism-obesity complex. In addition, we describe the more recent evidence linking the potential interactive roles of OSA and obesity on metabolic phenotype. PMID:26072337

  7. Structural Brain Alterations Associated with Rapid Eye Movement Sleep Behavior Disorder in Parkinson’s Disease

    PubMed Central

    Boucetta, Soufiane; Salimi, Ali; Dadar, Mahsa; Jones, Barbara E.; Collins, D. Louis; Dang-Vu, Thien Thanh

    2016-01-01

    Characterized by dream-enactment motor manifestations arising from rapid eye movement (REM) sleep, REM sleep behavior disorder (RBD) is frequently encountered in Parkinson’s disease (PD). Yet the specific neurostructural changes associated with RBD in PD patients remain to be revealed by neuroimaging. Here we identified such neurostructural alterations by comparing large samples of magnetic resonance imaging (MRI) scans in 69 PD patients with probable RBD, 240 patients without RBD and 138 healthy controls, using deformation-based morphometry (p < 0.05 corrected for multiple comparisons). All data were extracted from the Parkinson’s Progression Markers Initiative. PD patients with probable RBD showed smaller volumes than patients without RBD and than healthy controls in the pontomesencephalic tegmentum, medullary reticular formation, hypothalamus, thalamus, putamen, amygdala and anterior cingulate cortex. These results demonstrate that RBD is associated with a prominent loss of volume in the pontomesencephalic tegmentum, where cholinergic, GABAergic and glutamatergic neurons are located and implicated in the promotion of REM sleep and muscle atonia. It is additionally associated with more widespread atrophy in other subcortical and cortical regions whose loss also likely contributes to the altered regulation of sleep-wake states and motor activity underlying RBD in PD patients. PMID:27245317

  8. Structural Brain Alterations Associated with Rapid Eye Movement Sleep Behavior Disorder in Parkinson's Disease.

    PubMed

    Boucetta, Soufiane; Salimi, Ali; Dadar, Mahsa; Jones, Barbara E; Collins, D Louis; Dang-Vu, Thien Thanh

    2016-01-01

    Characterized by dream-enactment motor manifestations arising from rapid eye movement (REM) sleep, REM sleep behavior disorder (RBD) is frequently encountered in Parkinson's disease (PD). Yet the specific neurostructural changes associated with RBD in PD patients remain to be revealed by neuroimaging. Here we identified such neurostructural alterations by comparing large samples of magnetic resonance imaging (MRI) scans in 69 PD patients with probable RBD, 240 patients without RBD and 138 healthy controls, using deformation-based morphometry (p < 0.05 corrected for multiple comparisons). All data were extracted from the Parkinson's Progression Markers Initiative. PD patients with probable RBD showed smaller volumes than patients without RBD and than healthy controls in the pontomesencephalic tegmentum, medullary reticular formation, hypothalamus, thalamus, putamen, amygdala and anterior cingulate cortex. These results demonstrate that RBD is associated with a prominent loss of volume in the pontomesencephalic tegmentum, where cholinergic, GABAergic and glutamatergic neurons are located and implicated in the promotion of REM sleep and muscle atonia. It is additionally associated with more widespread atrophy in other subcortical and cortical regions whose loss also likely contributes to the altered regulation of sleep-wake states and motor activity underlying RBD in PD patients. PMID:27245317

  9. Multimodal neuroimaging investigations of alterations to consciousness: the relationship between absence epilepsy and sleep.

    PubMed

    Bagshaw, Andrew P; Rollings, David T; Khalsa, Sakh; Cavanna, Andrea E

    2014-01-01

    The link between epilepsy and sleep is well established on many levels. The focus of the current review is on recent neuroimaging investigations into the alterations of consciousness that are observed during absence seizures and the descent into sleep. Functional neuroimaging provides simultaneous cortical and subcortical recording of activity throughout the brain, allowing a detailed definition and characterization of large-scale brain networks and the interactions between them. This has led to the identification of a set of regions which collectively form the consciousness system, which includes contributions from the default mode network (DMN), ascending arousal systems, and the thalamus. Electrophysiological and neuroimaging investigations have also clearly demonstrated the importance of thalamocortical and corticothalamic networks in the evolution of sleep and absence epilepsy, two phenomena in which the subject experiences an alteration to the conscious state and a disconnection from external input. However, the precise relationship between the consciousness system, thalamocortical networks, and consciousness itself remains to be clarified. One of the fundamental challenges is to understand how distributed brain networks coordinate their activity in order to maintain and implement complex behaviors such as consciousness and how modifications to this network activity lead to alterations in consciousness. By taking into account not only the level of activation of individual brain regions but also their connectivity within specific networks and the activity and connectivity of other relevant networks, a more specific quantification of brain states can be achieved. This, in turn, may provide a more fundamental understanding of the alterations to consciousness experienced in sleep and epilepsy.

  10. Sleep allostasis in chronic sleep restriction: the role of the norepinephrine system

    PubMed Central

    Kim, Youngsoo; Chen, Lichao; McCarley, Robert W.; Strecker, Robert E.

    2013-01-01

    Sleep responses to chronic sleep restriction may be very different from those observed after acute total sleep deprivation. Specifically, when sleep restriction is repeated for several consecutive days, animals express attenuated compensatory increases in sleep time and intensity during daily sleep opportunities. The neurobiological mechanisms underlying these adaptive, or more specifically, allostatic, changes in sleep homeostasis are unknown. Several lines of evidence indicate that norepinephrine may play a key role in modulating arousal states and NREM EEG delta power, which is widely recognized as a marker for sleep intensity. Therefore, we investigated time course changes in brain adrenergic receptor mRNA levels in response to chronic sleep restriction using a rat model. Here, we observed that significantly altered mRNA levels of the α1- adrenergic receptor in the basal forebrain as well as α2- and β1-adrenergic receptor in the anterior cingulate cortex only on the first sleep restriction day. On the other hand, the frontal cortex α1-, α2-, and β1- adrenergic receptor mRNA levels were reduced throughout the period of sleep restriction. Combined with our earlier findings on EEG that sleep time and intensity significantly increased only on the first sleep restriction days, these results suggest that alterations in the brain norepinephrine system in the basal forebrain and cingulate cortex may mediate allostatic changes in sleep time and intensity observed during chronic sleep restriction. PMID:23916734

  11. Subacute calorie restriction and rapamycin discordantly alter mouse liver proteome homeostasis and reverse aging effects.

    PubMed

    Karunadharma, Pabalu P; Basisty, Nathan; Dai, Dao-Fu; Chiao, Ying A; Quarles, Ellen K; Hsieh, Edward J; Crispin, David; Bielas, Jason H; Ericson, Nolan G; Beyer, Richard P; MacKay, Vivian L; MacCoss, Michael J; Rabinovitch, Peter S

    2015-08-01

    Calorie restriction (CR) and rapamycin (RP) extend lifespan and improve health across model organisms. Both treatments inhibit mammalian target of rapamycin (mTOR) signaling, a conserved longevity pathway and a key regulator of protein homeostasis, yet their effects on proteome homeostasis are relatively unknown. To comprehensively study the effects of aging, CR, and RP on protein homeostasis, we performed the first simultaneous measurement of mRNA translation, protein turnover, and abundance in livers of young (3 month) and old (25 month) mice subjected to 10-week RP or 40% CR. Protein abundance and turnover were measured in vivo using (2) H3 -leucine heavy isotope labeling followed by LC-MS/MS, and translation was assessed by polysome profiling. We observed 35-60% increased protein half-lives after CR and 15% increased half-lives after RP compared to age-matched controls. Surprisingly, the effects of RP and CR on protein turnover and abundance differed greatly between canonical pathways, with opposite effects in mitochondrial (mt) dysfunction and eIF2 signaling pathways. CR most closely recapitulated the young phenotype in the top pathways. Polysome profiles indicated that CR reduced polysome loading while RP increased polysome loading in young and old mice, suggesting distinct mechanisms of reduced protein synthesis. CR and RP both attenuated protein oxidative damage. Our findings collectively suggest that CR and RP extend lifespan in part through the reduction of protein synthetic burden and damage and a concomitant increase in protein quality. However, these results challenge the notion that RP is a faithful CR mimetic and highlight mechanistic differences between the two interventions.

  12. Total Sleep Deprivation Alters Endothelial Function in Rats: A Nonsympathetic Mechanism

    PubMed Central

    Sauvet, Fabien; Florence, Geneviève; Van Beers, Pascal; Drogou, Catherine; Lagrume, Christophe; Chaumes, Cyrielle; Ciret, Sylvain; Leftheriotis, Georges; Chennaoui, Mounir

    2014-01-01

    cyclooxygenase pathway alterations. Citation: Sauvet F; Florence G; Van Beers P; Drogou C; Lagrume C; Chaumes C; Ciret S; Leftheriotis G; Chennaoui M. Total sleep deprivation alters endothelial function in rats: a nonsympathetic mechanism. SLEEP 2014;37(3):465-473. PMID:24587568

  13. Caffeine alters oxidative homeostasis in the body of BALB/c mice.

    PubMed

    Pohanka, M

    2014-01-01

    Caffeine is a metabolite from coffee genus and some other plants. It has disparate molecular targets in the body. Beside the major action based on antagonism on adenosine receptor, it is involved in other neurotransmission pathways as well. The complete mechanism of caffeine action remains unrevealed including link to oxidative homeostasis. For the reason, the current paper solves how caffeine influences oxidative homeostasis in BALB/c mouse model. Caffeine was given intramuscularly in doses 1-64 mg/kg and the animals were sacrificed in time intervals from 4 hours up to 3 days. In the experiment, a significant increase of thiobarbituric acid reactive substances (TBARS) levels in the kidney and decrease in the brain indicated up and down regulation of oxidative burden. Ferric reducing antioxidant power (FRAP) level in the kidney appoint at release of low molecular weight antioxidants in the organ. The remaining organs including heart, muscles and liver were intact. In the same way, caspase 3 level was steady and no apoptotic processes were proved (Fig. 3, Ref. 48). PMID:25428538

  14. Caffeine alters oxidative homeostasis in the body of BALB/c mice.

    PubMed

    Pohanka, M

    2014-01-01

    Caffeine is a metabolite from coffee genus and some other plants. It has disparate molecular targets in the body. Beside the major action based on antagonism on adenosine receptor, it is involved in other neurotransmission pathways as well. The complete mechanism of caffeine action remains unrevealed including link to oxidative homeostasis. For the reason, the current paper solves how caffeine influences oxidative homeostasis in BALB/c mouse model. Caffeine was given intramuscularly in doses 1-64 mg/kg and the animals were sacrificed in time intervals from 4 hours up to 3 days. In the experiment, a significant increase of thiobarbituric acid reactive substances (TBARS) levels in the kidney and decrease in the brain indicated up and down regulation of oxidative burden. Ferric reducing antioxidant power (FRAP) level in the kidney appoint at release of low molecular weight antioxidants in the organ. The remaining organs including heart, muscles and liver were intact. In the same way, caspase 3 level was steady and no apoptotic processes were proved (Fig. 3, Ref. 48).

  15. HIV- and FIV-derived gp120 alter spatial memory, LTP, and sleep in rats.

    PubMed

    Sánchez-Alavez, M; Criado, J; Gómez-Chavarín, M; Jiménez-Anguiano, A; Navarro, L; Díaz-Ruiz, O; Galicia, O; Sánchez-Narváez, F; Murillo-Rodríguez, E; Henriksen, S J; Elder, J H; Prospéro-García, O

    2000-08-01

    Human immunodeficiency virus (HIV)-associated dementia (HAD) has been detected in 20-30% of patients suffering AIDS. The envelope glycoprotein 120 (gp120) derived from HIV seems to play a critical role in the pathophysiology of this dementia. Likewise, the feline immunodeficiency virus (FIV)-derived gp120 causes neurological and electrophysiological abnormalitites in cats. We have studied the effects of gp120 derived from HIV or FIV on learning and memory processing, hippocampal long-term potentiation (LTP), hippocampal neuronal cAMP production, the sleep-waking cycle, and locomotor activity and equilibrium in rats. Results showed that while both HIV- and FIV-gp120 impaired the rat's performance in the Barnes maze task, only HIVgp120 impaired the induction and maintenance of LTP. However, both glycoproteins induced a significant decrease in the posttetanic potentiation. HIVgp120 also caused a significant reduction in cAMP production in the hippocampus. Regarding the sleep-waking cycle, HIV- and FIV-gp120 increased the waking state and slow-wave sleep 1 (SWS1), while decreasing both SWS2 and REM sleep. Locomotor activity and equilibrium were significantly altered by these glycoproteins. These results suggest that HIVgp120 causes neurophysiological abnormalities and therefore may facilitate HAD development in AIDS patients.

  16. Postnatal exposure to trichloroethylene alters glutathione redox homeostasis, methylation potential, and neurotrophin expression in the mouse hippocampus.

    PubMed

    Blossom, Sarah J; Melnyk, Stepan; Cooney, Craig A; Gilbert, Kathleen M; James, S Jill

    2012-12-01

    Previous studies have shown that continuous exposure throughout gestation until the juvenile period to environmentally relevant doses of trichloroethylene (TCE) in the drinking water of MRL+/+ mice promoted adverse behavior associated with glutathione depletion in the cerebellum indicating increased sensitivity to oxidative stress. The purpose of this study was to extend our findings and further characterize the impact of TCE exposure on redox homeostasis and biomarkers of oxidative stress in the hippocampus, a brain region prone to oxidative stress. Instead of a continuous exposure, the mice were exposed to water only or two environmentally relevant doses of TCE in the drinking water postnatally from birth until 6 weeks of age. Biomarkers of plasma metabolites in the transsulfuration pathway and the transmethylation pathway of the methionine cycle were also examined. Gene expression of neurotrophins was examined to investigate a possible relationship between oxidative stress, redox imbalance and neurotrophic factor expression with TCE exposure. Our results show that hippocampi isolated from male mice exposed to TCE showed altered glutathione redox homeostasis indicating a more oxidized state. Also observed was a significant, dose dependent increase in glutathione precursors. Plasma from the TCE treated mice showed alterations in metabolites in the transsulfuration and transmethylation pathways indicating redox imbalance and altered methylation capacity. 3-Nitrotyrosine, a biomarker of protein oxidative stress, was also significantly higher in plasma and hippocampus of TCE-exposed mice compared to controls. In contrast, expression of key neurotrophic factors in the hippocampus (BDNF, NGF, and NT-3) was significantly reduced compared to controls. Our results demonstrate that low-level postnatal and early life TCE exposure modulates neurotrophin gene expression in the mouse hippocampus and may provide a mechanism for TCE-mediated neurotoxicity.

  17. Haematopoietic focal adhesion kinase deficiency alters haematopoietic homeostasis to drive tumour metastasis.

    PubMed

    Batista, Silvia; Maniati, Eleni; Reynolds, Louise E; Tavora, Bernardo; Lees, Delphine M; Fernandez, Isabelle; Elia, George; Casanovas, Oriol; Lo Celso, Cristina; Hagemann, Thorsten; Hodivala-Dilke, Kairbaan

    2014-01-01

    Metastasis is the main cause of cancer-related death and thus understanding the molecular and cellular mechanisms underlying this process is critical. Here, our data demonstrate, contrary to established dogma, that loss of haematopoietic-derived focal adhesion kinase (FAK) is sufficient to enhance tumour metastasis. Using both experimental and spontaneous metastasis models, we show that genetic ablation of haematopoietic FAK does not affect primary tumour growth but enhances the incidence of metastasis significantly. At a molecular level, haematopoietic FAK deletion results in an increase in PU-1 levels and decrease in GATA-1 levels causing a shift of hematopoietic homeostasis towards a myeloid commitment. The subsequent increase in circulating granulocyte number, with an increase in serum CXCL12 and granulocyte CXCR4 levels, was required for augmented metastasis in mice lacking haematopoietic FAK. Overall our findings provide a mechanism by which haematopoietic FAK controls cancer metastasis. PMID:25270220

  18. Impact of streptozotocin on altering normal glucose homeostasis during insulin testing in diabetic rats compared to normoglycemic rats

    PubMed Central

    Qinna, Nidal A; Badwan, Adnan A

    2015-01-01

    Streptozotocin (STZ) is currently the most used diabetogenic agent in testing insulin and new antidiabetic drugs in animals. Due to the toxic and disruptive nature of STZ on organs, apart from pancreas, involved in preserving the body’s normal glucose homeostasis, this study aims to reassess the action of STZ in inducing different glucose response states in diabetic rats while testing insulin. Diabetic Sprague-Dawley rats induced with STZ were classified according to their initial blood glucose levels into stages. The effect of randomizing rats in such a manner was investigated for the severity of interrupting normal liver, pancreas, and kidney functions. Pharmacokinetic and pharmacodynamic actions of subcutaneously injected insulin in diabetic and nondiabetic rats were compared. Interruption of glucose homeostasis by STZ was challenged by single and repeated administrations of injected insulin and oral glucose to diabetic rats. In diabetic rats with high glucose (451–750 mg/dL), noticeable changes were seen in the liver and kidney functions compared to rats with lower basal glucose levels. Increased serum levels of recombinant human insulin were clearly indicated by a significant increase in the calculated maximum serum concentration and area under the concentration–time curve. Reversion of serum glucose levels to normal levels pre- and postinsulin and oral glucose administrations to STZ diabetic rats were found to be variable. In conclusion, diabetic animals were more responsive to insulin than nondiabetic animals. STZ was capable of inducing different levels of normal glucose homeostasis disruption in rats. Both pharmacokinetic and pharmacodynamic actions of insulin were altered when different initial blood glucose levels of STZ diabetic rats were selected for testing. Such findings emphasize the importance of selecting predefined and unified glucose levels when using STZ as a diabetogenic agent in experimental protocols evaluating new antidiabetic agents

  19. Mars 520-d mission simulation reveals protracted crew hypokinesis and alterations of sleep duration and timing

    PubMed Central

    Basner, Mathias; Dinges, David F.; Mollicone, Daniel; Ecker, Adrian; Jones, Christopher W.; Hyder, Eric C.; Di Antonio, Adrian; Savelev, Igor; Kan, Kevin; Goel, Namni; Morukov, Boris V.; Sutton, Jeffrey P.

    2013-01-01

    The success of interplanetary human spaceflight will depend on many factors, including the behavioral activity levels, sleep, and circadian timing of crews exposed to prolonged microgravity and confinement. To address the effects of the latter, we used a high-fidelity ground simulation of a Mars mission to objectively track sleep–wake dynamics in a multinational crew of six during 520 d of confined isolation. Measurements included continuous recordings of wrist actigraphy and light exposure (4.396 million min) and weekly computer-based neurobehavioral assessments (n = 888) to identify changes in the crew's activity levels, sleep quantity and quality, sleep–wake periodicity, vigilance performance, and workload throughout the record-long 17 mo of mission confinement. Actigraphy revealed that crew sedentariness increased across the mission as evident in decreased waking movement (i.e., hypokinesis) and increased sleep and rest times. Light exposure decreased during the mission. The majority of crewmembers also experienced one or more disturbances of sleep quality, vigilance deficits, or altered sleep–wake periodicity and timing, suggesting inadequate circadian entrainment. The results point to the need to identify markers of differential vulnerability to hypokinesis and sleep–wake changes during the prolonged isolation of exploration spaceflight and the need to ensure maintenance of circadian entrainment, sleep quantity and quality, and optimal activity levels during exploration missions. Therefore, successful adaptation to such missions will require crew to transit in spacecraft and live in surface habitats that instantiate aspects of Earth's geophysical signals (appropriately timed light exposure, food intake, exercise) required for temporal organization and maintenance of human behavior. PMID:23297197

  20. A new strategy to analyze possible association structures between dynamic nocturnal hormone activities and sleep alterations in humans.

    PubMed

    Kalus, Stefanie; Kneib, Thomas; Steiger, Axel; Holsboer, Florian; Yassouridis, Alexander

    2009-04-01

    The human sleep process shows dynamic alterations during the night. Methods are needed to examine whether and to what extent such alterations are affected by internal, possibly time-dependent, factors, such as endocrine activity. In an observational study, we examined simultaneously sleep EEG and nocturnal levels of renin, growth hormone (GH), and cortisol (between 2300 and 0700) in 47 healthy volunteers comprising 24 women (41.67 +/- 2.93 yr of age) and 23 men (37.26 +/- 2.85 yr of age). Hormone concentrations were measured every 20 min. Conventional sleep stage scoring at 30-s intervals was applied. Semiparametric multinomial logit models are used to study and quantify possible time-dependent hormone effects on sleep stage transition courses. Results show that increased cortisol levels decrease the probability of transition from rapid-eye-movement (REM) sleep to wakefulness (WAKE) and increase the probability of transition from REM to non-REM (NREM) sleep, irrespective of the time in the night. Via the model selection criterion Akaike's information criterion, it was found that all considered hormone effects on transition probabilities with the initial state WAKE change with time. Similarly, transition from slow-wave sleep (SWS) to light sleep (LS) is affected by a "hormone-time" interaction for cortisol and renin, but not GH. For example, there is a considerable increase in the probability of SWS-LS transition toward the end of the night, when cortisol concentrations are very high. In summary, alterations in human sleep possess dynamic forms and are partially influenced by the endocrine activity of certain hormones. Statistical methods, such as semiparametric multinomial and time-dependent logit regression, can offer ambitious ways to investigate and estimate the association intensities between the nonstationary sleep changes and the time-dependent endocrine activities. PMID:19144755

  1. Melatonin advances the circadian timing of EEG sleep and directly facilitates sleep without altering its duration in extended sleep opportunities in humans

    PubMed Central

    Rajaratnam, Shantha M W; Middleton, Benita; Stone, Barbara M; Arendt, Josephine; Dijk, Derk-Jan

    2004-01-01

    The rhythm of plasma melatonin originating from the pineal gland and driven by the circadian pacemaker located in the suprachiasmatic nucleus is closely associated with the circadian (approximately 24 h) variation in sleep propensity and sleep spindle activity in humans. We investigated the contribution of melatonin to variation in sleep propensity, structure, duration and EEG activity in a protocol in which sleep was scheduled to begin during the biological day, i.e. when endogenous melatonin concentrations are low. The two 14 day trials were conducted in an environmental scheduling facility. Each trial included two circadian phase assessments, baseline sleep and nine 16 h sleep opportunities (16.00–08.00 h) in near darkness. Eight healthy male volunteers (24.4 ± 4.4 years) without sleep complaints were recruited, and melatonin (1.5 mg) or placebo was administered at the start of the first eight 16 h sleep opportunities. During melatonin treatment, sleep in the first 8 h of the 16 h sleep opportunities was increased by 2 h. Sleep per 16 h was not significantly different and approached asymptotic values of 8.7 h in both conditions. The percentage of rapid eye movement (REM) sleep was not affected by melatonin, but the percentage of stage 2 sleep and sleep spindle activity increased, and the percentage of stage 3 sleep decreased. During the washout night, the melatonin-induced advance in sleep timing persisted, but was smaller than on the preceding treatment night and was consistent with the advance in the endogenous melatonin rhythm. These data demonstrate robust, direct sleep-facilitating and circadian effects of melatonin without concomitant changes in sleep duration, and support the use of melatonin in the treatment of sleep disorders in which the circadian melatonin rhythm is delayed relative to desired sleep time. PMID:15459246

  2. Altered Glucose Homeostasis and Hepatic Function in Obese Mice Deficient for Both Kinin Receptor Genes

    PubMed Central

    Barros, Carlos C.; Haro, Anderson; Russo, Fernanda J. V. P.; Schadock, Ines; Almeida, Sandro S.; Ribeiro, Rosane A.; Vanzela, Emerielle C.; Lanzoni, Valeria P.; Barros, Flavio C.; Moraes, Milton R.; Mori, Marcelo A.; Bacurau, Reury F. P.; Wurtele, Martin; Boschero, Antônio C.; Carneiro, Everardo M.; Bader, Michael; Pesquero, Joao B.; Araujo, Ronaldo C.

    2012-01-01

    The Kallikrein-Kinin System (KKS) has been implicated in several aspects of metabolism, including the regulation of glucose homeostasis and adiposity. Kinins and des-Arg-kinins are the major effectors of this system and promote their effects by binding to two different receptors, the kinin B2 and B1 receptors, respectively. To understand the influence of the KKS on the pathophysiology of obesity and type 2 diabetes (T2DM), we generated an animal model deficient for both kinin receptor genes and leptin (obB1B2KO). Six-month-old obB1B2KO mice showed increased blood glucose levels. Isolated islets of the transgenic animals were more responsive to glucose stimulation releasing greater amounts of insulin, mainly in 3-month-old mice, which was corroborated by elevated serum C-peptide concentrations. Furthermore, they presented hepatomegaly, pronounced steatosis, and increased levels of circulating transaminases. This mouse also demonstrated exacerbated gluconeogenesis during the pyruvate challenge test. The hepatic abnormalities were accompanied by changes in the gene expression of factors linked to glucose and lipid metabolisms in the liver. Thus, we conclude that kinin receptors are important for modulation of insulin secretion and for the preservation of normal glucose levels and hepatic functions in obese mice, suggesting a protective role of the KKS regarding complications associated with obesity and T2DM. PMID:22829877

  3. Partial sleep deprivation does not alter processes involved in semantic word priming: event-related potential evidence.

    PubMed

    Tavakoli, Paniz; Muller-Gass, Alexandra; Campbell, Kenneth

    2015-03-01

    Sleep deprivation has generally been observed to have a detrimental effect on tasks that require sustained attention for successful performance. It might however be possible to counter these effects by altering cognitive strategies. A recent semantic word priming study indicated that subjects used an effortful predictive-expectancy search of semantic memory following normal sleep, but changed to an automatic, effortless strategy following total sleep deprivation. Partial sleep deprivation occurs much more frequently than total sleep deprivation. The present study therefore employed a similar priming task following either 4h of sleep or following normal sleep. The purpose of the study was to determine whether partial sleep deprivation would also lead to a shift in cognitive strategy to compensate for an inability to sustain attention and effortful processing necessary for using the predicative expectancy strategy. Sixteen subjects were presented with word pairs, a prime and a target that were either strongly semantically associated (cat...dog), weakly associated (cow...barn) or not associated (apple...road). The subject's task was to determine if the target word was semantically associated to the prime. A strong priming effect was observed in both conditions. RTs were slower, accuracy lower, and N400 larger to unassociated targets, independent of the amount of sleep. The overall N400 did not differ as a function of sleep. The scalp distribution of the N400 was also similar following both normal sleep and sleep loss. There was thus little evidence of a difference in the processing of the target stimulus as a function of the amount sleep. Similarly, ERPs in the period between the onset of the prime and the subsequent target also did not differ between the normal sleep and sleep loss conditions. In contrast to total sleep deprivation, subjects therefore appeared to use a common predictive expectancy strategy in both conditions. This strategy does however require an

  4. Partial sleep deprivation does not alter processes involved in semantic word priming: event-related potential evidence.

    PubMed

    Tavakoli, Paniz; Muller-Gass, Alexandra; Campbell, Kenneth

    2015-03-01

    Sleep deprivation has generally been observed to have a detrimental effect on tasks that require sustained attention for successful performance. It might however be possible to counter these effects by altering cognitive strategies. A recent semantic word priming study indicated that subjects used an effortful predictive-expectancy search of semantic memory following normal sleep, but changed to an automatic, effortless strategy following total sleep deprivation. Partial sleep deprivation occurs much more frequently than total sleep deprivation. The present study therefore employed a similar priming task following either 4h of sleep or following normal sleep. The purpose of the study was to determine whether partial sleep deprivation would also lead to a shift in cognitive strategy to compensate for an inability to sustain attention and effortful processing necessary for using the predicative expectancy strategy. Sixteen subjects were presented with word pairs, a prime and a target that were either strongly semantically associated (cat...dog), weakly associated (cow...barn) or not associated (apple...road). The subject's task was to determine if the target word was semantically associated to the prime. A strong priming effect was observed in both conditions. RTs were slower, accuracy lower, and N400 larger to unassociated targets, independent of the amount of sleep. The overall N400 did not differ as a function of sleep. The scalp distribution of the N400 was also similar following both normal sleep and sleep loss. There was thus little evidence of a difference in the processing of the target stimulus as a function of the amount sleep. Similarly, ERPs in the period between the onset of the prime and the subsequent target also did not differ between the normal sleep and sleep loss conditions. In contrast to total sleep deprivation, subjects therefore appeared to use a common predictive expectancy strategy in both conditions. This strategy does however require an

  5. Short-term sleep deprivation with nocturnal light exposure alters time-dependent glucagon-like peptide-1 and insulin secretion in male volunteers.

    PubMed

    Gil-Lozano, Manuel; Hunter, Paola M; Behan, Lucy-Ann; Gladanac, Bojana; Casper, Robert F; Brubaker, Patricia L

    2016-01-01

    The intestinal L cell is the principal source of glucagon-like peptide-1 (GLP-1), a major determinant of insulin release. Because GLP-1 secretion is regulated in a circadian manner in rodents, we investigated whether the activity of the human L cell is also time sensitive. Rhythmic fluctuations in the mRNA levels of canonical clock genes were found in the human NCI-H716 L cell model, which also showed a time-dependent pattern in their response to well-established secretagogues. A diurnal variation in GLP-1 responses to identical meals (850 kcal), served 12 h apart in the normal dark (2300) and light (1100) periods, was also observed in male volunteers maintained under standard sleep and light conditions. These findings suggest the existence of a daily pattern of activity in the human L cell. Moreover, we separately tested the short-term effects of sleep deprivation and nocturnal light exposure on basal and postprandial GLP-1, insulin, and glucose levels in the same volunteers. Sleep deprivation with nocturnal light exposure disrupted the melatonin and cortisol profiles and increased insulin resistance. Moreover, it also induced profound derangements in GLP-1 and insulin responses such that postprandial GLP-1 and insulin levels were markedly elevated and the normal variation in GLP-1 responses was abrogated. These alterations were not observed in sleep-deprived participants maintained under dark conditions, indicating a direct effect of light on the mechanisms that regulate glucose homeostasis. Accordingly, the metabolic abnormalities known to occur in shift workers may be related to the effects of irregular light-dark cycles on these glucoregulatory pathways. PMID:26530153

  6. Short-term sleep deprivation with nocturnal light exposure alters time-dependent glucagon-like peptide-1 and insulin secretion in male volunteers.

    PubMed

    Gil-Lozano, Manuel; Hunter, Paola M; Behan, Lucy-Ann; Gladanac, Bojana; Casper, Robert F; Brubaker, Patricia L

    2016-01-01

    The intestinal L cell is the principal source of glucagon-like peptide-1 (GLP-1), a major determinant of insulin release. Because GLP-1 secretion is regulated in a circadian manner in rodents, we investigated whether the activity of the human L cell is also time sensitive. Rhythmic fluctuations in the mRNA levels of canonical clock genes were found in the human NCI-H716 L cell model, which also showed a time-dependent pattern in their response to well-established secretagogues. A diurnal variation in GLP-1 responses to identical meals (850 kcal), served 12 h apart in the normal dark (2300) and light (1100) periods, was also observed in male volunteers maintained under standard sleep and light conditions. These findings suggest the existence of a daily pattern of activity in the human L cell. Moreover, we separately tested the short-term effects of sleep deprivation and nocturnal light exposure on basal and postprandial GLP-1, insulin, and glucose levels in the same volunteers. Sleep deprivation with nocturnal light exposure disrupted the melatonin and cortisol profiles and increased insulin resistance. Moreover, it also induced profound derangements in GLP-1 and insulin responses such that postprandial GLP-1 and insulin levels were markedly elevated and the normal variation in GLP-1 responses was abrogated. These alterations were not observed in sleep-deprived participants maintained under dark conditions, indicating a direct effect of light on the mechanisms that regulate glucose homeostasis. Accordingly, the metabolic abnormalities known to occur in shift workers may be related to the effects of irregular light-dark cycles on these glucoregulatory pathways.

  7. Altered functional connectivity in lesional peduncular hallucinosis with REM sleep behavior disorder.

    PubMed

    Geddes, Maiya R; Tie, Yanmei; Gabrieli, John D E; McGinnis, Scott M; Golby, Alexandra J; Whitfield-Gabrieli, Susan

    2016-01-01

    Brainstem lesions causing peduncular hallucinosis (PH) produce vivid visual hallucinations occasionally accompanied by sleep disorders. Overlapping brainstem regions modulate visual pathways and REM sleep functions via gating of thalamocortical networks. A 66-year-old man with paroxysmal atrial fibrillation developed abrupt-onset complex visual hallucinations with preserved insight and violent dream enactment behavior. Brain MRI showed restricted diffusion in the left rostrodorsal pons suggestive of an acute ischemic stroke. REM sleep behavior disorder (RBD) was diagnosed on polysomnography. We investigated the integrity of ponto-geniculate-occipital circuits with seed-based resting-state functional connectivity MRI (rs-fcMRI) in this patient compared to 46 controls. Rs-fcMRI revealed significantly reduced functional connectivity between the lesion and lateral geniculate nuclei (LGN), and between LGN and visual association cortex compared to controls. Conversely, functional connectivity between brainstem and visual association cortex, and between visual association cortex and prefrontal cortex (PFC) was significantly increased in the patient. Focal damage to the rostrodorsal pons is sufficient to cause RBD and PH in humans, suggesting an overlapping mechanism in both syndromes. This lesion produced a pattern of altered functional connectivity consistent with disrupted visual cortex connectivity via de-afferentation of thalamocortical pathways.

  8. Altered functional connectivity in lesional peduncular hallucinosis with REM sleep behavior disorder.

    PubMed

    Geddes, Maiya R; Tie, Yanmei; Gabrieli, John D E; McGinnis, Scott M; Golby, Alexandra J; Whitfield-Gabrieli, Susan

    2016-01-01

    Brainstem lesions causing peduncular hallucinosis (PH) produce vivid visual hallucinations occasionally accompanied by sleep disorders. Overlapping brainstem regions modulate visual pathways and REM sleep functions via gating of thalamocortical networks. A 66-year-old man with paroxysmal atrial fibrillation developed abrupt-onset complex visual hallucinations with preserved insight and violent dream enactment behavior. Brain MRI showed restricted diffusion in the left rostrodorsal pons suggestive of an acute ischemic stroke. REM sleep behavior disorder (RBD) was diagnosed on polysomnography. We investigated the integrity of ponto-geniculate-occipital circuits with seed-based resting-state functional connectivity MRI (rs-fcMRI) in this patient compared to 46 controls. Rs-fcMRI revealed significantly reduced functional connectivity between the lesion and lateral geniculate nuclei (LGN), and between LGN and visual association cortex compared to controls. Conversely, functional connectivity between brainstem and visual association cortex, and between visual association cortex and prefrontal cortex (PFC) was significantly increased in the patient. Focal damage to the rostrodorsal pons is sufficient to cause RBD and PH in humans, suggesting an overlapping mechanism in both syndromes. This lesion produced a pattern of altered functional connectivity consistent with disrupted visual cortex connectivity via de-afferentation of thalamocortical pathways. PMID:26656284

  9. Pharmacogenetic Modulation of Orexin Neurons Alters Sleep/Wakefulness States in Mice

    PubMed Central

    Tsujino, Natsuko; Roth, Bryan; Sakurai, Takeshi

    2011-01-01

    Hypothalamic neurons expressing neuropeptide orexins are critically involved in the control of sleep and wakefulness. Although the activity of orexin neurons is thought to be influenced by various neuronal input as well as humoral factors, the direct consequences of changes in the activity of these neurons in an intact animal are largely unknown. We therefore examined the effects of orexin neuron-specific pharmacogenetic modulation in vivo by a new method called the Designer Receptors Exclusively Activated by Designer Drugs approach (DREADD). Using this system, we successfully activated and suppressed orexin neurons as measured by Fos staining. EEG and EMG recordings suggested that excitation of orexin neurons significantly increased the amount of time spent in wakefulness and decreased both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep times. Inhibition of orexin neurons decreased wakefulness time and increased NREM sleep time. These findings clearly show that changes in the activity of orexin neurons can alter the behavioral state of animals and also validate this novel approach for manipulating neuronal activity in awake, freely-moving animals. PMID:21647372

  10. Altered carnitine homeostasis is associated with decreased mitochondrial function and altered nitric oxide signaling in lambs with pulmonary hypertension

    PubMed Central

    Sharma, Shruti; Sud, Neetu; Wiseman, Dean A.; Carter, A. Lee; Kumar, Sanjiv; Hou, Yali; Rau, Thomas; Wilham, Jason; Harmon, Cynthia; Oishi, Peter; Fineman, Jeffrey R.; Black, Stephen M.

    2008-01-01

    Utilizing aortopulmonary vascular graft placement in the fetal lamb, we have developed a model (shunt) of pulmonary hypertension that mimics congenital heart disease with increased pulmonary blood flow. Our previous studies have identified a progressive development of endothelial dysfunction in shunt lambs that is dependent, at least in part, on decreased nitric oxide (NO) signaling. The purpose of this study was to evaluate the possible role of a disruption in carnitine metabolism in shunt lambs and to determine the effect on NO signaling. Our data indicate that at 2 wk of age, shunt lambs have significantly reduced expression (P < 0.05) of the key enzymes in carnitine metabolism: carnitine palmitoyltransferases 1 and 2 as well as carnitine acetyltransferase (CrAT). In addition, we found that CrAT activity was inhibited due to increased nitration. Furthermore, free carnitine levels were significantly decreased whereas acylcarnitine levels were significantly higher in shunt lambs (P < 0.05). We also found that alterations in carnitine metabolism resulted in mitochondrial dysfunction, since shunt lambs had significantly decreased pyruvate, increased lactate, and a reduced pyruvate/lactate ratio. In pulmonary arterial endothelial cells cultured from juvenile lambs, we found that mild uncoupling of the mitochondria led to a decrease in cellular ATP levels and a reduction in both endothelial NO synthase-heat shock protein 90 (eNOS-HSP90) interactions and NO signaling. Similarly, in shunt lambs we found a loss of eNOS-HSP90 interactions that correlated with a progressive decrease in NO signaling. Our data suggest that mitochondrial dysfunction may play a role in the development of endothelial dysfunction and pulmonary hypertension and increased pulmonary blood flow. PMID:18024721

  11. Loss of pdr-1/parkin influences Mn homeostasis through altered ferroportin expression in C. elegans

    PubMed Central

    Chakraborty, Sudipta; Chen, Pan; Bornhorst, Julia; Schwerdtle, Tanja; Schumacher, Fabian; Kleuser, Burkhard; Bowman, Aaron B.; Aschner, Michael

    2015-01-01

    Overexposure to the essential metal manganese (Mn) can result in an irreversible condition known as manganism that shares similar pathophysiology with Parkinson’s disease (PD), including dopaminergic (DAergic) cell loss that leads to motor and cognitive impairments. However, the mechanisms behind this neurotoxicity and its relationship with PD remain unclear. Many genes confer risk for autosomal recessive, early-onset PD, including the parkin/PARK2 gene that encodes for the E3 ubiquitin ligase Parkin. Using Caenorhabditis elegans (C. elegans) as an invertebrate model that conserves the DAergic system, we previously reported significantly increased Mn accumulation in pdr-1/parkin mutants compared to wildtype (WT) animals. For the current study, we hypothesize that this enhanced accumulation is due to alterations in Mn transport in the pdr-1 mutants. While no change in mRNA expression of the major Mn importer proteins (smf-1-3) was found in pdr-1 mutants, significant downregulation in mRNA levels of the putative Mn exporter ferroportin (fpn-1.1) was observed. Using a strain overexpressing fpn-1.1 in worms lacking pdr-1, we show evidence for attenuation of several endpoints of Mn-induced toxicity, including survival, metal accumulation, mitochondrial copy number and DAergic integrity, compared to pdr-1 mutants alone. These changes suggest a novel role of pdr-1 in modulating Mn export through altered transporter expression, and provides further support of metal dyshomeostasis as a component of Parkinsonism pathophysiology. PMID:25769119

  12. Compromised redox homeostasis, altered nitroso–redox balance, and therapeutic possibilities in atrial fibrillation

    PubMed Central

    Simon, Jillian N.; Ziberna, Klemen; Casadei, Barbara

    2016-01-01

    Although the initiation, development, and maintenance of atrial fibrillation (AF) have been linked to alterations in myocyte redox state, the field lacks a complete understanding of the impact these changes may have on cellular signalling, atrial electrophysiology, and disease progression. Recent studies demonstrate spatiotemporal changes in reactive oxygen species production shortly after the induction of AF in animal models with an uncoupling of nitric oxide synthase activity ensuing in the presence of long-standing persistent AF, ultimately leading to a major shift in nitroso–redox balance. However, it remains unclear which radical or non-radical species are primarily involved in the underlying mechanisms of AF or which proteins are targeted for redox modification. In most instances, only free radical oxygen species have been assessed; yet evidence from the redox signalling field suggests that non-radical species are more likely to regulate cellular processes. A wider appreciation for the distinction of these species and how both species may be involved in the development and maintenance of AF could impact treatment strategies. In this review, we summarize how redox second-messenger systems are regulated and discuss the recent evidence for alterations in redox regulation in the atrial myocardium in the presence of AF, while identifying some critical missing links. We also examine studies looking at antioxidants for the prevention and treatment of AF and propose alternative redox targets that may serve as superior therapeutic options for the treatment of AF. PMID:26786158

  13. Alterations in calcium homeostasis and bone during actual and simulated space flight

    NASA Technical Reports Server (NTRS)

    Wronski, T. J.; Morey, E. R.

    1983-01-01

    Skeletal alteration in experimental animals induced by actual and simulated spaceflight are discussed, noting that the main factor contributing to bone loss in growing rats placed in orbit aboard Soviet Cosmos biosatellites appears to be diminished bone formation. Mechanical unloading is seen as the most obvious cause of bone loss in a state of weightlessness. Reference is made to a study by Roberts et al. (1981), which showed that osteoblast differentiation in the periodontal ligament of the maxilla was suppressed in rats flown in space. Since the maxilla lacks a weight-bearing function, this finding indicates that the skeletal alterations associated with orbital flight may be systemic rather than confined to weight-bearing bones. In addition, the skeletal response to simulated weightlessness may also be systemic (wronski and Morey, 1982). In suspended rats, the hindlimbs lost all weight-bearing functions, while the forelimbs maintained contact with the floor of the hypokinetic model. On this basis, it was to be expected that there would be different responses at the two skeletal sites if the observed abnormalities were due to mechanical unloading alone. The changes induced by simulated weightlessness in the proximal tibia and humerus, however, were generally comparable. This evidence for systemic skeletal responses has drawn attention to endocrine factors.

  14. Compromised redox homeostasis, altered nitroso-redox balance, and therapeutic possibilities in atrial fibrillation.

    PubMed

    Simon, Jillian N; Ziberna, Klemen; Casadei, Barbara

    2016-04-01

    Although the initiation, development, and maintenance of atrial fibrillation (AF) have been linked to alterations in myocyte redox state, the field lacks a complete understanding of the impact these changes may have on cellular signalling, atrial electrophysiology, and disease progression. Recent studies demonstrate spatiotemporal changes in reactive oxygen species production shortly after the induction of AF in animal models with an uncoupling of nitric oxide synthase activity ensuing in the presence of long-standing persistent AF, ultimately leading to a major shift in nitroso-redox balance. However, it remains unclear which radical or non-radical species are primarily involved in the underlying mechanisms of AF or which proteins are targeted for redox modification. In most instances, only free radical oxygen species have been assessed; yet evidence from the redox signalling field suggests that non-radical species are more likely to regulate cellular processes. A wider appreciation for the distinction of these species and how both species may be involved in the development and maintenance of AF could impact treatment strategies. In this review, we summarize how redox second-messenger systems are regulated and discuss the recent evidence for alterations in redox regulation in the atrial myocardium in the presence of AF, while identifying some critical missing links. We also examine studies looking at antioxidants for the prevention and treatment of AF and propose alternative redox targets that may serve as superior therapeutic options for the treatment of AF.

  15. Long-term mTOR inhibitors administration evokes altered calcium homeostasis and platelet dysfunction in kidney transplant patients

    PubMed Central

    López, Esther; Berna-Erro, Alejandro; Bermejo, Nuria; Brull, José María; Martinez, Rocío; Garcia Pino, Guadalupe; Alvarado, Raul; Salido, Ginés María; Rosado, Juan Antonio; Cubero, Juan José; Redondo, Pedro Cosme

    2013-01-01

    The use of the mammal target of rapamycin (mTOR) inhibitors has been consolidated as the therapy of election for preventing graft rejection in kidney transplant patients, despite their immunosuppressive activity is less strong than anti-calcineurin agents like tacrolimus and cyclosporine A. Furthermore, as mTOR is widely expressed, rapamycin (a macrolide antibiotic produced by Streptomyces hygroscopicus) is recommended in patients presenting neoplasia due to its antiproliferative actions. Hence, we have investigated whether rapamycin presents side effects in the physiology of other cell types different from leucocytes, such as platelets. Blood samples were drawn from healthy volunteers and kidney transplant patients long-term medicated with rapamycin: sirolimus and everolimus. Platelets were either loaded with fura-2 or directly stimulated, and immunoassayed or fixed with Laemmli's buffer to perform the subsequent analysis of platelet physiology. Our results indicate that rapamycin evokes a biphasic time-dependent alteration in calcium homeostasis and function in platelets from kidney transplant patients under rapamycin regime, as demonstrated by the reduction in granule secretion observed and subsequent impairment of platelet aggregation in these patients compared with healthy volunteers. Platelet count was also reduced in these patients, thus 41% of patients presented thrombocytopenia. All together our results show that long-term administration of rapamycin to kidney transplant patients evokes alteration in platelet function. PMID:23577651

  16. Altered Metabolic Homeostasis in Amyotrophic Lateral Sclerosis: Mechanisms of Energy Imbalance and Contribution to Disease Progression.

    PubMed

    Ioannides, Zara A; Ngo, Shyuan T; Henderson, Robert D; McCombe, Pamela A; Steyn, Frederik J

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the death of motor neurones, which leads to paralysis and death in an average of 3 years following diagnosis. The cause of ALS is unknown, but there is substantial evidence that metabolic factors, including nutritional state and body weight, affect disease progression and survival. This review provides an overview of the characteristics of metabolic dysregulation in ALS focusing on mechanisms that lead to disrupted energy supply (at a whole-body and cellular level) and altered energy expenditure. We discuss how a decrease in energy supply occurs in parallel with an increase in energy demand and leads to a state of chronic energy deficit which has a negative impact on disease outcome in ALS. We conclude by presenting potential and tested strategies to compensate for, or correct this energy imbalance, and speculate on promising areas for further research. PMID:27400276

  17. Age-associated alterations in cholesterol homeostasis: evidence from a cross-sectional study in a Northern Italy population

    PubMed Central

    Bertolotti, Marco; Mussi, Chiara; Pellegrini, Elisa; Magni, Alessandro; Del Puppo, Marina; Ognibene, Silvia; Carulli, Lucia; Anzivino, Claudia; Baldelli, Enrica; Loria, Paola; Carulli, Nicola

    2014-01-01

    Background The modifications of cholesterol metabolism associated with aging are ill-defined. The objective of this study was to define age-associated alterations of the different metabolic pathways controlling cholesterol homeostasis by analyzing circulating sterols. Methods We analyzed serum samples collected from 201 adult (75 male, 126 female) subjects within the epidemiological MICOL study (Multicentrica Italiana Colelitiasi). The age range was 38–79 years; 103 had evidence of gallstones. The concentrations of the different sterols, recognized as markers of the main pathways of cholesterol homeostasis, were analyzed by gas chromatography-mass spectrometry, including lathosterol (synthesis), campesterol and sitosterol (absorption), and 7α-hydroxy-4-cholesten-3-one (degradation to bile acids). Results A significant direct correlation was detected between age and cholesterol levels (r =0.34, P<0.01). The lathosterol/cholesterol ratio was lower in older age quartiles (P<0.05 by analysis of variance), with an inverse correlation between the lathosterol/cholesterol ratio and age (r=−0.32, P<0.01). Such correlation was particularly evident in females. The campesterol/cholesterol and sitosterol/cholesterol ratios were inversely correlated with aging in control, but not in gallstone patients. The levels of 7α-hydroxy-4-cholesten-3-one were not correlated with age. Conclusion These data show a reduction of cholesterol synthesis with aging which is associated with increased circulating cholesterol levels. The finding might be related to a reduced metabolic need for cholesterol in advancing age, leading to a downregulation of the main mechanisms of cholesterol intake in the liver. A different age-related behavior was observed in gallstone-free versus gallstone patients regarding cholesterol absorption. The possible implications in terms of the pharmacological management of hypercholesterolemia in the elderly remain to be defined. PMID:24669190

  18. Nod1 and Nod2 signaling does not alter the composition of intestinal bacterial communities at homeostasis.

    PubMed

    Robertson, Susan J; Zhou, Jun Yu; Geddes, Kaoru; Rubino, Stephen J; Cho, Joon Ho; Girardin, Stephen E; Philpott, Dana J

    2013-01-01

    Patients with inflammatory bowel diseases (IBD) harbour intestinal bacterial communities with altered composition compared with healthy counterparts; however, it is unknown whether changes in the microbiota are associated with genetic susceptibility of individuals for developing disease or instead reflect other changes in the intestinal environment related to the disease itself. Since deficiencies in the innate immune receptors Nod1 and Nod2 are linked to IBD, we tested the hypothesis that Nod-signaling alters intestinal immune profiles and subsequently alters bacterial community structure. We used qPCR to analyze expression patterns of selected immune mediators in the ileum and cecum of Nod-deficient mice compared with their Nod-sufficient littermates and assessed the relative abundance of major bacterial groups sampled from the ileum, cecum and colon. The Nod1-deficient ileum exhibited significantly lower expression of Nod2, Muc2, α- and β-defensins and keratinocyte-derived chemokine (KC), suggesting a weakened epithelial barrier compared with WT littermates; however, there were no significant differences in the relative abundance of targeted bacterial groups, indicating that Nod1-associated immune differences alone do not promote dysbiosis. Furthermore, Nod2-deficient mice did not display any changes in the expression of immune markers or bacterial communities. Shifts in bacterial communities that were observed in this study correlated with housing conditions and were independent of genotype. These findings emphasize the importance of using F2 littermate controls to minimize environmental sources of variation in microbial analyses, to establish baseline conditions for host-microbe homeostasis in Nod-deficient mice and to strengthen models for testing factors contributing to microbial dysbiosis associated with IBD. PMID:23549220

  19. Deletion of the Snord116/SNORD116 Alters Sleep in Mice and Patients with Prader-Willi Syndrome

    PubMed Central

    Lassi, Glenda; Priano, Lorenzo; Maggi, Silvia; Garcia-Garcia, Celina; Balzani, Edoardo; El-Assawy, Nadia; Pagani, Marco; Tinarelli, Federico; Giardino, Daniela; Mauro, Alessandro; Peters, Jo; Gozzi, Alessandro; Grugni, Graziano; Tucci, Valter

    2016-01-01

    Study Objectives: Sleep-wake disturbances are often reported in Prader-Willi syndrome (PWS), a rare neurodevelopmental syndrome that is associated with paternally-expressed genomic imprinting defects within the human chromosome region 15q11-13. One of the candidate genes, prevalently expressed in the brain, is the small nucleolar ribonucleic acid-116 (SNORD116). Here we conducted a translational study into the sleep abnormalities of PWS, testing the hypothesis that SNORD116 is responsible for sleep defects that characterize the syndrome. Methods: We studied sleep in mutant mice that carry a deletion of Snord116 at the orthologous locus (mouse chromosome 7) of the human PWS critical region (PWScr). In particular, we assessed EEG and temperature profiles, across 24-h, in PWScr m+/p− heterozygous mutants compared to wild-type littermates. High-resolution magnetic resonance imaging (MRI) was performed to explore morphoanatomical differences according to the genotype. Moreover, we complemented the mouse work by presenting two patients with a diagnosis of PWS and characterized by atypical small deletions of SNORD116. We compared the individual EEG parameters of patients with healthy subjects and with a cohort of obese subjects. Results: By studying the mouse mutant line PWScrm+/p−, we observed specific rapid eye movement (REM) sleep alterations including abnormal electroencephalograph (EEG) theta waves. Remarkably, we observed identical sleep/EEG defects in the two PWS cases. We report brain morphological abnormalities that are associated with the EEG alterations. In particular, mouse mutants have a bilateral reduction of the gray matter volume in the ventral hippocampus and in the septum areas, which are pivotal structures for maintaining theta rhythms throughout the brain. In PWScrm+/p− mice we also observed increased body temperature that is coherent with REM sleep alterations in mice and human patients. Conclusions: Our study indicates that paternally expressed

  20. Expression of Arabidopsis CAX1 in tobacco: altered calcium homeostasis and increased stress sensitivity.

    PubMed Central

    Hirschi, K D

    1999-01-01

    Calcium (Ca(2)+) efflux from the cytosol modulates Ca(2+) concentrations in the cytosol, loads Ca(2+) into intracellular compartments, and supplies Ca(2+) to organelles to support biochemical functions. The Ca(2+)/H(+) antiporter CAX1 (for CALCIUM EXCHANGER 1) of Arabidopsis is thought to be a key mediator of these processes. To clarify the regulation of CAX1, we examined CAX1 RNA expression in response to various stimuli. CAX1 was highly expressed in response to exogenous Ca(2+). Transgenic tobacco plants expressing CAX1 displayed symptoms of Ca(2+) deficiencies, including hypersensitivity to ion imbalances, such as increased magnesium and potassium concentrations, and to cold shock, but increasing the Ca(2+) in the media abrogated these sensitivities. Tobacco plants expressing CAX1 also demonstrated increased Ca(2+) accumulation and altered activity of the tonoplast-enriched Ca(2+)/H(+) antiporter. These results emphasize that regulated expression of Ca(2+)/H(+) antiport activity is critical for normal growth and adaptation to certain stresses. PMID:10559438

  1. Disordered myocardial Ca(2+) homeostasis results in substructural alterations that may promote occurrence of malignant arrhythmias.

    PubMed

    Tribulova, N; Knezl, V; Szeiffova Bacova, B; Egan Benova, T; Viczenczova, C; Gonçalvesova, E; Slezak, J

    2016-09-19

    We aimed to determine the impact of Ca(2+)-related disorders induced in intact animal hearts on ultrastructure of the cardiomyocytes prior to occurrence of severe arrhythmias. Three types of acute experiments were performed that are known to be accompanied by disturbances in Ca(2+) handling. Langedorff-perfused rat or guinea pig hearts subjected to K(+)-deficient perfusion to induce ventricular fibrillation (VF), burst atrial pacing to induce atrial fibrillation (AF) and open chest pig heart exposed to intramyocardial noradrenaline infusion to induce ventricular tachycardia (VT). Tissue samples for electron microscopic examination were taken during basal condition, prior and during occurrence of malignant arrhythmias. Cardiomyocyte alterations preceding occurrence of arrhythmias consisted of non-uniform sarcomere shortening, disruption of myofilaments and injury of mitochondria that most likely reflected cytosolic Ca(2+) disturbances and Ca(2+) overload. These disorders were linked with non-uniform pattern of neighboring cardiomyocytes and dissociation of adhesive junctions suggesting defects in cardiac cell-to-cell coupling. Our findings identified heterogeneously distributed high [Ca(2+)](i)-induced subcellular injury of the cardiomyocytes and their junctions as a common feature prior occurrence of VT, VF or AF. In conclusion, there is a link between Ca(2+)-related disorders in contractility and coupling of the cardiomyocytes pointing out a novel paradigm implicated in development of severe arrhythmias. PMID:27643936

  2. Whole transcriptome analysis of transgenic barley with altered cytokinin homeostasis and increased tolerance to drought stress.

    PubMed

    Vojta, Petr; Kokáš, Filip; Husičková, Alexandra; Grúz, Jiří; Bergougnoux, Veronique; Marchetti, Cintia F; Jiskrová, Eva; Ježilová, Eliška; Mik, Václav; Ikeda, Yoshihisa; Galuszka, Petr

    2016-09-25

    Cytokinin plant hormones have been shown to play an important role in plant response to abiotic stresses. Herein, we expand upon the findings of Pospíšilová et al. [30] regarding preparation of novel transgenic barley lines overexpressing cytokinin dehydrogenase 1 gene from Arabidopsis under the control of mild root-specific promotor of maize β-glycosidase. These lines showed drought-tolerant phenotype mainly due to alteration of root architecture and stronger lignification of root tissue. A detailed transcriptomic analysis of roots of transgenic plants subjected to revitalization after drought stress revealed attenuated response through the HvHK3 cytokinin receptor and up-regulation of two transcription factors implicated in stress responses and abscisic acid sensitivity. Increased expression of several genes involved in the phenylpropanoid pathway as well as of genes encoding arogenate dehydratase/lyase participating in phenylalanine synthesis was found in roots during revitalization. Although more precursors of lignin synthesis were present in roots after drought stress, final lignin accumulation did not change compared to that in plants grown under optimal conditions. Changes in transcriptome indicated a higher auxin turnover in transgenic roots. The same analysis in leaves revealed that genes encoding putative enzymes responsible for production of jasmonates and other volatile compounds were up-regulated. Although transgenic barley leaves showed lower chlorophyll content and down-regulation of genes encoding proteins involved in photosynthesis than did wild-type plants when cultivated under optimal conditions, they did show a tendency to return to initial photochemical activities faster than did wild-type leaves when re-watered after severe drought stress. In contrast to optimal conditions, comparative transcriptomic analysis of revitalized leaves displayed up-regulation of genes encoding enzymes and proteins involved in photosynthesis, and especially

  3. Restraint Stress Impairs Glucose Homeostasis Through Altered Insulin Signalling in Sprague-Dawley Rat.

    PubMed

    Morakinyo, Ayodele O; Ajiboye, Kolawole I; Oludare, Gabriel O; Samuel, Titilola A

    2016-01-01

    The study investigated the potential alteration in the level of insulin and adiponectin, as well as the expression of insulin receptors (INSR) and glucose transporter 4 GLUT-4 in chronic restraint stress rats. Sprague-Dawley rats were randomly divided into two groups: the control group and stress group in which the rats were exposed to one of the four different restraint stressors; 1 h, twice daily for a period of 7 days (S7D), 14 days (S14D) and 28 days (S28D). Glucose tolerance and insulin sensitivity were evaluated following the final stress exposure. ELISA were performed to assess the level of insulin and adiponectin as well as expression of INSR and GLUT4 protein in skeletal muscle. Plasma corticosterone level was also determined as a marker of stress exposure. Restraint stress for 7 days caused transient glucose intolerance, while S14D rats demonstrated increased glucose intolerance and insulin insensitivity. However, restraint stress for 28 days had no effect on glucose tolerance, but did cause an increase in glucose response to insulin challenge. The serum level of adiponectin was significantly (p< 0.05) lower compared with the control value while insulin remained unchanged except at in S28D rats that had a significant (p<0.05) increase. The expression of INSR and GLUT4 receptors were significantly (p< 0.05) decreased in the skeletal muscle of restraint stress exposed rats. There was a significant (p< 0.05) increase in the plasma corticosterone level of the stress rats compared with their control counterparts. Restraint stress caused glucose intolerance and insulin insensitivity in male Sprague-Dawley rats, which becomes accommodated with prolonged exposure and was likely related to the blunted insulin signalling in skeletal muscle. PMID:27574760

  4. REM sleep deprivation reverses neurochemical and other depressive-like alterations induced by olfactory bulbectomy.

    PubMed

    Maturana, Maira J; Pudell, Cláudia; Targa, Adriano D S; Rodrigues, Laís S; Noseda, Ana Carolina D; Fortes, Mariana H; Dos Santos, Patrícia; Da Cunha, Cláudio; Zanata, Sílvio M; Ferraz, Anete C; Lima, Marcelo M S

    2015-02-01

    There is compelling evidence that sleep deprivation (SD) is an effective strategy in promoting antidepressant effects in humans, whereas few studies were performed in relevant animal models of depression. Acute administration of antidepressants in humans and rats generates a quite similar effect, i.e., suppression of rapid eye movement (REM) sleep. Then, we decided to investigate the neurochemical alterations generated by a protocol of rapid eye movement sleep deprivation (REMSD) in the notably known animal model of depression induced by the bilateral olfactory bulbectomy (OBX). REMSD triggered antidepressant mechanisms such as the increment of brain-derived neurotrophic factor (BDNF) levels, within the substantia nigra pars compacta (SNpc), which were strongly correlated to the swimming time (r = 0.83; P < 0.0001) and hippocampal serotonin (5-HT) content (r = 0.66; P = 0.004). Moreover, there was a strong correlation between swimming time and hippocampal 5-HT levels (r = 0.70; P = 0.003), strengthen the notion of an antidepressant effect associated to REMSD in the OBX rats. In addition, REMSD robustly attenuated the hippocampal 5-HT deficiency produced by the OBX procedure. Regarding the rebound (REB) period, we observed the occurrence of a sustained antidepressant effect, indicated mainly by the swimming and climbing times which could be explained by the maintenance of the increased nigral BDNF expression. Hence, hippocampal 5-HT levels remained enhanced in the OBX group after this period. We suggested that the neurochemical complexity inflicted by the OBX model, counteracted by REMSD, is directly correlated to the nigral BDNF expression and hippocampal 5-HT levels. The present findings provide new information regarding the antidepressant mechanisms triggered by REMSD.

  5. The impact of effective continuous positive airway pressure on homeostasis model assessment insulin resistance in non-diabetic patients with moderate to severe obstructive sleep apnea.

    PubMed

    Yang, Dan; Liu, Zhihong; Yang, Haixing

    2012-09-01

    Previous studies on the effects of continuous positive airway pressure (CPAP) on homeostasis model assessment insulin resistance (HOMA-IR) in obstructive sleep apnea patients have yielded conflicting results. Therefore, we conducted this meta-analysis to evaluate the impact of effective CPAP on HOMA-IR in non-diabetic patients with moderate to severe obstructive sleep apnea. We searched PubMed, HighWire Press, Ovid Medline (R), Cochrane library and EMBASE before December 2011 on original English language studies. The data on HOMA-IR and body mass index (BMI) were extracted from these studies. As compared with baseline values, 8 to 24 weeks of effective CPAP (>4 h/night) treatment significantly reduced HOMA-IR by an average of 0.75(95% CI, from -0.96 to -0.53; p < 0.001). However, in subjects with irregular CPAP (<4 h/night), this effect was not observed (-0.22; 95%CI, from -2.24 to 1.80; p = 0.83). There were no intervention-related changes in BMI in both regular and irregular CPAP. Our analysis showed that 8 to 24 weeks of effective CPAP could significantly improve HOMA-IR in non-diabetic patients with moderate to severe obstructive sleep apnea, while no significant changes in BMI were detected. Further large scale, randomized and controlled trials are needed to evaluate the longer treatment and its possible effects on weight control and cardiovascular disease.

  6. Neutral buoyancy and sleep-deprived serum factors alter expression of cytokines regulating osteogenesis

    NASA Astrophysics Data System (ADS)

    Gorczynski, Reginald M.; Gorczynski, Christopher P.; Gorczynski, Laura Y.; Hu, Jiang; Lu, Jin; Manuel, Justin; Lee, Lydia

    2005-05-01

    We examined expression of genes associated with cytokine production, and genes implicated in regulating bone metabolism, in bone stromal and osteoblast cells incubated under standard ground conditions and under conditions of neutral buoyancy, and in the presence/absence of serum from normal or sleep-deprived mice. We observed a clear interaction between these two conditions (exposure to neutral buoyancy and serum stimulation) in promoting enhanced osteoclastogenesis. Both conditions independently altered expression of a number of cytokines implicated in the regulation of bone metabolism. However, using stromal cells from IL-1 and TNF α cytokine r KO mice, we concluded that the increased bone loss under microgravity conditions was not primarily cytokine mediated.

  7. Sleep loss alters synaptic and intrinsic neuronal properties in mouse prefrontal cortex

    PubMed Central

    Winters, Bradley D.; Huang, Yanhua H.; Dong, Yan; Krueger, James M.

    2011-01-01

    Despite sleep-loss-induced cognitive deficits, little is known about the cellular adaptations that occur with sleep loss. We used brain slices obtained from mice that were sleep deprived for 8 h to examine the electrophysiological effects of sleep deprivation (SD). We employed a modified pedestal (flowerpot) over water method for SD that eliminated rapid eye movement sleep and greatly reduced non-rapid eye movement sleep. In layer V/VI pyramidal cells of the medial prefrontal cortex, miniature excitatory post synaptic current amplitude was slightly reduced, miniature inhibitory post synaptic currents were unaffected, and intrinsic membrane excitability was increased after SD. PMID:21962531

  8. Nighttime Sleep Macrostructure Is Altered in Otherwise Healthy 10-Year-Old Overweight Children

    PubMed Central

    Chamorro, Rodrigo; Algarín, Cecilia; Garrido, Marcelo; Causa, Leonardo; Held, Claudio; Lozoff, Betsy; Peirano, Patricio

    2014-01-01

    Objective Epidemiological evidence shows an inverse relationship between sleep duration and overweight/obesity risk. However, there are few polysomnographic studies that relate the organization of sleep stages to pediatric overweight (OW). We compared sleep organization in otherwise healthy OW and normal weight (NW) 10-year-old children. Subjects Polysomnographic assessments were performed in 37 NW and 59 OW children drawn from a longitudinal study beginning in infancy. Weight and height were used to evaluate body-mass index (BMI) according to international criteria. Non-REM (NREM) sleep (stages N1, N2 and N3), rapid eye movement (REM) sleep (stage R), and wakefulness (stage W) were visually scored. Sleep parameters were compared in NW and OW groups for the whole total sleep period (SPT) and for each successive third of it using independent student t-tests or non-parametric tests. The relationship between BMI and sleep variables was evaluated by correlation analyses controlling for relevant covariates. Results The groups were similar in timing of sleep onset and offset, and sleep period time. BMI was inversely related to total sleep time (TST) and sleep efficiency. OW children showed reduced TST, sleep efficiency, and stage R amount, but higher stage W amount. In analysis by thirds of the SPT, the duration of stage N3 episodes, was shorter in the first third and longer in the second third in OW children, compared with NW children. Conclusions Our results show reduced sleep amount and quality in otherwise healthy OW children. The lower stage R amount and changes involving stage N3 throughout the night suggest that OW in childhood is associated with modifications not only in sleep duration, but also in the ongoing nighttime patterns of NREM sleep and REM sleep stages. PMID:24352291

  9. Pain hypersensitivity induced by paradoxical sleep deprivation is not due to altered binding to brain mu-opioid receptors.

    PubMed

    Nascimento, Danielle C; Andersen, Monica L; Hipólide, Débora Cristina; Nobrega, José N; Tufik, Sergio

    2007-03-28

    Previous studies have established a relationship between sleep disruption and pain, and it has been suggested that hyperalgesia induced by paradoxical sleep deprivation (PSD) could be due to a reduction of opioidergic neurotransmission in the brain. In the present study rats deprived of sleep for 96 h as well as rats allowed to recover for 24h after PSD and normal controls received vehicle or morphine (2.5, 5 and 10 mg/kg, i.p.) and were tested on a hot plate 1h later. Quantitative receptor autoradiography was used to map alterations in binding to brain mu-opioid receptors in separate groups. Results demonstrated that PSD induced a significant reduction in thermal pain threshold, as measured by paw withdrawal latencies. This effect did not return to baseline control values after 24h of sleep recovery. The usual analgesic effect of morphine was observed in the control group but not in PSD or rebound groups except at the highest dose (10 mg/kg). Binding of [3H]DAMGO to mu sites did not differ significantly among the three groups in any of the 33 brain regions examined. These results do not exclude the participation of the opioid system in PSD-induced pain hypersensitivity since sleep-deprived rats were clearly resistant to morphine. However, the fact no changes were seen in [3H]DAMGO binding indicates that mechanisms other than altered mu-opioid binding must be sought to explain the phenomenon.

  10. Mice Lacking the Circadian Modulators SHARP1 and SHARP2 Display Altered Sleep and Mixed State Endophenotypes of Psychiatric Disorders

    PubMed Central

    Shahmoradi, Ali; Reinecke, Lisa; Kroos, Christina; Wichert, Sven P.; Oster, Henrik; Wehr, Michael C.; Taneja, Reshma; Hirrlinger, Johannes; Rossner, Moritz J.

    2014-01-01

    Increasing evidence suggests that clock genes may be implicated in a spectrum of psychiatric diseases, including sleep and mood related disorders as well as schizophrenia. The bHLH transcription factors SHARP1/DEC2/BHLHE41 and SHARP2/DEC1/BHLHE40 are modulators of the circadian system and SHARP1/DEC2/BHLHE40 has been shown to regulate homeostatic sleep drive in humans. In this study, we characterized Sharp1 and Sharp2 double mutant mice (S1/2-/-) using online EEG recordings in living animals, behavioral assays and global gene expression profiling. EEG recordings revealed attenuated sleep/wake amplitudes and alterations of theta oscillations. Increased sleep in the dark phase is paralleled by reduced voluntary activity and cortical gene expression signatures reveal associations with psychiatric diseases. S1/2-/- mice display alterations in novelty induced activity, anxiety and curiosity. Moreover, mutant mice exhibit impaired working memory and deficits in prepulse inhibition resembling symptoms of psychiatric diseases. Network modeling indicates a connection between neural plasticity and clock genes, particularly for SHARP1 and PER1. Our findings support the hypothesis that abnormal sleep and certain (endo)phenotypes of psychiatric diseases may be caused by common mechanisms involving components of the molecular clock including SHARP1 and SHARP2. PMID:25340473

  11. Withstanding the obstructive sleep apnea syndrome at the expense of arousal instability, altered cerebral autoregulation and neurocognitive decline.

    PubMed

    Torabi-Nami, Mohammad; Mehrabi, Samrad; Borhani-Haghighi, Afshin; Derman, Sabri

    2015-06-01

    The present review attempts to put together the available evidence and potential research paradigms at the interface of obstructive sleep apnea syndrome (OSAS), sleep micro- and macrostructure, cerebral vasoreactivity and cognitive neuroscience. Besides the significant health-related consequences of OSAS including hypertension, increased risk of cardio- and cerebrovascular events, notable neurocognitive lapses and excessive daytime somnolence are considered as potential burdens. The intermittent nocturnal hypoxia and hypercapnia which occur in OSAS are known to affect cerebral circulation and result in brain hypoperfusion. Arousal instability is then resulted from altered cyclic alternating patterns (CAPs) reflected in sleep EEG. In chronic state, some pathological loss of gray matter may be resulted from obstructive sleep apnea. This is proposed to be related to an upregulated proinflammatory state which may potentially result in apoptotic cell loss in the brain. On this basis, a pragmatic framework of the possible neural mechanisms which underpin obstructive sleep apnea-related neurocognitive decline has been discussed in this review. In addition, the impact of OSAS on cerebral autoregulation and sleep microstructure has been articulated. PMID:25916253

  12. The common inhaled anesthetic isoflurane increases aggregation of huntingtin and alters calcium homeostasis in a cell model of Huntington's disease

    SciTech Connect

    Wang Qiujun; Liang Ge; Yang Hui; Wang Shouping; Eckenhoff, Maryellen F.; Wei Huafeng

    2011-02-01

    Isoflurane is known to increase {beta}-amyloid aggregation and neuronal damage. We hypothesized that isoflurane will have similar effects on the polyglutamine huntingtin protein and will cause alterations in intracellular calcium homeostasis. We tested this hypothesis in striatal cells from the expanded glutamine huntingtin knock-in mouse (STHdh{sup Q111/Q111}) and wild type (STHdh{sup Q7/Q7}) striatal neurons. The primary cultured neurons were exposed for 24 h to equipotent concentrations of isoflurane, sevoflurane, and desflurane in the presence or absence of extracellular calcium and with or without xestospongin C, a potent endoplasmic reticulum inositol 1,4,5-trisphosphate (InsP{sub 3}) receptor antagonist. Aggregation of huntingtin protein, cell viability, and calcium concentrations were measured. Isoflurane, sevoflurane, and desflurane all increased the aggregation of huntingtin in STHdh{sup Q111/Q111} cells, with isoflurane having the largest effect. Isoflurane induced greater calcium release from the ER and relatively more cell damage in the STHdh{sup Q111/Q111} huntingtin cells than in the wild type STHdh{sup Q7/Q7} striatal cells. However, sevoflurane and desflurane caused less calcium release from the ER and less cell damage. Xestospongin C inhibited the isoflurane-induced calcium release from the ER, aggregation of huntingtin, and cell damage in the STHdh{sup Q111/Q111} cells. In summary, the Q111 form of huntingtin increases the vulnerability of striatal neurons to isoflurane neurotoxicity through combined actions on the ER IP{sub 3} receptors. Calcium release from the ER contributes to the anesthetic induced huntingtin aggregation in STHdh{sup Q111/Q111} striatal cells.

  13. Cardiac-Specific Disruption of GH Receptor Alters Glucose Homeostasis While Maintaining Normal Cardiac Performance in Adult Male Mice.

    PubMed

    Jara, Adam; Liu, Xingbo; Sim, Don; Benner, Chance M; Duran-Ortiz, Silvana; Qian, Yanrong; List, Edward O; Berryman, Darlene E; Kim, Jason K; Kopchick, John J

    2016-05-01

    GH is considered necessary for the proper development and maintenance of several tissues, including the heart. Studies conducted in both GH receptor null and bovine GH transgenic mice have demonstrated specific cardiac structural and functional changes. In each of these mouse lines, however, GH-induced signaling is altered systemically, being decreased in GH receptor null mice and increased in bovine GH transgenic mice. Therefore, to clarify the direct effects GH has on cardiac tissue, we developed a tamoxifen-inducible, cardiac-specific GHR disrupted (iC-GHRKO) mouse line. Cardiac GH receptor was disrupted in 4-month-old iC-GHRKO mice to avoid developmental effects due to perinatal GHR gene disruption. Surprisingly, iC-GHRKO mice showed no difference vs controls in baseline or postdobutamine stress test echocardiography measurements, nor did iC-GHRKO mice show differences in longitudinal systolic blood pressure measurements. Interestingly, iC-GHRKO mice had decreased fat mass and improved insulin sensitivity at 6.5 months of age. By 12.5 months of age, however, iC-GHRKO mice no longer had significant decreases in fat mass and had developed glucose intolerance and insulin resistance. Furthermore, investigation via immunoblot analysis demonstrated that iC-GHRKO mice had appreciably decreased insulin stimulated Akt phosphorylation, specifically in heart and liver, but not in epididymal white adipose tissue. These changes were accompanied by a decrease in circulating IGF-1 levels in 12.5-month-old iC-GHRKO mice. These data indicate that whereas the disruption of cardiomyocyte GH-induced signaling in adult mice does not affect cardiac function, it does play a role in systemic glucose homeostasis, in part through modulation of circulating IGF-1. PMID:27035649

  14. Gestational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin alters retinoid homeostasis in maternal and perinatal tissues of the Holtzman rat

    SciTech Connect

    Kransler, Kevin M. Tonucci, David A. McGarrigle, Barbara P. Napoli, Joseph L. Olson, James R.

    2007-10-01

    2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), one of the most widely studied environmental contaminants, causes a variety of adverse health effects including teratogenesis and altered development which may be related to disruptions in retinoid homeostasis. The purpose of this study was to determine the effect that gestational administration of TCDD has on retinoid homeostasis in both pregnant Holtzman rats and developing fetuses and neonates. A single oral dose of TCDD (0, 1.5, 3, or 6 {mu}g/kg) was administered to pregnant rats on gestation day 10, with fetuses analyzed on gestation days 17 and 20, and neonates analyzed on post natal day 7. Exposure to TCDD generally produced decreases in the concentrations of retinyl esters, such as retinyl palmitate, and retinol in maternal and perinatal liver and lung, while increasing levels in the maternal kidney. Additionally, perinatal hepatic retinol binding protein 1-dependent retinyl ester hydrolysis was also decrease by TCDD. Sensitivity of the developing perinates to TCDD appeared to have an age-related component demonstrated by an increased rate of mortality and significant alterations to body weight and length on post natal day 7 relative to that observed at gestation day 20. A unique observation made in this study was a significant decrease in lung weight observed in the perinates exposed to TCDD. Taken together, these data demonstrate that TCDD significantly alters retinoid homeostasis in tissues of the developing fetus and neonate, suggesting that their unique sensitivity to TCDD may at least be in part the result of altered retinoid homeostasis.

  15. Homeostatic regulation of sleep in arrhythmic Siberian hamsters.

    PubMed

    Larkin, Jennie E; Yokogawa, Tohei; Heller, H Craig; Franken, Paul; Ruby, Norman F

    2004-07-01

    Sleep is regulated by independent yet interacting circadian and homeostatic processes. The present study used a novel approach to study sleep homeostasis in the absence of circadian influences by exposing Siberian hamsters to a simple phase delay of the photocycle to make them arrhythmic. Because these hamsters lacked any circadian organization, their sleep homeostasis could be studied in the absence of circadian interactions. Control animals retained circadian rhythmicity after the phase shift and re-entrained to the phase-shifted photocycle. These animals displayed robust daily sleep-wake rhythms with consolidated sleep during the light phase beginning about 1 h after light onset. This marked sleep-wake pattern was circadian in that it persisted in constant darkness. The distribution of sleep in the arrhythmic hamsters over 24 h was similar to that in the light phase of rhythmic animals. Therefore, daily sleep amounts were higher in arrhythmic animals compared with rhythmic ones. During 2- and 6-h sleep deprivations (SD), it was more difficult to keep arrhythmic hamsters awake than it was for rhythmic hamsters. Because the arrhythmic animals obtained more non-rapid eye movement sleep (NREMS) during the SD, they showed a diminished compensatory response in NREMS EEG slow-wave activity during recovery sleep. When amounts of sleep during the SD were taken into account, there were no differences in sleep homeostasis between experimental and control hamsters. Thus loss of circadian control did not alter the homeostatic response to SD. This supports the view that circadian and homeostatic influences on sleep regulation are independent processes.

  16. Altered thalamocortical and intra-thalamic functional connectivity during light sleep compared with wake.

    PubMed

    Hale, Joanne R; White, Thomas P; Mayhew, Stephen D; Wilson, Rebecca S; Rollings, David T; Khalsa, Sakhvinder; Arvanitis, Theodoros N; Bagshaw, Andrew P

    2016-01-15

    The transition from wakefulness into sleep is accompanied by modified activity in the brain's thalamocortical network. Sleep-related decreases in thalamocortical functional connectivity (FC) have previously been reported, but the extent to which these changes differ between thalamocortical pathways, and patterns of intra-thalamic FC during sleep remain untested. To non-invasively investigate thalamocortical and intra-thalamic FC as a function of sleep stage we recorded simultaneous EEG-fMRI data in 13 healthy participants during their descent into light sleep. Visual scoring of EEG data permitted sleep staging. We derived a functional thalamic parcellation during wakefulness by computing seed-based FC, measured between thalamic voxels and a set of pre-defined cortical regions. Sleep differentially affected FC between these distinct thalamic subdivisions and their associated cortical projections, with significant increases in FC during sleep restricted to sensorimotor connections. In contrast, intra-thalamic FC, both within and between functional thalamic subdivisions, showed significant increases with advancement into sleep. This work demonstrates the complexity and state-specific nature of functional thalamic relationships--both with the cortex and internally--over the sleep/wake cycle, and further highlights the importance of a thalamocortical focus in the study of sleep mechanisms.

  17. Homeostasis in Primates in the Hyperdynamic Environment. [circadian timekeeping and effects of lower body positive pressure on sleep

    NASA Technical Reports Server (NTRS)

    Fuller, C. A.

    1985-01-01

    The influence of chronic centrifugation upon the homestatic regulation of the circadian timekeeping system was examined. The interactions of body temperature regulation and the behavioral state of arousal were studied by evaluating the influence of cephalic fluid shifts induced by lower body positive air pressure (LBPP), upon these systems. The small diurnal squirrel monkey (Saimiri sciureus) was used as the non-human primate model. Results show that the circadian timekeeping system of these primates is functional in the hyperdynamic environment, however, some of its components appear to be regulated at different homeostatic levels. The LBPP resulted in an approximate 0.7 C decrease in DBT (p 0.01). However, although on video some animals appeared drowsy during LBPP, sleep recording revealed no significant changes in state of arousal. Thus, the physiological mechanisms underlying this lowering of body temperature can be independent of the arousal state.

  18. Dynamic alterations of the tongue in obstructive sleep apnea-hypopnea syndrome during sleep: analysis using ultrafast MRI.

    PubMed

    Wang, Y; Mcdonald, J P; Liu, Y; Pan, K; Zhang, X; Hu, R

    2014-06-17

    Patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) were evaluated using ultrafast magnetic resonance imaging (UMRI) while asleep and awake to analyze tongue changes. The upper airway of 21 OSAHS patients and 20 normal controls were examined during sleep using UMRI. A series of midline sagittal images of the upper airway were obtained to measure dynamic changes in tongue size and the distance from the tongue to the x-axis (an extended line from the anterior nasal spine to posterior nasal spine) and the y-axis (a perpendicular line from the center of the pituitary to the x-axis). The maximum and minimum sagittal diameters of the tongue were shorter in the OSAHS group than in the control group (P<0.01) while awake, whereas the difference between the maximum and minimum vertical diameters of the tongue and the upper and central part of tongue between the posterior border and the retropharyngeal wall were greater (P<0.05). During sleep, the maximum values and differences between the maximum and minimum tongue sizes in the OSAHS group were larger than in the control group (P<0.05), whereas the minimum values were lower than in the control group (P<0.01). Tongue size significantly differs between OSAHS patients and normal controls during sleep. The tongue tends to move downward during OSAHS, which may be attributed to increased upper airway resistance.

  19. Antagonism of corticotropin-releasing hormone alters serotonergic-induced changes in brain temperature, but not sleep, of rats.

    PubMed

    Imeri, Luca; Bianchi, Susanna; Opp, Mark R

    2005-10-01

    Serotonin is involved in many physiological processes, including the regulation of sleep and body temperature. Administration into rats of low doses (25, 50 mg/kg) of the 5-HT precursor l-5-hydroxytryptophan (5-HTP) at the beginning of the dark period of the 12:12-h light-dark cycle initially increases wakefulness. Higher doses (75, 100 mg/kg) increase nonrapid eye movement (NREM) sleep. The initial enhancement of wakefulness after low-dose 5-HTP administration may be a direct action of 5-HT in brain or due to 5-HT-induced activation of other arousal-promoting systems. One candidate arousal-promoting system is corticotropin-releasing hormone (CRH) and the hypothalamic-pituitary-adrenal axis. Serotonergic activation by 5-HTP at the beginning of the dark period also induces hypothermia. Because sleep and body temperature are influenced by circadian factors, one aim of this study was to determine responses to 5-HTP when administered at a different circadian time, the beginning of the light period. Results obtained show that all doses of 5-HTP (25-100 mg/kg) administered at light onset initially increase wakefulness; NREM sleep increases only after a long delay, during the subsequent dark period. Serotonergic activation by 5-HTP at light onset induces hypothermia, the time course of which is biphasic after higher doses (75, 100 mg/kg). Intracerebroventricular pretreatment with the CRH receptor antagonist alpha-helical CRH does not alter the impact of 5-HTP on sleep-wake behavior but potentiates the hypothermic response to 50 mg/kg 5-HTP. These data suggest that serotonergic activation by peripheral administration of 5-HTP may modulate sleep-wake behavior by mechanisms in addition to direct actions in brain and that circadian systems are important determinants of the impact of serotonergic activation on sleep and body temperature. PMID:15994374

  20. Chlordecone, a mixed pregnane X receptor (PXR) and estrogen receptor alpha (ER{alpha}) agonist, alters cholesterol homeostasis and lipoprotein metabolism in C57BL/6 mice

    SciTech Connect

    Lee, Junga; Scheri, Richard C.; Zhang Yuan; Curtis, Lawrence R.

    2008-12-01

    Chlordecone (CD) is one of many banned organochlorine (OC) insecticides that are widespread persistent organic pollutants. OC insecticides alter lipid homeostasis in rodents at doses that are not neurotoxic or carcinogenic. Pretreatment of mice or rats with CD altered tissue distribution of a subsequent dose of [{sup 14}C]CD or [{sup 14}C]cholesterol (CH). Nuclear receptors regulate expression of genes important in the homeostasis of CH and other lipids. In this study, we report that CD suppresses in vitro reporter systems for human liver X receptors (LXRs) and activates those for human farnesoid X receptor (FXR), pregnane X receptor (PXR) and estrogen receptor {alpha} (ER{alpha}) in a concentration-dependent manner (0-50 {mu}M). Consistent with human PXR activation in vitro, three days after a single dose of CD (15 mg/kg) hepatic microsomal CYP3A11 protein increases in C57BL/6 mice. CD decreases hepatic CH ester content without altering total CH concentration. Apolipoprotein A-I (apoA-I) contents of hepatic lipoprotein-rich and microsomal fractions of CD-treated mice are higher than controls. There is a significant reduction in non-high density lipoprotein CH but not apolipoprotein B-48/100 (apoB-48/100) in plasma from CD-treated mice after a 4 h fast. At 14 days after 15 mg CD/kg apoA-I and apoB-100 proteins but not CYP3A11 protein in hepatic microsomes are similar to controls. This work indicates that altered CH homeostasis is a mode of OC insecticide action of relevance after a single dose. This at least partially explains altered CH tissue distribution in CD-pretreated mice.

  1. Electroencephalographic studies of sleep

    NASA Technical Reports Server (NTRS)

    Webb, W. B.; Agnew, H. W., Jr.

    1975-01-01

    Various experimental studies on sleep are described. The following areas are discussed: (1) effect of altered day length on sleep, (2) effect of a partial loss of sleep on subsequent nocturnal sleep; (3) effect of rigid control over sleep-wake-up times; (4) sleep and wakefulness in a time-free environment; (5) distribution of spindles during a full night of sleep; and (6) effect on sleep and performance of swiftly changing shifts of work.

  2. Loss of Goosecoid-like and DiGeorge syndrome critical region 14 in interpeduncular nucleus results in altered regulation of rapid eye movement sleep

    PubMed Central

    Funato, Hiromasa; Sato, Makito; Sinton, Christopher M.; Gautron, Laurent; Williams, S. Clay; Skach, Amber; Elmquist, Joel K.; Skoultchi, Arthur I.; Yanagisawa, Masashi

    2010-01-01

    Sleep and wakefulness are regulated primarily by inhibitory interactions between the hypothalamus and brainstem. The expression of the states of rapid eye movement (REM) sleep and non-REM (NREM) sleep also are correlated with the activity of groups of REM-off and REM-on neurons in the dorsal brainstem. However, the contribution of ventral brainstem nuclei to sleep regulation has been little characterized to date. Here we examined sleep and wakefulness in mice deficient in a homeobox transcription factor, Goosecoid-like (Gscl), which is one of the genes deleted in DiGeorge syndrome or 22q11 deletion syndrome. The expression of Gscl is restricted to the interpeduncular nucleus (IP) in the ventral region of the midbrain–hindbrain transition. The IP has reciprocal connections with several cell groups implicated in sleep/wakefulness regulation. Although Gscl−/− mice have apparently normal anatomy and connections of the IP, they exhibited a reduced total time spent in REM sleep and fewer REM sleep episodes. In addition, Gscl−/− mice showed reduced theta power during REM sleep and increased arousability during REM sleep. Gscl−/− mice also lacked the expression of DiGeorge syndrome critical region 14 (Dgcr14) in the IP. These results indicate that the absence of Gscl and Dgcr14 in the IP results in altered regulation of REM sleep. PMID:20921407

  3. The Bidirectional Relationship between Sleep and Immunity against Infections

    PubMed Central

    Ibarra-Coronado, Elizabeth G.; Pantaleón-Martínez, Ana Ma.; Velazquéz-Moctezuma, Javier; Prospéro-García, Oscar; Méndez-Díaz, Mónica; Pérez-Tapia, Mayra; Pavón, Lenin; Morales-Montor, Jorge

    2015-01-01

    Sleep is considered an important modulator of the immune response. Thus, a lack of sleep can weaken immunity, increasing organism susceptibility to infection. For instance, shorter sleep durations are associated with a rise in suffering from the common cold. The function of sleep in altering immune responses must be determined to understand how sleep deprivation increases the susceptibility to viral, bacterial, and parasitic infections. There are several explanations for greater susceptibility to infections after reduced sleep, such as impaired mitogenic proliferation of lymphocytes, decreased HLA-DR expression, the upregulation of CD14+, and variations in CD4+ and CD8+ T lymphocytes, which have been observed during partial sleep deprivation. Also, steroid hormones, in addition to regulating sexual behavior, influence sleep. Thus, we hypothesize that sleep and the immune-endocrine system have a bidirectional relationship in governing various physiological processes, including immunity to infections. This review discusses the evidence on the bidirectional effects of the immune response against viral, bacterial, and parasitic infections on sleep patterns and how the lack of sleep affects the immune response against such agents. Because sleep is essential in the maintenance of homeostasis, these situations must be adapted to elicit changes in sleep patterns and other physiological parameters during the immune response to infections to which the organism is continuously exposed. PMID:26417606

  4. The Bidirectional Relationship between Sleep and Immunity against Infections.

    PubMed

    Ibarra-Coronado, Elizabeth G; Pantaleón-Martínez, Ana Ma; Velazquéz-Moctezuma, Javier; Prospéro-García, Oscar; Méndez-Díaz, Mónica; Pérez-Tapia, Mayra; Pavón, Lenin; Morales-Montor, Jorge

    2015-01-01

    Sleep is considered an important modulator of the immune response. Thus, a lack of sleep can weaken immunity, increasing organism susceptibility to infection. For instance, shorter sleep durations are associated with a rise in suffering from the common cold. The function of sleep in altering immune responses must be determined to understand how sleep deprivation increases the susceptibility to viral, bacterial, and parasitic infections. There are several explanations for greater susceptibility to infections after reduced sleep, such as impaired mitogenic proliferation of lymphocytes, decreased HLA-DR expression, the upregulation of CD14+, and variations in CD4+ and CD8+ T lymphocytes, which have been observed during partial sleep deprivation. Also, steroid hormones, in addition to regulating sexual behavior, influence sleep. Thus, we hypothesize that sleep and the immune-endocrine system have a bidirectional relationship in governing various physiological processes, including immunity to infections. This review discusses the evidence on the bidirectional effects of the immune response against viral, bacterial, and parasitic infections on sleep patterns and how the lack of sleep affects the immune response against such agents. Because sleep is essential in the maintenance of homeostasis, these situations must be adapted to elicit changes in sleep patterns and other physiological parameters during the immune response to infections to which the organism is continuously exposed. PMID:26417606

  5. Short-term total sleep deprivation alters delay-conditioned memory in the rat.

    PubMed

    Tripathi, Shweta; Jha, Sushil K

    2016-06-01

    Short-term sleep deprivation soon after training may impair memory consolidation. Also, a particular sleep stage or its components increase after learning some tasks, such as negative and positive reinforcement tasks, avoidance tasks, and spatial learning tasks, and so forth. It suggests that discrete memory types may require specific sleep stage or its components for their optimal processing. The classical conditioning paradigms are widely used to study learning and memory but the role of sleep in a complex conditioned learning is unclear. Here, we have investigated the effects of short-term sleep deprivation on the consolidation of delay-conditioned memory and the changes in sleep architecture after conditioning. Rats were trained for the delay-conditioned task (for conditioning, house-light [conditioned stimulus] was paired with fruit juice [unconditioned stimulus]). Animals were divided into 3 groups: (a) sleep deprived (SD); (b) nonsleep deprived (NSD); and (c) stress control (SC) groups. Two-way ANOVA revealed a significant interaction between groups and days (training and testing) during the conditioned stimulus-unconditioned stimulus presentation. Further, Tukey post hoc comparison revealed that the NSD and SC animals exhibited significant increase in performances during testing. The SD animals, however, performed significantly less during testing. Further, we observed that wakefulness and NREM sleep did not change after training and testing. Interestingly, REM sleep increased significantly on both days compared to baseline more specifically during the initial 4-hr time window after conditioning. Our results suggest that the consolidation of delay-conditioned memory is sleep-dependent and requires augmented REM sleep during an explicit time window soon after training. (PsycINFO Database Record PMID:26890247

  6. Altering Misperception of Sleep in Insomnia: Behavioral Experiment Versus Verbal Feedback

    ERIC Educational Resources Information Center

    Tang, Nicole K. Y.; Harvey, Allison G.

    2006-01-01

    Forty-eight individuals with insomnia were asked to wear an actigraph and keep a sleep diary for 2 nights. On the following day, half were shown the discrepancy between the data recorded on the actigraph and their sleep diary via a behavioral experiment, whereas the other half were told of the discrepancy verbally. Participants were then asked to…

  7. Objective sleep, a novel risk factor for alterations in kidney function: the CARDIA Study

    PubMed Central

    Petrov, Megan E.; Kim, Yongin; Lauderdale, Diane S.; Lewis, Cora E.; Reis, Jared P.; Carnethon, Mercedes R.; Knutson, Kristen L.; Glasser, Stephen P.

    2014-01-01

    Objective To determine the association between objectively measured sleep and 10-year changes in estimated glomerular filtration rate (eGFR). Methods From 2003 to 2005, an ancillary sleep study was conducted at the Chicago site of the Coronary Artery Disease in Young Adults (CARDIA) study. Community-based black and white adults (aged 32–51 years) wore a wrist actigraph up to six nights to record sleep duration and fragmentation. Sleep quality was measured with the Pittsburgh Sleep Quality Index (PSQI). Participants without history of cardiovascular or chronic kidney diseases, proteinuria, or hypertension at the 2000–2001 CARDIA examination were followed over 10 years (n = 463). eGFR was estimated from serum creatinine (eGFRCr) at the 2000–2001, 2005–2006, and 2010–2011 CARDIA examinations, whereas cystatin-C-estimated eGFR (eGFRCys) was measured at the 2000–2001 and 2005–2006 examinations. Generalized estimating equation regression and linear models estimated the associations of each sleep parameter with changes in eGFRCr and eGFRCys, controlling for cardiovascular and renal risk. Results Sleep parameters were not related to 5-year change in eGFRCys. However, each 1 h decrease in sleep duration was significantly associated with a 1.5 mL/min/1.73 m2 higher eGFRCr [95% confidence interval (CI), 0.2–2.7], and each one-point increase in PSQI was significantly associated with a 0.5 mL/min/1.73 m2 higher eGFRCr (95% CI, 0.04–0.9) over 10 years. Conclusion In this community-based sample, shorter sleep and poorer sleep quality were related to higher kidney filtration rates over 10 years. PMID:25037841

  8. The loss of ATP2C1 impairs the DNA damage response and induces altered skin homeostasis: Consequences for epidermal biology in Hailey-Hailey disease.

    PubMed

    Cialfi, Samantha; Le Pera, Loredana; De Blasio, Carlo; Mariano, Germano; Palermo, Rocco; Zonfrilli, Azzurra; Uccelletti, Daniela; Palleschi, Claudio; Biolcati, Gianfranco; Barbieri, Luca; Screpanti, Isabella; Talora, Claudio

    2016-01-01

    Mutation of the Golgi Ca(2+)-ATPase ATP2C1 is associated with deregulated calcium homeostasis and altered skin function. ATP2C1 mutations have been identified as having a causative role in Hailey-Hailey disease, an autosomal-dominant skin disorder. Here, we identified ATP2C1 as a crucial regulator of epidermal homeostasis through the regulation of oxidative stress. Upon ATP2C1 inactivation, oxidative stress and Notch1 activation were increased in cultured human keratinocytes. Using RNA-seq experiments, we found that the DNA damage response (DDR) was consistently down-regulated in keratinocytes derived from the lesions of patients with Hailey-Hailey disease. Although oxidative stress activates the DDR, ATP2C1 inactivation down-regulates DDR gene expression. We showed that the DDR response was a major target of oxidative stress-induced Notch1 activation. Here, we show that this activation is functionally important because early Notch1 activation in keratinocytes induces keratinocyte differentiation and represses the DDR. These results indicate that an ATP2C1/NOTCH1 axis might be critical for keratinocyte function and cutaneous homeostasis, suggesting a plausible model for the pathological features of Hailey-Hailey disease. PMID:27528123

  9. The loss of ATP2C1 impairs the DNA damage response and induces altered skin homeostasis: Consequences for epidermal biology in Hailey-Hailey disease

    PubMed Central

    Cialfi, Samantha; Le Pera, Loredana; De Blasio, Carlo; Mariano, Germano; Palermo, Rocco; Zonfrilli, Azzurra; Uccelletti, Daniela; Palleschi, Claudio; Biolcati, Gianfranco; Barbieri, Luca; Screpanti, Isabella; Talora, Claudio

    2016-01-01

    Mutation of the Golgi Ca2+-ATPase ATP2C1 is associated with deregulated calcium homeostasis and altered skin function. ATP2C1 mutations have been identified as having a causative role in Hailey-Hailey disease, an autosomal-dominant skin disorder. Here, we identified ATP2C1 as a crucial regulator of epidermal homeostasis through the regulation of oxidative stress. Upon ATP2C1 inactivation, oxidative stress and Notch1 activation were increased in cultured human keratinocytes. Using RNA-seq experiments, we found that the DNA damage response (DDR) was consistently down-regulated in keratinocytes derived from the lesions of patients with Hailey-Hailey disease. Although oxidative stress activates the DDR, ATP2C1 inactivation down-regulates DDR gene expression. We showed that the DDR response was a major target of oxidative stress-induced Notch1 activation. Here, we show that this activation is functionally important because early Notch1 activation in keratinocytes induces keratinocyte differentiation and represses the DDR. These results indicate that an ATP2C1/NOTCH1 axis might be critical for keratinocyte function and cutaneous homeostasis, suggesting a plausible model for the pathological features of Hailey-Hailey disease. PMID:27528123

  10. Global deletion of MGL in mice delays lipid absorption and alters energy homeostasis and diet-induced obesity

    PubMed Central

    Douglass, John D.; Zhou, Yin Xiu; Wu, Amy; Zadrogra, John A.; Gajda, Angela M.; Lackey, Atreju I.; Lang, Wensheng; Chevalier, Kristen M.; Sutton, Steven W.; Zhang, Sui-Po; Flores, Christopher M.; Connelly, Margery A.; Storch, Judith

    2015-01-01

    Monoacylglycerol lipase (MGL) is a ubiquitously expressed enzyme that catalyzes the hydrolysis of monoacylglycerols (MGs) to yield FFAs and glycerol. MGL contributes to energy homeostasis through the mobilization of fat stores and also via the degradation of the endocannabinoid 2-arachidonoyl glycerol. To further examine the role of MG metabolism in energy homeostasis, MGL−/− mice were fed either a 10% (kilocalories) low-fat diet (LFD) or a 45% (kilocalories) high-fat diet (HFD) for 12 weeks. Profound increases of MG species in the MGL−/− mice compared with WT control mice were found. Weight gain over the 12 weeks was blunted in both diet groups. MGL−/− mice were leaner than WT mice at both baseline and after 12 weeks of LFD feeding. Circulating lipids were decreased in HFD-fed MGL−/− mice, as were the levels of several plasma peptides involved in glucose homeostasis and energy balance. Interestingly, MGL−/− mice had markedly reduced intestinal TG secretion following an oral fat challenge, suggesting delayed lipid absorption. Overall, the results indicate that global MGL deletion leads to systemic changes that produce a leaner phenotype and an improved serum metabolic profile. PMID:25842377

  11. Does sleep deprivation alter functional EEG networks in children with focal epilepsy?

    PubMed

    van Diessen, Eric; Otte, Willem M; Braun, Kees P J; Stam, Cornelis J; Jansen, Floor E

    2014-01-01

    Electroencephalography (EEG) recordings after sleep deprivation increase the diagnostic yield in patients suspected of epilepsy if the routine EEG remains inconclusive. Sleep deprivation is associated with increased interictal EEG abnormalities in patients with epilepsy, but the exact mechanism is unknown. In this feasibility study, we used a network analytical approach to provide novel insights into this clinical observation. The aim was to characterize the effect of sleep deprivation on the interictal functional network organization using a unique dataset of paired routine and sleep deprivation recordings in patients and controls. We included 21 children referred to the first seizure clinic of our center with suspected new onset focal epilepsy in whom a routine interictal and a sleep deprivation EEG (SD-EEG) were performed. Seventeen children, in whom the diagnosis of epilepsy was excluded, served as controls. For both time points weighted functional networks were constructed based on interictal artifact free time-series. Routine and sleep deprivation networks were characterized at different frequency bands using minimum spanning tree (MST) measures (leaf number and diameter) and classical measures of integration (path length) and segregation (clustering coefficient). A significant interaction was found for leaf number and diameter between patients and controls after sleep deprivation: patients showed a shift toward a more path-like MST network whereas controls showed a shift toward a more star-like MST network. This shift in network organization after sleep deprivation in patients is in accordance with previous studies showing a more regular network organization in the ictal state and might relate to the increased epileptiform abnormalities found in patients after sleep deprivation. Larger studies are needed to verify these results. Finally, MST measures were more sensitive in detecting network changes as compared to the classical measures of integration and

  12. Misassembly of full-length Disrupted-in-Schizophrenia 1 protein is linked to altered dopamine homeostasis and behavioral deficits

    PubMed Central

    Trossbach, S V; Bader, V; Hecher, L; Pum, M E; Masoud, S T; Prikulis, I; Schäble, S; de Souza Silva, M A; Su, P; Boulat, B; Chwiesko, C; Poschmann, G; Stühler, K; Lohr, K M; Stout, K A; Oskamp, A; Godsave, S F; Müller-Schiffmann, A; Bilzer, T; Steiner, H; Peters, P J; Bauer, A; Sauvage, M; Ramsey, A J; Miller, G W; Liu, F; Seeman, P; Brandon, N J; Huston, J P; Korth, C

    2016-01-01

    Disrupted-in-schizophrenia 1 (DISC1) is a mental illness gene first identified in a Scottish pedigree. So far, DISC1-dependent phenotypes in animal models have been confined to expressing mutant DISC1. Here we investigated how pathology of full-length DISC1 protein could be a major mechanism in sporadic mental illness. We demonstrate that a novel transgenic rat model, modestly overexpressing the full-length DISC1 transgene, showed phenotypes consistent with a significant role of DISC1 misassembly in mental illness. The tgDISC1 rat displayed mainly perinuclear DISC1 aggregates in neurons. Furthermore, the tgDISC1 rat showed a robust signature of behavioral phenotypes that includes amphetamine supersensitivity, hyperexploratory behavior and rotarod deficits, all pointing to changes in dopamine (DA) neurotransmission. To understand the etiology of the behavioral deficits, we undertook a series of molecular studies in the dorsal striatum of tgDISC1 rats. We observed an 80% increase in high-affinity DA D2 receptors, an increased translocation of the dopamine transporter to the plasma membrane and a corresponding increase in DA inflow as observed by cyclic voltammetry. A reciprocal relationship between DISC1 protein assembly and DA homeostasis was corroborated by in vitro studies. Elevated cytosolic dopamine caused an increase in DISC1 multimerization, insolubility and complexing with the dopamine transporter, suggesting a physiological mechanism linking DISC1 assembly and dopamine homeostasis. DISC1 protein pathology and its interaction with dopamine homeostasis is a novel cellular mechanism that is relevant for behavioral control and may have a role in mental illness. PMID:26754951

  13. Altered regulation of sleep and feeding contributes to starvation resistance in Drosophila melanogaster.

    PubMed

    Masek, Pavel; Reynolds, Lauren A; Bollinger, Wesley L; Moody, Catriona; Mehta, Aradhana; Murakami, Kazuma; Yoshizawa, Masato; Gibbs, Allen G; Keene, Alex C

    2014-09-01

    Animals respond to changes in food availability by adjusting sleep and foraging strategies to optimize their fitness. Wild populations of the fruit fly, Drosophila melanogaster, display highly variable levels of starvation resistance that are dependent on geographic location, food availability and evolutionary history. How behaviors that include sleep and feeding vary in Drosophila with increased starvation resistance is unclear. We have generated starvation-resistant flies through experimental evolution to investigate the relationship between foraging behaviors and starvation resistance. Outbred populations of D. melanogaster were selected for starvation resistance over 60 generations. This selection process resulted in flies with a threefold increase in total lipids that survive up to 18 days without food. We tested starvation-selected (S) flies for sleep and feeding behaviors to determine the effect that selection for starvation resistance has had on foraging behavior. Flies from three replicated starvation-selected populations displayed a dramatic reduction in feeding and prolonged sleep duration compared to fed control (F) populations, suggesting that modified sleep and feeding may contribute to starvation resistance. A prolonged larval developmental period contributes to the elevated energy stores present in starvation-selected flies. By preventing S larvae from feeding longer than F larvae, we were able to reduce energy stores in adult S flies to the levels seen in adult F flies, thus allowing us to control for energy storage levels. However, the reduction of energy stores in S flies fails to generate normal sleep and feeding behavior seen in F flies with similar energy stores. These findings suggest that the behavioral changes observed in S flies are due to genetic regulation of behavior rather than elevated lipid levels. Testing S-F hybrid individuals for both feeding and sleep revealed a lack of correlation between food consumption and sleep duration

  14. Chronic Sleep Disruption Alters Gut Microbiota, Induces Systemic and Adipose Tissue Inflammation and Insulin Resistance in Mice

    PubMed Central

    Poroyko, Valeriy A.; Carreras, Alba; Khalyfa, Abdelnaby; Khalyfa, Ahamed A.; Leone, Vanessa; Peris, Eduard; Almendros, Isaac; Gileles-Hillel, Alex; Qiao, Zhuanhong; Hubert, Nathaniel; Farré, Ramon; Chang, Eugene B.; Gozal, David

    2016-01-01

    Chronic sleep fragmentation (SF) commonly occurs in human populations, and although it does not involve circadian shifts or sleep deprivation, it markedly alters feeding behaviors ultimately promoting obesity and insulin resistance. These symptoms are known to be related to the host gut microbiota. Mice were exposed to SF for 4 weeks and then allowed to recover for 2 weeks. Taxonomic profiles of fecal microbiota were obtained prospectively, and conventionalization experiments were performed in germ-free mice. Adipose tissue insulin sensitivity and inflammation, as well as circulating measures of inflammation, were assayed. Effect of fecal water on colonic epithelial permeability was also examined. Chronic SF-induced increased food intake and reversible gut microbiota changes characterized by the preferential growth of highly fermentative members of Lachnospiraceae and Ruminococcaceae and a decrease of Lactobacillaceae families. These lead to systemic and visceral white adipose tissue inflammation in addition to altered insulin sensitivity in mice, most likely via enhanced colonic epithelium barrier disruption. Conventionalization of germ-free mice with SF-derived microbiota confirmed these findings. Thus, SF-induced metabolic alterations may be mediated, in part, by concurrent changes in gut microbiota, thereby opening the way for gut microbiome-targeted therapeutics aimed at reducing the major end-organ morbidities of chronic SF. PMID:27739530

  15. Sex-specific alterations in glucose homeostasis and metabolic parameters during ageing of caspase-2-deficient mice.

    PubMed

    Wilson, C H; Nikolic, A; Kentish, S J; Shalini, S; Hatzinikolas, G; Page, A J; Dorstyn, L; Kumar, S

    2016-01-01

    Gender-specific differences are commonly found in metabolic pathways and in response to nutritional manipulation. Previously, we identified a role for caspase-2 in age-related glucose homeostasis and lipid metabolism using male caspase-2-deficient (Casp2 (-/-) ) mice. Here we show that the resistance to age-induced glucose tolerance does not occur in female Casp2 (-/-) mice and it appears to be independent of insulin sensitivity in males. Using fasting (18 h) as a means to further investigate the role of caspase-2 in energy and lipid metabolism, we identified sex-specific differences in the fasting response and lipid mobilization. In aged (18-22 months) male Casp2 (-/-) mice, a significant decrease in fasting liver mass, but not total body weight, was observed while in females, total body weight, but not liver mass, was reduced when compared with wild-type (WT) animals. Fasting-induced lipolysis of adipose tissue was enhanced in male Casp2 (-/-) mice as indicated by a significant reduction in white adipocyte cell size, and increased serum-free fatty acids. In females, white adipocyte cell size was significantly smaller in both fed and fasted Casp2 (-/-) mice. No difference in fasting-induced hepatosteatosis was observed in the absence of caspase-2. Further analysis of white adipose tissue (WAT) indicated that female Casp2 (-/-) mice may have enhanced fatty acid recycling and metabolism with expression of genes involved in glyceroneogenesis and fatty acid oxidation increased. Loss of Casp2 also increased fasting-induced autophagy in both male and female liver and in female skeletal muscle. Our observations suggest that caspase-2 can regulate glucose homeostasis and lipid metabolism in a tissue and sex-specific manner. PMID:27551503

  16. Sex-specific alterations in glucose homeostasis and metabolic parameters during ageing of caspase-2-deficient mice

    PubMed Central

    Wilson, C H; Nikolic, A; Kentish, S J; Shalini, S; Hatzinikolas, G; Page, A J; Dorstyn, L; Kumar, S

    2016-01-01

    Gender-specific differences are commonly found in metabolic pathways and in response to nutritional manipulation. Previously, we identified a role for caspase-2 in age-related glucose homeostasis and lipid metabolism using male caspase-2-deficient (Casp2−/−) mice. Here we show that the resistance to age-induced glucose tolerance does not occur in female Casp2−/− mice and it appears to be independent of insulin sensitivity in males. Using fasting (18 h) as a means to further investigate the role of caspase-2 in energy and lipid metabolism, we identified sex-specific differences in the fasting response and lipid mobilization. In aged (18–22 months) male Casp2−/− mice, a significant decrease in fasting liver mass, but not total body weight, was observed while in females, total body weight, but not liver mass, was reduced when compared with wild-type (WT) animals. Fasting-induced lipolysis of adipose tissue was enhanced in male Casp2−/− mice as indicated by a significant reduction in white adipocyte cell size, and increased serum-free fatty acids. In females, white adipocyte cell size was significantly smaller in both fed and fasted Casp2−/− mice. No difference in fasting-induced hepatosteatosis was observed in the absence of caspase-2. Further analysis of white adipose tissue (WAT) indicated that female Casp2−/− mice may have enhanced fatty acid recycling and metabolism with expression of genes involved in glyceroneogenesis and fatty acid oxidation increased. Loss of Casp2 also increased fasting-induced autophagy in both male and female liver and in female skeletal muscle. Our observations suggest that caspase-2 can regulate glucose homeostasis and lipid metabolism in a tissue and sex-specific manner. PMID:27551503

  17. Melanin-Concentrating Hormone: A New Sleep Factor?

    PubMed Central

    Torterolo, Pablo; Lagos, Patricia; Monti, Jaime M.

    2011-01-01

    Neurons containing the neuropeptide melanin-concentrating hormone (MCH) are mainly located in the lateral hypothalamus and the incerto-hypothalamic area, and have widespread projections throughout the brain. While the biological functions of this neuropeptide are exerted in humans through two metabotropic receptors, the MCHR1 and MCHR2, only the MCHR1 is present in rodents. Recently, it has been shown that the MCHergic system is involved in the control of sleep. We can summarize the experimental findings as follows: (1) The areas related to the control of sleep and wakefulness have a high density of MCHergic fibers and receptors. (2) MCHergic neurons are active during sleep, especially during rapid eye movement (REM) sleep. (3) MCH knockout mice have less REM sleep, notably under conditions of negative energy balance. Animals with genetically inactivated MCHR1 also exhibit altered vigilance state architecture and sleep homeostasis. (4) Systemically administered MCHR1 antagonists reduce sleep. (5) Intraventricular microinjection of MCH increases both slow wave sleep (SWS) and REM sleep; however, the increment in REM sleep is more pronounced. (6) Microinjection of MCH into the dorsal raphe nucleus increases REM sleep time. REM seep is inhibited by immunoneutralization of MCH within this nucleus. (7) Microinjection of MCH in the nucleus pontis oralis of the cat enhances REM sleep time and reduces REM sleep latency. All these data strongly suggest that MCH has a potent role in the promotion of sleep. Although both SWS and REM sleep are facilitated by MCH, REM sleep seems to be more sensitive to MCH modulation. PMID:21516258

  18. Spatiotemporally Regulated Ablation of Klf4 in Adult Mouse Corneal Epithelial Cells Results in Altered Epithelial Cell Identity and Disrupted Homeostasis

    PubMed Central

    Delp, Emili E.; Swamynathan, Sudha; Kao, Winston W.; Swamynathan, Shivalingappa K.

    2015-01-01

    Purpose. In previous studies, conditional disruption of Klf4 in the developing mouse ocular surface from embryonic day 10 resulted in corneal epithelial fragility, stromal edema, and loss of conjunctival goblet cells, revealing the importance of Klf4 in ocular surface maturation. Here, we use spatiotemporally regulated ablation of Klf4 to investigate its functions in maintenance of adult corneal epithelial homeostasis. Methods. Expression of Cre was induced in ternary transgenic (Klf4LoxP/LoxP/Krt12rtTA/rtTA/Tet-O-Cre) mouse corneal epithelium by doxycycline administered through intraperitoneal injections and drinking water, to generate corneal epithelium–specific deletion of Klf4 (Klf4Δ/ΔCE). Corneal epithelial barrier function was tested by fluorescein staining. Expression of selected Klf4-target genes was determined by quantitative PCR (QPCR), immunoblotting, and immunofluorescent staining. Results. Klf4 was efficiently ablated within 5 days of doxycycline administration in adult Klf4Δ/ΔCE corneal epithelium. The Klf4Δ/ΔCE corneal epithelial barrier function was disrupted, and the basal cells were swollen and rounded after 15 days of doxycycline treatment. Increased numbers of cell layers and Ki67-positive proliferating cells suggested deregulated Klf4Δ/ΔCE corneal epithelial homeostasis. Expression of tight junction proteins ZO-1 and occludin, desmosomal Dsg and Dsp, basement membrane laminin-332, and corneal epithelial–specific keratin-12 was decreased, while that of matrix metalloproteinase Mmp9 and noncorneal keratin-17 increased, suggesting altered Klf4Δ/ΔCE corneal epithelial cell identity. Conclusions. Ablation of Klf4 in the adult mouse corneas resulted in the absence of characteristic corneal epithelial cell differentiation, disrupted barrier function, and squamous metaplasia, revealing that Klf4 is essential for maintenance of the adult corneal epithelial cell identity and homeostasis. PMID:26047041

  19. Sleep Disturbance and Altered Expression of Circadian Clock Genes in Patients With Sudden Sensorineural Hearing Loss.

    PubMed

    Yang, Chao-Hui; Hwang, Chung-Feng; Lin, Pai-Mei; Chuang, Jiin-Haur; Hsu, Cheng-Ming; Lin, Sheng-Fung; Yang, Ming-Yu

    2015-07-01

    The cause of sudden sensorineural hearing loss (SSNHL) remains unclear and therefore it is often considered as idiopathic. Sleep disturbance has been linked to SSNHL and circadian rhythm disruption, but the link between circadian rhythm disruption and SSNHL has never been investigated.In this study, we surveyed the sleep quality of 38 patients with SSNHL using a simple insomnia sleep questionnaire. The expression of circadian clock genes in peripheral blood (PB) leukocytes from 38 patients with SSNHL and 71 healthy subjects was accessed using real-time quantitative reverse transcriptase-polymerase chain reaction and validated using immunocytochemical staining.We found that 61.8% of patients with SSNHL suffered from insomnia before the insult of hearing loss. Besides, significantly decreased expression of PER1, CRY1, CRY2, CLOCK, BMAL1, and CKlε was found in PB leukocytes of patients with SSNHL when compared with healthy subjects. SSNHL patients with vertigo had significantly lower expression of CRY1 and CKlε than patients without vertigo symptoms. Our results imply the association of sleep disturbance and disrupted circadian rhythm in SSNHL.

  20. Complexity analysis of sleep and alterations with insomnia based on non-invasive techniques.

    PubMed

    Holloway, Philip M; Angelova, Maia; Lombardo, Sara; St Clair Gibson, Alan; Lee, David; Ellis, Jason

    2014-04-01

    For the first time, fractal analysis techniques are implemented to study the correlations present in sleep actigraphy for individuals suffering from acute insomnia with comparisons made against healthy subjects. Analysis was carried out for 21 healthy individuals with no diagnosed sleep disorders and 26 subjects diagnosed with acute insomnia during night-time hours. Detrended fluctuation analysis was applied in order to look for 1/f-fluctuations indicative of high complexity. The aim is to investigate whether complexity analysis can differentiate between people who sleep normally and people who suffer from acute insomnia. We hypothesize that the complexity will be higher in subjects who suffer from acute insomnia owing to increased night-time arousals. This hypothesis, although contrary to much of the literature surrounding complexity in physiology, was found to be correct-for our study. The complexity results for nearly all of the subjects fell within a 1/f-range, indicating the presence of underlying control mechanisms. The subjects with acute insomnia displayed significantly higher correlations, confirmed by significance testing-possibly a result of too much activity in the underlying regulatory systems. Moreover, we found a linear relationship between complexity and variability, both of which increased with the onset of insomnia. Complexity analysis is very promising and could prove to be a useful non-invasive identifier for people who suffer from sleep disorders such as insomnia.

  1. High concentrations of hexavalent chromium in drinking water alter iron homeostasis in F344 rats and B6C3F1 mice.

    PubMed

    Suh, Mina; Thompson, Chad M; Kirman, Christopher R; Carakostas, Michael C; Haws, Laurie C; Harris, Mark A; Proctor, Deborah M

    2014-03-01

    Hexavalent chromium [Cr(VI)] induces hematological signs of microcytic anemia in rodents. Considering that Cr(VI) can oxidize ferrous (Fe(2+)) to ferric (Fe(3+)) iron, and that only the former is transported across the duodenum, we hypothesize that, at high concentrations, Cr(VI) oxidizes Fe(2+) in the lumen of the small intestine and perturbs iron absorption. Herein we report that 90-day exposure to Cr(VI) in drinking water resulted in dose-dependent decreases in Fe levels in the duodenum, liver, serum, and bone marrow. Toxicogenomic analyses from the duodenum indicate responses consistent with Fe deficiency, including significant induction of divalent metal transporter 1 (DMT1, Slc11a2) and transferrin receptor 1 (TFR1, Tfr1). In addition, at ⩾20mg Cr(VI)/L in drinking water, Cr RBC:plasma ratios in rats were increased and exceeded unity, indicating saturation of reductive capacity and intracellular absorption of Cr(VI) into red blood cells (RBCs). These effects occurred in both species but were generally more severe in rats. These data suggest that high concentrations of Cr(VI) in drinking limit Fe absorption and alter iron homeostasis. Furthermore, some effects observed at high doses in recent Cr(VI) chronic and subchronic bioassays may be explained, at least in part, by iron deficiency and disruption of homeostasis.

  2. Sleep alterations in an environmental neurotoxin-induced model of parkinsonism☆

    PubMed Central

    McDowell, Kimberly A.; Hadjimarkou, Maria M.; Viechweg, Shaun; Rose, Avigail E.; Clark, Sarah M.; Yarowsky, Paul J.; Mong, Jessica A.

    2010-01-01

    Parkinson’s disease (PD) is classically defined as a motor disorder resulting from decreased dopamine production in the basal ganglia circuit. In an attempt to better diagnose and treat PD before the onset of severe motor dysfunction, recent attention has focused on the early, non-motor symptoms, which include but are not limited to sleep disorders such as excessive daytime sleepiness (EDS) and REM behavioral disorder (RBD). However, few animal models have been able to replicate both the motor and non-motor symptoms of PD. Here, we present a progressive rat model of parkinsonism that displays disturbances in sleep/wake patterns. Epidemiological studies elucidated a link between the Guamanian variant of Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC) and the consumption of flour made from the washed seeds of the plant Cycas micronesica (cycad). Our study examined the effects of prolonged cycad consumption on sleep/wake activity in male, Sprague–Dawley rats. Cycad-fed rats exhibited an increase in length and/or number of bouts of rapid eye movement (REM) sleep and Non-REM (NREM) sleep at the expense of wakefulness during the active period when compared to control rats. This hypersomnolent behavior suggests an inability to maintain arousal. In addition, cycad-fed rats had significantly fewer orexin cells in the hypothalamus. Our results reveal a novel rodent model of parkinsonism that includes an EDS-like syndrome that may be associated with a dysregulation of orexin neurons. Further characterization of this early, non-motor symptom, may provide potential therapeutic interventions in the treatment of PD. PMID:20713046

  3. Sleep alterations in an environmental neurotoxin-induced model of parkinsonism.

    PubMed

    McDowell, Kimberly A; Hadjimarkou, Maria M; Viechweg, Shaun; Rose, Avigail E; Clark, Sarah M; Yarowsky, Paul J; Mong, Jessica A

    2010-11-01

    Parkinson's disease (PD) is classically defined as a motor disorder resulting from decreased dopamine production in the basal ganglia circuit. In an attempt to better diagnose and treat PD before the onset of severe motor dysfunction, recent attention has focused on the early, non-motor symptoms, which include but are not limited to sleep disorders such as excessive daytime sleepiness (EDS) and REM behavioral disorder (RBD). However, few animal models have been able to replicate both the motor and non-motor symptoms of PD. Here, we present a progressive rat model of parkinsonism that displays disturbances in sleep/wake patterns. Epidemiological studies elucidated a link between the Guamanian variant of Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC) and the consumption of flour made from the washed seeds of the plant Cycas micronesica (cycad). Our study examined the effects of prolonged cycad consumption on sleep/wake activity in male, Sprague-Dawley rats. Cycad-fed rats exhibited an increase in length and/or number of bouts of rapid eye movement (REM) sleep and Non-REM (NREM) sleep at the expense of wakefulness during the active period when compared to control rats. This hypersomnolent behavior suggests an inability to maintain arousal. In addition, cycad-fed rats had significantly fewer orexin cells in the hypothalamus. Our results reveal a novel rodent model of parkinsonism that includes an EDS-like syndrome that may be associated with a dysregulation of orexin neurons. Further characterization of this early, non-motor symptom, may provide potential therapeutic interventions in the treatment of PD.

  4. Defective autophagy in vascular smooth muscle cells alters contractility and Ca²⁺ homeostasis in mice.

    PubMed

    Michiels, Cédéric F; Fransen, Paul; De Munck, Dorien G; De Meyer, Guido R Y; Martinet, Wim

    2015-03-15

    Autophagy is an evolutionary preserved process that prevents the accumulation of unwanted cytosolic material through the formation of autophagosomes. Although autophagy has been extensively studied to understand its function in normal physiology, the role of vascular smooth muscle (SM) cell (VSMC) autophagy in Ca(2+) mobilization and contraction remains poorly understood. Recent evidence shows that autophagy is involved in controlling contractile function and Ca(2+) homeostasis in certain cell types. Therefore, autophagy might also regulate contractile capacity and Ca(2+)-mobilizing pathways in VSMCs. Contractility (organ chambers) and Ca(2+) homeostasis (myograph) were investigated in aortic segments of 3.5-mo-old mice containing a SM cell-specific deletion of autophagy-related 7 (Atg7; Atg7(fl/fl) SM22α-Cre(+) mice) and in segments of corresponding control mice (Atg7(+/+) SM22α-Cre(+)). Our results indicate that voltage-gated Ca(2+) channels (VGCCs) of Atg7(fl/fl) SM22α-Cre(+) VSMCs were more sensitive to depolarization, independent of changes in resting membrane potential. Contractions elicited with K(+) (50 mM) or the VGCC agonist BAY K8644 (100 nM) were significantly higher due to increased VGCC expression and activity. Interestingly, the sarcoplasmic reticulum of Atg7(fl/fl) SM22α-Cre(+) VSMCs was enlarged, which, combined with increased sarco(endo)plasmic reticulum Ca(2+)-ATPase 2 expression and higher store-operated Ca(2+) entry, promoted inositol 1,4,5-trisphosphate-mediated contractions of Atg7(fl/fl) SM22α-Cre(+) segments and maximized the Ca(2+) storing capacity of the sarcoplasmic reticulum. Moreover, decreased plasma membrane Ca(2+)-ATPase expression in Atg7(fl/fl) SM22α-Cre(+) VSMCs hampered Ca(2+) extrusion to the extracellular environment. Overall, our study indicates that defective autophagy in VSMCs leads to an imbalance between Ca(2+) release/influx and Ca(2+) reuptake/extrusion, resulting in higher basal Ca(2+) concentrations and

  5. Cyclic glycine-proline regulates IGF-1 homeostasis by altering the binding of IGFBP-3 to IGF-1

    PubMed Central

    Guan, Jian; Gluckman, Peter; Yang, Panzao; Krissansen, Geoff; Sun, Xueying; Zhou, Yongzhi; Wen, Jingyuan; Phillips, Gemma; Shorten, Paul R.; McMahon, Chris D.; Wake, Graeme C.; Chan, Wendy H. K.; Thomas, Mark F.; Ren, April; Moon, Steve; Liu, Dong-Xu

    2014-01-01

    The homeostasis of insulin-like growth factor-1 (IGF-1) is essential for metabolism, development and survival. Insufficient IGF-1 is associated with poor recovery from wounds whereas excessive IGF-1 contributes to growth of tumours. We have shown that cyclic glycine-proline (cGP), a metabolite of IGF-1, can normalise IGF-1 function by showing its efficacy in improving the recovery from ischemic brain injury in rats and inhibiting the growth of lymphomic tumours in mice. Further investigation in cell culture suggested that cGP promoted the activity of IGF-1 when it was insufficient, but inhibited the activity of IGF-1 when it was excessive. Mathematical modelling revealed that the efficacy of cGP was a modulated IGF-1 effect via changing the binding of IGF-1 to its binding proteins, which dynamically regulates the balance between bioavailable and non-bioavailable IGF-1. Our data reveal a novel mechanism of auto-regulation of IGF-1, which has physiological and pathophysiological consequences and potential pharmacological utility. PMID:24633053

  6. Cyclic glycine-proline regulates IGF-1 homeostasis by altering the binding of IGFBP-3 to IGF-1

    NASA Astrophysics Data System (ADS)

    Guan, Jian; Gluckman, Peter; Yang, Panzao; Krissansen, Geoff; Sun, Xueying; Zhou, Yongzhi; Wen, Jingyuan; Phillips, Gemma; Shorten, Paul R.; McMahon, Chris D.; Wake, Graeme C.; Chan, Wendy H. K.; Thomas, Mark F.; Ren, April; Moon, Steve; Liu, Dong-Xu

    2014-03-01

    The homeostasis of insulin-like growth factor-1 (IGF-1) is essential for metabolism, development and survival. Insufficient IGF-1 is associated with poor recovery from wounds whereas excessive IGF-1 contributes to growth of tumours. We have shown that cyclic glycine-proline (cGP), a metabolite of IGF-1, can normalise IGF-1 function by showing its efficacy in improving the recovery from ischemic brain injury in rats and inhibiting the growth of lymphomic tumours in mice. Further investigation in cell culture suggested that cGP promoted the activity of IGF-1 when it was insufficient, but inhibited the activity of IGF-1 when it was excessive. Mathematical modelling revealed that the efficacy of cGP was a modulated IGF-1 effect via changing the binding of IGF-1 to its binding proteins, which dynamically regulates the balance between bioavailable and non-bioavailable IGF-1. Our data reveal a novel mechanism of auto-regulation of IGF-1, which has physiological and pathophysiological consequences and potential pharmacological utility.

  7. Arsenic-induced alteration in intracellular calcium homeostasis induces head kidney macrophage apoptosis involving the activation of calpain-2 and ERK in Clarias batrachus

    SciTech Connect

    Banerjee, Chaitali; Goswami, Ramansu; Datta, Soma; Rajagopal, R.; Mazumder, Shibnath

    2011-10-01

    We had earlier shown that exposure to arsenic (0.50 {mu}M) caused caspase-3 mediated head kidney macrophage (HKM) apoptosis involving the p38-JNK pathway in Clarias batrachus. Here we examined the roles of calcium (Ca{sup 2+}) and extra-cellular signal-regulated protein kinase (ERK), the other member of MAPK-pathway on arsenic-induced HKM apoptosis. Arsenic-induced HKM apoptosis involved increased expression of ERK and calpain-2. Nifedipine, verapamil and EGTA pre-treatment inhibited the activation of calpain-2, ERK and reduced arsenic-induced HKM apoptosis as evidenced from reduced caspase-3 activity, Annexin V-FITC-propidium iodide and Hoechst 33342 staining. Pre-incubation with ERK inhibitor U 0126 inhibited the activation of calpain-2 and interfered with arsenic-induced HKM apoptosis. Additionally, pre-incubation with calpain-2 inhibitor also interfered with the activation of ERK and inhibited arsenic-induced HKM apoptosis. The NADPH oxidase inhibitor apocynin and diphenyleneiodonium chloride also inhibited ERK activation indicating activation of ERK in arsenic-exposed HKM also depends on signals from NADPH oxidase pathway. Our study demonstrates the critical role of Ca{sup 2+} homeostasis on arsenic-induced HKM apoptosis. We suggest that arsenic-induced alteration in intracellular Ca{sup 2+} levels initiates pro-apoptotic ERK and calpain-2; the two pathways influence each other positively and induce caspase-3 mediated HKM apoptosis. Besides, our study also indicates the role of ROS in the activation of ERK pathway in arsenic-induced HKM apoptosis in C. batrachus. - Highlights: > Altered Ca{sup 2+} homeostasis leads to arsenic-induced HKM apoptosis. > Calpain-2 plays a critical role in the process. > ERK is pro-apoptotic in arsenic-induced HKM apoptosis. > Arsenic-induced HKM apoptosis involves cross talk between calpain-2 and ERK.

  8. Neurexin-1 regulates sleep and synaptic plasticity in Drosophila melanogaster.

    PubMed

    Larkin, Aoife; Chen, Ming-Yu; Kirszenblat, Leonie; Reinhard, Judith; van Swinderen, Bruno; Claudianos, Charles

    2015-10-01

    Neurexins are cell adhesion molecules that are important for synaptic plasticity and homeostasis, although links to sleep have not yet been investigated. We examined the effects of neurexin-1 perturbation on sleep in Drosophila, showing that neurexin-1 nulls displayed fragmented sleep and altered circadian rhythm. Conversely, the over-expression of neurexin-1 could increase and consolidate night-time sleep. This was not solely due to developmental effects as it could be induced acutely in adulthood, and was coupled with evidence of synaptic growth. The timing of over-expression could differentially impact sleep patterns, with specific night-time effects. These results show that neurexin-1 was dynamically involved in synaptic plasticity and sleep in Drosophila. Neurexin-1 and a number of its binding partners have been repeatedly associated with mental health disorders, including autism spectrum disorders, schizophrenia and Tourette syndrome, all of which are also linked to altered sleep patterns. How and when plasticity-related proteins such as neurexin-1 function during sleep can provide vital information on the interaction between synaptic homeostasis and sleep, paving the way for more informed treatments of human disorders.

  9. Regulation of Sleep by Neuropeptide Y-Like System in Drosophila melanogaster

    PubMed Central

    He, Chunxia; Yang, Yunyan; Zhang, Mingming; Price, Jeffrey L.; Zhao, Zhangwu

    2013-01-01

    Sleep is important for maintenance of normal physiology in animals. In mammals, neuropeptide Y (NPY), a homolog of Drosophila neuropeptide F (NPF), is involved in sleep regulation, with different effects in human and rat. However, the function of NPF on sleep in Drosophila melanogaster has not yet been described. In this study, we investigated the effects of NPF and its receptor-neuropeptide F receptor (NPFR1) on Drosophila sleep. Male flies over-expressing NPF or NPFR1 exhibited increased sleep during the nighttime. Further analysis demonstrated that sleep episode duration during nighttime was greatly increased and sleep latency was significantly reduced, indicating that NPF and NPFR1 promote sleep quality, and their action on sleep is not because of an impact of the NPF signal system on development. Moreover, the homeostatic regulation of flies after sleep deprivation was disrupted by altered NPF signaling, since sleep deprivation decreased transcription of NPF in control flies, and there were less sleep loss during sleep deprivation and less sleep gain after sleep deprivation in flies overexpressing NPF and NPFR1 than in control flies, suggesting that NPF system auto-regulation plays an important role in sleep homeostasis. However, these effects did not occur in females, suggesting a sex-dependent regulatory function in sleep for NPF and NPFR1. NPF in D1 brain neurons showed male-specific expression, providing the cellular locus for male-specific regulation of sleep by NPF and NPFR1. This study brings a new understanding into sleep studies of a sexually dimorphic regulatory mode in female and male flies. PMID:24040211

  10. Transcriptomics Profiling of Alzheimer's Disease Reveal Neurovascular Defects, Altered Amyloid-β Homeostasis, and Deregulated Expression of Long Noncoding RNAs.

    PubMed

    Magistri, Marco; Velmeshev, Dmitry; Makhmutova, Madina; Faghihi, Mohammad Ali

    2015-01-01

    The underlying genetic variations of late-onset Alzheimer's disease (LOAD) cases remain largely unknown. A combination of genetic variations with variable penetrance and lifetime epigenetic factors may converge on transcriptomic alterations that drive LOAD pathological process. Transcriptome profiling using deep sequencing technology offers insight into common altered pathways regardless of underpinning genetic or epigenetic factors and thus represents an ideal tool to investigate molecular mechanisms related to the pathophysiology of LOAD. We performed directional RNA sequencing on high quality RNA samples extracted from hippocampi of LOAD and age-matched controls. We further validated our data using qRT-PCR on a larger set of postmortem brain tissues, confirming downregulation of the gene encoding substance P (TAC1) and upregulation of the gene encoding the plasminogen activator inhibitor-1 (SERPINE1). Pathway analysis indicates dysregulation in neural communication, cerebral vasculature, and amyloid-β clearance. Beside protein coding genes, we identified several annotated and non-annotated long noncoding RNAs that are differentially expressed in LOAD brain tissues, three of them are activity-dependent regulated and one is induced by Aβ(1-42) exposure of human neural cells. Our data provide a comprehensive list of transcriptomics alterations in LOAD hippocampi and warrant holistic approach including both coding and non-coding RNAs in functional studies aimed to understand the pathophysiology of LOAD.

  11. Circadian Disruption Leads to Loss of Homeostasis and Disease

    PubMed Central

    Escobar, Carolina; Salgado-Delgado, Roberto; Gonzalez-Guerra, Eduardo; Tapia Osorio, Araceli; Angeles-Castellanos, Manuel; Buijs, Ruud M.

    2011-01-01

    The relevance of a synchronized temporal order for adaptation and homeostasis is discussed in this review. We present evidence suggesting that an altered temporal order between the biological clock and external temporal signals leads to disease. Evidence mainly based on a rodent model of “night work” using forced activity during the sleep phase suggests that altered activity and feeding schedules, out of phase from the light/dark cycle, may be the main cause for the loss of circadian synchrony and disease. It is proposed that by avoiding food intake during sleep hours the circadian misalignment and adverse consequences can be prevented. This review does not attempt to present a thorough revision of the literature, but instead it aims to highlight the association between circadian disruption and disease with special emphasis on the contribution of feeding schedules in circadian synchrony. PMID:23471148

  12. Mitochondrial Morphology and Fundamental Parameters of the Mitochondrial Respiratory Chain Are Altered in Caenorhabditis elegans Strains Deficient in Mitochondrial Dynamics and Homeostasis Processes.

    PubMed

    Luz, Anthony L; Rooney, John P; Kubik, Laura L; Gonzalez, Claudia P; Song, Dong Hoon; Meyer, Joel N

    2015-01-01

    Mitochondrial dysfunction has been linked to myriad human diseases and toxicant exposures, highlighting the need for assays capable of rapidly assessing mitochondrial health in vivo. Here, using the Seahorse XFe24 Analyzer and the pharmacological inhibitors dicyclohexylcarbodiimide and oligomycin (ATP-synthase inhibitors), carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (mitochondrial uncoupler) and sodium azide (cytochrome c oxidase inhibitor), we measured the fundamental parameters of mitochondrial respiratory chain function: basal oxygen consumption, ATP-linked respiration, maximal respiratory capacity, spare respiratory capacity and proton leak in the model organism Caenhorhabditis elegans. Since mutations in mitochondrial homeostasis genes cause mitochondrial dysfunction and have been linked to human disease, we measured mitochondrial respiratory function in mitochondrial fission (drp-1)-, fusion (fzo-1)-, mitophagy (pdr-1, pink-1)-, and electron transport chain complex III (isp-1)-deficient C. elegans. All showed altered function, but the nature of the alterations varied between the tested strains. We report increased basal oxygen consumption in drp-1; reduced maximal respiration in drp-1, fzo-1, and isp-1; reduced spare respiratory capacity in drp-1 and fzo-1; reduced proton leak in fzo-1 and isp-1; and increased proton leak in pink-1 nematodes. As mitochondrial morphology can play a role in mitochondrial energetics, we also quantified the mitochondrial aspect ratio for each mutant strain using a novel method, and for the first time report increased aspect ratios in pdr-1- and pink-1-deficient nematodes. PMID:26106885

  13. The structural alteration and aggregation propensity of glycated lens crystallins in the presence of calcium: Importance of lens calcium homeostasis in development of diabetic cataracts.

    PubMed

    Zm, Sara Zafaranchi; Khoshaman, Kazem; Masoudi, Raheleh; Hemmateenejad, Bahram; Yousefi, Reza

    2017-01-01

    The imbalance of the calcium homeostasis in the lenticular tissues of diabetic patients is an important risk factor for development of cataract diseases. In the current study, the impact of elevated levels of calcium ions were investigated on structure and aggregation propensity of glycated lens crystallins using gel electrophoresis and spectroscopic assessments. The glycated proteins indicated significant resistance against calcium-induced structural insults and aggregation. While, glycated crystallins revealed an increased conformational stability; a slight instability was observed for these proteins upon interaction with calcium ions. Also, in the presence of calcium, the proteolytic pattern of native crystallins was altered and that of glycated protein counterparts remained almost unchanged. According to results of this study it is suggested that the structural alteration of lens crystallins upon glycation may significantly reduce their calcium buffering capacity in eye lenses. Therefore, under chronic hyperglycemia accumulation of this cataractogenic metal ion in the lenticular tissues may subsequently culminate in activation of different pathogenic pathways, leading to development of lens opacity and cataract diseases. PMID:27434877

  14. Adaptogenic potential of curcumin in experimental chronic stress and chronic unpredictable stress-induced memory deficits and alterations in functional homeostasis.

    PubMed

    Bhatia, Nitish; Jaggi, Amteshwar Singh; Singh, Nirmal; Anand, Preet; Dhawan, Ravi

    2011-07-01

    The present study was designed to investigate the role of curcumin in chronic stress and chronic unpredictable stress-induced memory deficits and alteration of functional homeostasis in mice. Chronic stress was induced by immobilizing the animal for 2 h daily for 10 days, whereas chronic unpredictable stress was induced by employing a battery of stressors of variable magnitude and time for 10 days. Curcumin was administered to drug-treated mice prior to induction of stress. Body weight, adrenal gland weight, ulcer index and biochemical levels of glucose, creatine kinase, cholesterol, corticosterone, thiobarbituric acid reactive substances (TBARS) and reduced glutathione (GSH) were evaluated to assess stress-induced functional changes. Memory deficits were evaluated using the elevated plus maze (EPM) model. Chronic stress and chronic unpredictable stress significantly increased the levels of corticosterone, glucose and creatine kinase and decreased cholesterol levels. Moreover, chronic stress and chronic unpredictable stress resulted in severe memory deficits along with adrenal hypertrophy, weight loss and gastric ulceration. Chronic stress and chronic unpredictable stress also increased oxidative stress assessed in terms of increase in TBARS and decrease in GSH levels. Pretreatment with curcumin (25 and 50 mg/kg p.o.) attenuated chronic stress and chronic unpredictable stress-associated memory deficits, biochemical alterations, pathological outcomes and oxidative stress. It may be concluded that curcumin-mediated antioxidant actions and decrease in corticosterone secretion are responsible for its adaptogenic and memory restorative actions in chronic and chronic unpredictable stress.

  15. Mitochondrial Morphology and Fundamental Parameters of the Mitochondrial Respiratory Chain Are Altered in Caenorhabditis elegans Strains Deficient in Mitochondrial Dynamics and Homeostasis Processes.

    PubMed

    Luz, Anthony L; Rooney, John P; Kubik, Laura L; Gonzalez, Claudia P; Song, Dong Hoon; Meyer, Joel N

    2015-01-01

    Mitochondrial dysfunction has been linked to myriad human diseases and toxicant exposures, highlighting the need for assays capable of rapidly assessing mitochondrial health in vivo. Here, using the Seahorse XFe24 Analyzer and the pharmacological inhibitors dicyclohexylcarbodiimide and oligomycin (ATP-synthase inhibitors), carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (mitochondrial uncoupler) and sodium azide (cytochrome c oxidase inhibitor), we measured the fundamental parameters of mitochondrial respiratory chain function: basal oxygen consumption, ATP-linked respiration, maximal respiratory capacity, spare respiratory capacity and proton leak in the model organism Caenhorhabditis elegans. Since mutations in mitochondrial homeostasis genes cause mitochondrial dysfunction and have been linked to human disease, we measured mitochondrial respiratory function in mitochondrial fission (drp-1)-, fusion (fzo-1)-, mitophagy (pdr-1, pink-1)-, and electron transport chain complex III (isp-1)-deficient C. elegans. All showed altered function, but the nature of the alterations varied between the tested strains. We report increased basal oxygen consumption in drp-1; reduced maximal respiration in drp-1, fzo-1, and isp-1; reduced spare respiratory capacity in drp-1 and fzo-1; reduced proton leak in fzo-1 and isp-1; and increased proton leak in pink-1 nematodes. As mitochondrial morphology can play a role in mitochondrial energetics, we also quantified the mitochondrial aspect ratio for each mutant strain using a novel method, and for the first time report increased aspect ratios in pdr-1- and pink-1-deficient nematodes.

  16. Mitochondrial Morphology and Fundamental Parameters of the Mitochondrial Respiratory Chain Are Altered in Caenorhabditis elegans Strains Deficient in Mitochondrial Dynamics and Homeostasis Processes

    PubMed Central

    Luz, Anthony L.; Rooney, John P.; Kubik, Laura L.; Gonzalez, Claudia P.; Song, Dong Hoon; Meyer, Joel N.

    2015-01-01

    Mitochondrial dysfunction has been linked to myriad human diseases and toxicant exposures, highlighting the need for assays capable of rapidly assessing mitochondrial health in vivo. Here, using the Seahorse XFe24 Analyzer and the pharmacological inhibitors dicyclohexylcarbodiimide and oligomycin (ATP-synthase inhibitors), carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (mitochondrial uncoupler) and sodium azide (cytochrome c oxidase inhibitor), we measured the fundamental parameters of mitochondrial respiratory chain function: basal oxygen consumption, ATP-linked respiration, maximal respiratory capacity, spare respiratory capacity and proton leak in the model organism Caenhorhabditis elegans. Since mutations in mitochondrial homeostasis genes cause mitochondrial dysfunction and have been linked to human disease, we measured mitochondrial respiratory function in mitochondrial fission (drp-1)-, fusion (fzo-1)-, mitophagy (pdr-1, pink-1)-, and electron transport chain complex III (isp-1)-deficient C. elegans. All showed altered function, but the nature of the alterations varied between the tested strains. We report increased basal oxygen consumption in drp-1; reduced maximal respiration in drp-1, fzo-1, and isp-1; reduced spare respiratory capacity in drp-1 and fzo-1; reduced proton leak in fzo-1 and isp-1; and increased proton leak in pink-1 nematodes. As mitochondrial morphology can play a role in mitochondrial energetics, we also quantified the mitochondrial aspect ratio for each mutant strain using a novel method, and for the first time report increased aspect ratios in pdr-1- and pink-1-deficient nematodes. PMID:26106885

  17. Sleep Tight.

    ERIC Educational Resources Information Center

    Black, Susan

    2000-01-01

    At the same time their biological systems program them for later sleep and waking times, adolescents' schedules and lifestyles keep them from getting a healthy amount of sleep. Although a few schools have altered their schedules, most are confounded by costs and contractual complications. Minnesota schools are leaders. (MLH)

  18. Alteration of JNK-1 Signaling in Skeletal Muscle Fails to Affect Glucose Homeostasis and Obesity-Associated Insulin Resistance in Mice

    PubMed Central

    Spohn, Gabriele; Brönneke, Hella S.; Schmidt-Supprian, Marc; Wunderlich, F. Thomas

    2013-01-01

    Obesity and associated metabolic disturbances, such as increased circulating fatty acids cause prolonged low grade activation of inflammatory signaling pathways in liver, skeletal muscle, adipose tissue and even in the CNS. Activation of inflammatory pathways in turn impairs insulin signaling, ultimately leading to obesity-associated type 2 diabetes mellitus. Conventional JNK-1 knock out mice are protected from high fat diet-induced insulin resistance, characterizing JNK-1-inhibition as a potential approach to improve glucose metabolism in obese patients. However, the cell type-specific role of elevated JNK-1 signaling as present during the course of obesity has not been fully elucidated yet. To investigate the functional contribution of altered JNK-1 activation in skeletal muscle, we have generated a ROSA26 insertion mouse strain allowing for Cre-activatable expression of a JNK-1 constitutive active construct (JNKC). To examine the consequence of skeletal muscle-restricted JNK-1 overactivation in the development of insulin resistance and glucose metabolism, JNKC mice were crossed to Mck-Cre mice yielding JNKSM-C mice. However, despite increased muscle-specific JNK activation, energy homeostasis and glucose metabolism in JNKSM-C mice remained largely unaltered compared to controls. In line with these findings, obese mice with skeletal muscle specific disruption of JNK-1, did not affect energy and glucose homeostasis. These experiments indicate that JNK-1 activation in skeletal muscle does not account for the major effects on diet-induced, JNK-1-mediated deterioration of insulin action and points towards a so far underappreciated role of JNK-1 in other tissues than skeletal muscle during the development of obesity-associated insulin resistance. PMID:23349837

  19. Endoplasmic reticulum stress and disturbed calcium homeostasis are involved in copper-induced alteration in hepatic lipid metabolism in yellow catfish Pelteobagrus fulvidraco.

    PubMed

    Song, Yu-Feng; Luo, Zhi; Zhang, Li-Han; Hogstrand, Christer; Pan, Ya-Xiong

    2016-02-01

    The present study was conducted to investigate the effect of Cu exposure on ER stress and Ca(2+) homeostasis, and explore the underlying mechanism of the ER stress and disturbed Ca(2+) homeostasis in the regulation of hepatic lipid metabolism in yellow catfish Pelteobagrus fulvidraco. To this end, three experiments were conducted. In experiment 1, P. fulvidraco were exposed to three waterborne Cu concentrations for 56 days. Waterborne Cu exposure evoked ER stress and SREBP-1c activation and resulted in dysregulation of hepatic lipid metabolism in liver of P. fulvidraco in a time-dependent manner. In experiment 2, specific inhibitors 2-APB (IP3 receptor inhibitor) and dantrolene (RyR receptor inhibitor) were used to explore whether Ca(2+) release from ER was involved in the Cu-induced ER stress change. Dantrolene and 2-APB prevented Cu-induced intracellular Ca(2+) elevation, demonstrating that the release of Ca(2+) from the ER, mediated by both RyR and IP3R, contributed to dysregulation of lipid metabolism. In experiment 3, a chemical chaperone (PBA) was used to demonstrate whether Cu-induced alteration in lipid metabolism was suppressed through the attenuation of ER stress. PBA attenuated the Cu-induced elevation of mRNA expression of SREBP-1c, SCAP, ACC, FAS, GRP78/BiP, GRP94, CRT, eIF2α and XBP-1, and alleviated the Cu-induced downregulation of Insig-1. Based on these observations, these results reveal a link between ER stress and the change of lipid metabolism induced by Cu, which will help to understand the Cu-induced toxicity on cellular and molecular level, and provide some novel insights into the regulation of lipid metabolism in fish. PMID:26615493

  20. Endoplasmic reticulum stress and disturbed calcium homeostasis are involved in copper-induced alteration in hepatic lipid metabolism in yellow catfish Pelteobagrus fulvidraco.

    PubMed

    Song, Yu-Feng; Luo, Zhi; Zhang, Li-Han; Hogstrand, Christer; Pan, Ya-Xiong

    2016-02-01

    The present study was conducted to investigate the effect of Cu exposure on ER stress and Ca(2+) homeostasis, and explore the underlying mechanism of the ER stress and disturbed Ca(2+) homeostasis in the regulation of hepatic lipid metabolism in yellow catfish Pelteobagrus fulvidraco. To this end, three experiments were conducted. In experiment 1, P. fulvidraco were exposed to three waterborne Cu concentrations for 56 days. Waterborne Cu exposure evoked ER stress and SREBP-1c activation and resulted in dysregulation of hepatic lipid metabolism in liver of P. fulvidraco in a time-dependent manner. In experiment 2, specific inhibitors 2-APB (IP3 receptor inhibitor) and dantrolene (RyR receptor inhibitor) were used to explore whether Ca(2+) release from ER was involved in the Cu-induced ER stress change. Dantrolene and 2-APB prevented Cu-induced intracellular Ca(2+) elevation, demonstrating that the release of Ca(2+) from the ER, mediated by both RyR and IP3R, contributed to dysregulation of lipid metabolism. In experiment 3, a chemical chaperone (PBA) was used to demonstrate whether Cu-induced alteration in lipid metabolism was suppressed through the attenuation of ER stress. PBA attenuated the Cu-induced elevation of mRNA expression of SREBP-1c, SCAP, ACC, FAS, GRP78/BiP, GRP94, CRT, eIF2α and XBP-1, and alleviated the Cu-induced downregulation of Insig-1. Based on these observations, these results reveal a link between ER stress and the change of lipid metabolism induced by Cu, which will help to understand the Cu-induced toxicity on cellular and molecular level, and provide some novel insights into the regulation of lipid metabolism in fish.

  1. Coffee Consumption, Newly Diagnosed Diabetes, and Other Alterations in Glucose Homeostasis: A Cross-Sectional Analysis of the Longitudinal Study of Adult Health (ELSA-Brasil)

    PubMed Central

    Yarmolinsky, James; Mueller, Noel T.; Duncan, Bruce B.; Bisi Molina, Maria del Carmen; Goulart, Alessandra C.; Schmidt, Maria Inês

    2015-01-01

    Introduction Observational studies have reported fairly consistent inverse associations between coffee consumption and risk of type 2 diabetes, but this association has been little investigated with regard to lesser degrees of hyperglycemia and other alterations in glucose homeostasis. Additionally, the association between coffee consumption and diabetes has been rarely investigated in South American populations. We examined the cross-sectional relationships of coffee intake with newly diagnosed diabetes and measures of glucose homeostasis, insulin sensitivity, and insulin secretion, in a large Brazilian cohort of middle-aged and elderly individuals. Methods We used baseline data from 12,586 participants of the Longitudinal Study of Adult Health (ELSA-Brasil). Logistic regression analyses were performed to examine associations between coffee consumption and newly diagnosed diabetes. Analysis of covariance was used to assess coffee intake in relation to two-hour glucose from an oral glucose tolerance test, fasting glucose, glycated hemoglobin, fasting and –2-hour postload insulin and measures of insulin sensitivity. Results We found an inverse association between coffee consumption and newly diagnosed diabetes, after adjusting for multiple covariates [23% and 26% lower odds of diabetes for those consuming coffee 2–3 and >3 times per day, respectively, compared to those reporting never or almost never consuming coffee, (p = .02)]. An inverse association was also found for 2-hour postload glucose [Never/almost never: 7.57 mmol/L, ≤1 time/day: 7.48 mmol/L, 2-3 times/day: 7.22 mmol/L, >3 times/day: 7.12 mol/L, p<0.0001] but not with fasting glucose concentrations (p = 0.07). Coffee was additionally associated with 2-hour postload insulin [Never/almost never: 287.2 pmol/L, ≤1 time/day: 280.1 pmol/L, 2–3 times/day: 275.3 pmol/L, >3 times/day: 262.2 pmol/L, p = 0.0005) but not with fasting insulin concentrations (p = .58). Conclusion Our present study provides

  2. Defects in TRPM7 channel function deregulate thrombopoiesis through altered cellular Mg2+ homeostasis and cytoskeletal architecture

    PubMed Central

    Stritt, Simon; Nurden, Paquita; Favier, Remi; Favier, Marie; Ferioli, Silvia; Gotru, Sanjeev K.; van Eeuwijk, Judith M M.; Schulze, Harald; Nurden, Alan T.; Lambert, Michele P.; Turro, Ernest; Burger-Stritt, Stephanie; Matsushita, Masayuki; Mittermeier, Lorenz; Ballerini, Paola; Zierler, Susanna; Laffan, Michael A.; Chubanov, Vladimir; Gudermann, Thomas; Nieswandt, Bernhard; Braun, Attila

    2016-01-01

    Mg2+ plays a vital role in platelet function, but despite implications for life-threatening conditions such as stroke or myocardial infarction, the mechanisms controlling [Mg2+]i in megakaryocytes (MKs) and platelets are largely unknown. Transient receptor potential melastatin-like 7 channel (TRPM7) is a ubiquitous, constitutively active cation channel with a cytosolic α-kinase domain that is critical for embryonic development and cell survival. Here we report that impaired channel function of TRPM7 in MKs causes macrothrombocytopenia in mice (Trpm7fl/fl-Pf4Cre) and likely in several members of a human pedigree that, in addition, suffer from atrial fibrillation. The defect in platelet biogenesis is mainly caused by cytoskeletal alterations resulting in impaired proplatelet formation by Trpm7fl/fl-Pf4Cre MKs, which is rescued by Mg2+ supplementation or chemical inhibition of non-muscle myosin IIA heavy chain activity. Collectively, our findings reveal that TRPM7 dysfunction may cause macrothrombocytopenia in humans and mice. PMID:27020697

  3. BMP4-mediated brown fat-like changes in white adipose tissue alter glucose and energy homeostasis.

    PubMed

    Qian, Shu-Wen; Tang, Yan; Li, Xi; Liu, Yuan; Zhang, You-You; Huang, Hai-Yan; Xue, Rui-Dan; Yu, Hao-Yong; Guo, Liang; Gao, Hui-Di; Liu, Yan; Sun, Xia; Li, Yi-Ming; Jia, Wei-Ping; Tang, Qi-Qun

    2013-02-26

    Expression of bone morphogenetic protein 4 (BMP4) in adipocytes of white adipose tissue (WAT) produces "white adipocytes" with characteristics of brown fat and leads to a reduction of adiposity and its metabolic complications. Although BMP4 is known to induce commitment of pluripotent stem cells to the adipocyte lineage by producing cells that possess the characteristics of preadipocytes, its effects on the mature white adipocyte phenotype and function were unknown. Forced expression of a BMP4 transgene in white adipocytes of mice gives rise to reduced WAT mass and white adipocyte size along with an increased number of a white adipocyte cell types with brown adipocyte characteristics comparable to those of beige or brite adipocytes. These changes correlate closely with increased energy expenditure, improved insulin sensitivity, and protection against diet-induced obesity and diabetes. Conversely, BMP4-deficient mice exhibit enlarged white adipocyte morphology and impaired insulin sensitivity. We identify peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α) as the target of BMP signaling required for these brown fat-like changes in WAT. This effect of BMP4 on WAT appears to extend to human adipose tissue, because the level of expression of BMP4 in WAT correlates inversely with body mass index. These findings provide a genetic and metabolic basis for BMP4's role in altering insulin sensitivity by affecting WAT development.

  4. Diet/Energy Balance Affect Sleep and Wakefulness Independent of Body Weight

    PubMed Central

    Perron, Isaac J.; Pack, Allan I.; Veasey, Sigrid

    2015-01-01

    Study Objectives: Excessive daytime sleepiness commonly affects obese people, even in those without sleep apnea, yet its causes remain uncertain. We sought to determine whether acute dietary changes could induce or rescue wake impairments independent of body weight. Design: We implemented a novel feeding paradigm that generates two groups of mice with equal body weight but opposing energetic balance. Two subsets of mice consuming either regular chow (RC) or high-fat diet (HFD) for 8 w were switched to the opposite diet for 1 w. Sleep recordings were conducted at Week 0 (baseline), Week 8 (pre-diet switch), and Week 9 (post-diet switch) for all groups. Sleep homeostasis was measured at Week 8 and Week 9. Participants: Young adult, male C57BL/6J mice. Measurements and Results: Differences in total wake, nonrapid eye movement (NREM), and rapid eye movement (REM) time were quantified, in addition to changes in bout fragmentation/consolidation. At Week 9, the two diet switch groups had similar body weight. However, animals switched to HFD (and thus gaining weight) had decreased wake time, increased NREM sleep time, and worsened sleep/wake fragmentation compared to mice switched to RC (which were in weight loss). These effects were driven by significant sleep/wake changes induced by acute dietary manipulations (Week 8 → Week 9). Sleep homeostasis, as measured by delta power increase following sleep deprivation, was unaffected by our feeding paradigm. Conclusions: Acute dietary manipulations are sufficient to alter sleep and wakefulness independent of body weight and without effects on sleep homeostasis. Citation: Perron IJ, Pack AI, Veasey S. Diet/energy balance affect sleep and wakefulness independent of body weight. SLEEP 2015;38(12):1893–1903. PMID:26158893

  5. Hypobaric hypoxia modulates brain biogenic amines and disturbs sleep architecture.

    PubMed

    Ray, Koushik; Dutta, Arkadeb; Panjwani, Usha; Thakur, Lalan; Anand, J P; Kumar, Sanjeev

    2011-01-01

    Sojourners to high altitude experience poor-quality of sleep due to hypobaric hypoxia (HH). Brain neurotransmitters are the key regulators of sleep wakefulness. Scientific literature has limited information on the role of brain neurotransmitters involved in sleep disturbance in HH. The present study aimed to investigate the time dependent changes in neurotransmitter levels and enzymes involved in the biosynthesis of brain neurotransmitters in frontal cortex, brain stem, cerebellum, pons and medulla and the effect of these alterations on sleep architecture in HH. Thirty adult Sprague-Dawley rats, body weight of 230-250 g were exposed to simulated altitude ∼7620 m, 282 mm Hg, partial pressure of O(2) 59 mm Hg for 7 and 14 days continuously in an animal decompression chamber. After 7 and 14 days of HH, brain nor-epinephrine and dopamine levels were significantly increased in frontal cortex, brain stem, cerebellum and pons and medulla whereas serotonin level was significantly reduced in frontal cortex and pons and medulla after 14 days of HH. Tyrosine hydroxylase level in locus coeruleus (LC) was significantly increased whereas Choline Acetyl Transferase and Glutamic Acid Decarboxylase (GAD) levels were significantly reduced in laterodorsal-tegmentum and pedunculopontine-tegmentum after 7 days of HH. GAD was also reduced in LC after 7 days HH. Alteration in these neurotransmitters and enzyme levels was accompanied with reduction in quality and quantity of sleep. There was a significant increase in sleep latency, rapid eye movement (REM) latency, duration of active awake, quiet awake, quiet sleep and a significant decrease in duration of REM sleep and deep sleep on day 7 and 14 of HH. It was concluded that HH alters the expression of enzymes linked to sleep neurotransmitter synthesis pathway and subsequent loss of homeostasis at neurotransmitter level disrupts the sleep pattern in hypobaric hypoxia.

  6. Possible nitric oxide modulation in protective effect of (Curcuma longa, Zingiberaceae) against sleep deprivation-induced behavioral alterations and oxidative damage in mice.

    PubMed

    Kumar, Anil; Singh, Anant

    2008-08-01

    Sleep is essential for the physical and mental health of a human being. Problems of sleep deprivation are increasing in modern society nowadays. Recently, various antioxidants have been implicated as neuroprotectants in the treatment of stress and stress related problems. The present study was designed to explore the possible role of nitric oxide in the protective effect of Curcumin (Curcuma longa, Zingiberaceae) against 72-h sleep deprivation-induced behavioral alterations and oxidative damage in mice. 72-h sleep deprivation significantly caused weight loss, anxiety like behavior, impaired locomotor activity and oxidative damage (increased lipid peroxidation, nitrite level and deplete glutathione and catalase activity) in animals. Treatment with Curcumin extract (10 and 20mg/kg, ip) for 5 days significantly prevented weight loss, impairment in locomotor activity, anxiety like effects in all behavioral paradigms tasks (mirror chamber, plus maze, zero maze) as compared to control (72-h sleep-deprived) (P<0.05). Biochemically, Curcumin extract treatment significantly restored depleted reduced glutathione, catalase activity, attenuated raised lipid peroxidation and nitrite level as compared to control (72-h sleep-deprived) animals. Further, pretreatment of l-arginine (50mg/kg, ip), nitric oxide precursor reversed the protective effect of Curcumin (10 mg/kg, ip) (P<0.05). However, pretreatment of l-NAME (5 mg/kg, ip), nitric oxide synthase inhibitor caused a potentiation in the protective effect of Curcumin (P<0.05). The present study suggests that nitric oxide modulation is involved in the protective effect of Curcumin in ameliorating sleep deprivation-induced behavioral alterations and oxidative damage.

  7. High butyric acid amounts induce oxidative stress, alter calcium homeostasis, and cause neurite retraction in nerve growth factor-treated PC12 cells.

    PubMed

    Cueno, Marni E; Kamio, Noriaki; Seki, Keisuke; Kurita-Ochiai, Tomoko; Ochiai, Kuniyasu

    2015-07-01

    Butyric acid (BA) is a common secondary metabolite by-product produced by oral pathogenic bacteria and is detected in high amounts in the gingival tissue of patients with periodontal disease. Previous works have demonstrated that BA can cause oxidative stress in various cell types; however, this was never explored using neuronal cells. Here, we exposed nerve growth factor (NGF)-treated PC1(2) cells to varying BA concentrations (0.5, 1.0, 5.0 mM). We measured total heme, H(2)O(2), catalase, and calcium levels through biochemical assays and visualized the neurite outgrowth after BA treatment. Similarly, we determined the effects of other common periodontal short-chain fatty acids (SCFAs) on neurite outgrowth for comparison. We found that high (1.0 and 5.0 mM) BA concentrations induced oxidative stress and altered calcium homeostasis, whereas low (0.5 mM) BA concentration had no significant effect. Moreover, compared to other SCFAs, we established that only BA was able to induce neurite retraction.

  8. Endoplasmic reticulum stress and dysregulation of calcium homeostasis mediate Cu-induced alteration in hepatic lipid metabolism of javelin goby Synechogobius hasta.

    PubMed

    Song, Yu-Feng; Huang, Chao; Shi, Xi; Pan, Ya-Xiong; Liu, Xu; Luo, Zhi

    2016-06-01

    The present study was conducted to investigate the effect of Cu exposure on endoplasmic reticulum (ER) stress and Ca(2+) homeostasis, and also explore the underlying mechanism of the ER stress and Ca(2+) homeostasis in the Cu-induced change of hepatic lipid metabolism in javelin goby Synechogobius hasta. To this end, four experiments were conducted. In experiment 1, the full-length cDNA sequences of two ER molecular chaperones [glucose-regulated protein 78 (GRP78) and calreticulin (CRT)] and three ER stress sensors [PKR-like ER kinase (PERK), inositol requiring enzyme (IRE)-1α, and activating transcription factor (ATF)-6α] cDNAs were firstly characterized from S. hasta. The predicted amino acid sequences for the S. hasta GRP78, CRT, PERK, IRE-1α and ATF-6α revealed that the proteins contained all of the structural features characteristic in other species. mRNAs of the five genes were expressed in various tissues, but their mRNA levels varied among tissues. In experiment 2, S. hasta were exposed to four waterborne Cu concentrations (control, 19μg/l, 38μg/l, and 57μg/l, respectively) for 60days. Cu exposure evoked ER stress in liver of S. hasta in a time- and concentration-course change. In experiment 3, specific inhibitors, 2-aminoethyldiphenyl borate (2-APB) and dantrolene, were used to explore whether Ca(2+) release from ER was involved in the Cu-induced ER stress change. Dantrolene and 2-APB prevented Cu-induced intracellular Ca(2+) elevation, which demonstrated the release of Ca(2+) from the ER was mediated by both RyR and IP3R. In experiment 4, a chemical chaperone, 4-phenyl butyric acid (4-PBA), was used to demonstrate whether Cu-induced alteration in lipid metabolism was suppressed through the attenuation of ER stress. Cu exposure evoked ER stress and sterol-regulator element-binding protein-1c (SREBP-1c) activation in hepatocytes of S. hasta, resulting in dysregulation of hepatic lipid metabolism. 4-PBA attenuated the Cu-induced elevation of m

  9. Improvement of mood and sleep alterations in posttraumatic stress disorder patients by eye movement desensitization and reprocessing

    PubMed Central

    Raboni, Mara R.; Alonso, Fabiana F. D.; Tufik, Sergio; Suchecki, Deborah

    2014-01-01

    Posttraumatic stress disorder (PTSD) patients exhibit depressive and anxiety symptoms, in addition to nightmares, which interfere with sleep continuity. Pharmacologic treatment of these sleep problems improves PTSD symptoms, but very few studies have used psychotherapeutic interventions to treat PTSD and examined their effects on sleep quality. Therefore, in the present study, we sought to investigate the effects of Eye Movement Desensitization Reprocessing therapy on indices of mood, anxiety, subjective, and objective sleep. The sample was composed of 11 healthy controls and 13 PTSD patients that were victims of assault and/or kidnapping. All participants were assessed before, and 1 day after, the end of treatment for depressive and anxiety profile, general well-being and subjective sleep by filling out specific questionnaires. In addition, objective sleep patterns were evaluated by polysomnographic recording. Healthy volunteers were submitted to the therapy for three weekly sessions, whereas PTSD patients underwent five sessions, on average. Before treatment, PTSD patients exhibited high levels of anxiety and depression, poor quality of life and poor sleep, assessed both subjectively and objectively; the latter was reflected by increased time of waking after sleep onset. After completion of treatment, patients exhibited improvement in depression and anxiety symptoms, and in quality of life; with indices that were no longer different from control volunteers. Moreover, these patients showed more consolidated sleep, with reduction of time spent awake after sleep onset. In conclusion, Eye Movement Desensitization and Reprocessing was an effective treatment of PTSD patients and improved the associated sleep and psychological symptoms. PMID:24959123

  10. Altered Resting-State Amygdala Functional Connectivity after 36 Hours of Total Sleep Deprivation

    PubMed Central

    Shao, Yongcong; Lei, Yu; Wang, Lubin; Zhai, Tianye; Jin, Xiao; Ni, Wei; Yang, Yue; Tan, Shuwen; Wen, Bo; Ye, Enmao; Yang, Zheng

    2014-01-01

    Objectives Recent neuroimaging studies have identified a potentially critical role of the amygdala in disrupted emotion neurocircuitry in individuals after total sleep deprivation (TSD). However, connectivity between the amygdala and cerebral cortex due to TSD remains to be elucidated. In this study, we used resting-state functional MRI (fMRI) to investigate the functional connectivity changes of the basolateral amygdala (BLA) and centromedial amygdala (CMA) in the brain after 36 h of TSD. Materials and Methods Fourteen healthy adult men aged 25.9±2.3 years (range, 18–28 years) were enrolled in a within-subject crossover study. Using the BLA and CMA as separate seed regions, we examined resting-state functional connectivity with fMRI during rested wakefulness (RW) and after 36 h of TSD. Results TSD resulted in a significant decrease in the functional connectivity between the BLA and several executive control regions (left dorsolateral prefrontal cortex [DLPFC], right dorsal anterior cingulate cortex [ACC], right inferior frontal gyrus [IFG]). Increased functional connectivity was found between the BLA and areas including the left posterior cingulate cortex/precuneus (PCC/PrCu) and right parahippocampal gyrus. With regard to CMA, increased functional connectivity was observed with the rostral anterior cingulate cortex (rACC) and right precentral gyrus. Conclusion These findings demonstrate that disturbance in amygdala related circuits may contribute to TSD psychophysiology and suggest that functional connectivity studies of the amygdala during the resting state may be used to discern aberrant patterns of coupling within these circuits after TSD. PMID:25372882

  11. Neuroimmunologic aspects of sleep and sleep loss

    NASA Technical Reports Server (NTRS)

    Rogers, N. L.; Szuba, M. P.; Staab, J. P.; Evans, D. L.; Dinges, D. F.

    2001-01-01

    The complex and intimate interactions between the sleep and immune systems have been the focus of study for several years. Immune factors, particularly the interleukins, regulate sleep and in turn are altered by sleep and sleep deprivation. The sleep-wake cycle likewise regulates normal functioning of the immune system. Although a large number of studies have focused on the relationship between the immune system and sleep, relatively few studies have examined the effects of sleep deprivation on immune parameters. Studies of sleep deprivation's effects are important for several reasons. First, in the 21st century, various societal pressures require humans to work longer and sleep less. Sleep deprivation is becoming an occupational hazard in many industries. Second, to garner a greater understanding of the regulatory effects of sleep on the immune system, one must understand the consequences of sleep deprivation on the immune system. Significant detrimental effects on immune functioning can be seen after a few days of total sleep deprivation or even several days of partial sleep deprivation. Interestingly, not all of the changes in immune physiology that occur as a result of sleep deprivation appear to be negative. Numerous medical disorders involving the immune system are associated with changes in the sleep-wake physiology--either being caused by sleep dysfunction or being exacerbated by sleep disruption. These disorders include infectious diseases, fibromyalgia, cancers, and major depressive disorder. In this article, we will describe the relationships between sleep physiology and the immune system, in states of health and disease. Interspersed will be proposals for future research that may illuminate the clinical relevance of the relationships between sleeping, sleep loss and immune function in humans. Copyright 2001 by W.B. Saunders Company.

  12. Hypertension secondary to early-stage kidney disease: the pathogenetic role of altered cytosolic calcium (Ca2+) homeostasis of vascular smooth muscle cells.

    PubMed

    Schiffl, H; Fricke, H; Sitter, T

    1993-05-01

    We have examined cardiovascular pressor responsiveness to infused norepinephrine (NE) as related to endogenous plasma NE and plasma renin and to platelet free cytosolic (Ca2+) in 36 patients with early-stage kidney disease and 27 matched normal subjects. The 27 hypertensive patients and the normal subjects did not differ in blood volume, plasma renin, and NE; however, the hypertensive patients had a higher exchangeable body sodium content. Basal plasma NE levels, the relationship between plasma NE measured during NE infusion and the corresponding NE infusion rate, as well as the total plasma clearance for NE did also not differ significantly between the two study groups. In contrast, the threshold or pressor doses of infused NE significantly decreased in the patients with kidney disease. Antihypertensive pharmacotherapy with (Ca2+) channel blockers and/or loop diuretics normalized blood pressure and cardiovascular NE hyperresponsiveness and reduced blood volume, exchangeable body sodium, and platelet free cytosolic (Ca2+). In contrast, experimental digitalisation as a model for in vivo sodium/potassium adenosine triphosphatase inhibition augmented NE responsiveness and raised platelet free cytosolic (Ca2+). Incubation of platelets from normal subjects with plasma ultrafiltrate from hypertensive patients gave evidence for an endogenous factor capable to raise free cytosolic (Ca2+) and to act synergistically with digoxin. Hypertension secondary to early-stage kidney disease is related to an impairment of sodium excretion leading to an expansion of blood volume and exchangeable body sodium. This may result in increased secretion of endogenous factors, leading to alterations of cytosolic (Ca2+) homeostasis of vascular smooth muscle cells followed by elevated peripheral resistance and thus blood pressure. PMID:8494019

  13. Loss of polyubiquitin gene Ubb leads to metabolic and sleep abnormalities in mice

    PubMed Central

    Ryu, K.-Y.; Fujiki, N.; Kazantzis, M.; Garza, J. C.; Bouley, D. M.; Stahl, A.; Lu, X.-Y.; Nishino, S.; Kopito, R. R.

    2010-01-01

    Aims Ubiquitin performs essential roles in a myriad of signalling pathways required for cellular function and survival. Recently, we reported that disruption of the stress-inducible ubiquitin-encoding gene Ubb reduces ubiquitin content in the hypothalamus and leads to adult-onset obesity coupled with a loss of arcuate nucleus neurones and disrupted energy homeostasis in mice. Neuropeptides expressed in the hypothalamus control both metabolic and sleep behaviours. In order to demonstrate that the loss of Ubb results in broad hypothalamic abnormalities, we attempted to determine whether metabolic and sleep behaviours were altered in Ubb knockout mice. Methods Metabolic rate and energy expenditure were measured in a metabolic chamber, and sleep stage was monitored via electroencephalographic/electromyographic recording. The presence of neurodegeneration and increased reactive gliosis in the hypothalamus were also evaluated. Results We found that Ubb disruption leads to early-onset reduced activity and metabolic rate. Additionally, we have demonstrated that sleep behaviour is altered and sleep homeostasis is disrupted in Ubb knockout mice. These early metabolic and sleep abnormalities are accompanied by persistent reactive gliosis and the loss of arcuate nucleus neurones, but are independent of neurodegeneration in the lateral hypothalamus. Conclusions Ubb knockout mice exhibit phenotypes consistent with hypothalamic dysfunction. Our data also indicate that Ubb is essential for the maintenance of the ubiquitin levels required for proper regulation of metabolic and sleep behaviours in mice. PMID:20002312

  14. Ancestral sleep.

    PubMed

    de la Iglesia, Horacio O; Moreno, Claudia; Lowden, Arne; Louzada, Fernando; Marqueze, Elaine; Levandovski, Rosa; Pilz, Luisa K; Valeggia, Claudia; Fernandez-Duque, Eduardo; Golombek, Diego A; Czeisler, Charles A; Skene, Debra J; Duffy, Jeanne F; Roenneberg, Till

    2016-04-01

    While we do not yet understand all the functions of sleep, its critical role for normal physiology and behaviour is evident. Its amount and temporal pattern depend on species and condition. Humans sleep about a third of the day with the longest, consolidated episode during the night. The change in lifestyle from hunter-gatherers via agricultural communities to densely populated industrialized centres has certainly affected sleep, and a major concern in the medical community is the impact of insufficient sleep on health [1,2]. One of the causal mechanisms leading to insufficient sleep is altered exposure to the natural light-dark cycle. This includes the wide availability of electric light, attenuated exposure to daylight within buildings, and evening use of light-emitting devices, all of which decrease the strength of natural light-dark signals that entrain circadian systems [3].

  15. Ancestral sleep.

    PubMed

    de la Iglesia, Horacio O; Moreno, Claudia; Lowden, Arne; Louzada, Fernando; Marqueze, Elaine; Levandovski, Rosa; Pilz, Luisa K; Valeggia, Claudia; Fernandez-Duque, Eduardo; Golombek, Diego A; Czeisler, Charles A; Skene, Debra J; Duffy, Jeanne F; Roenneberg, Till

    2016-04-01

    While we do not yet understand all the functions of sleep, its critical role for normal physiology and behaviour is evident. Its amount and temporal pattern depend on species and condition. Humans sleep about a third of the day with the longest, consolidated episode during the night. The change in lifestyle from hunter-gatherers via agricultural communities to densely populated industrialized centres has certainly affected sleep, and a major concern in the medical community is the impact of insufficient sleep on health [1,2]. One of the causal mechanisms leading to insufficient sleep is altered exposure to the natural light-dark cycle. This includes the wide availability of electric light, attenuated exposure to daylight within buildings, and evening use of light-emitting devices, all of which decrease the strength of natural light-dark signals that entrain circadian systems [3]. PMID:27046809

  16. Identification of Genes Associated with Resilience/Vulnerability to Sleep Deprivation and Starvation in Drosophila

    PubMed Central

    Thimgan, Matthew S.; Seugnet, Laurent; Turk, John; Shaw, Paul J.

    2015-01-01

    Background and Study Objectives: Flies mutant for the canonical clock protein cycle (cyc01) exhibit a sleep rebound that is ∼10 times larger than wild-type flies and die after only 10 h of sleep deprivation. Surprisingly, when starved, cyc01 mutants can remain awake for 28 h without demonstrating negative outcomes. Thus, we hypothesized that identifying transcripts that are differentially regulated between waking induced by sleep deprivation and waking induced by starvation would identify genes that underlie the deleterious effects of sleep deprivation and/or protect flies from the negative consequences of waking. Design: We used partial complementary DNA microarrays to identify transcripts that are differentially expressed between cyc01 mutants that had been sleep deprived or starved for 7 h. We then used genetics to determine whether disrupting genes involved in lipid metabolism would exhibit alterations in their response to sleep deprivation. Setting: Laboratory. Patients or Participants: Drosophila melanogaster. Interventions: Sleep deprivation and starvation. Measurements and Results: We identified 84 genes with transcript levels that were differentially modulated by 7 h of sleep deprivation and starvation in cyc01 mutants and were confirmed in independent samples using quantitative polymerase chain reaction. Several of these genes were predicted to be lipid metabolism genes, including bubblegum, cueball, and CG4500, which based on our data we have renamed heimdall (hll). Using lipidomics we confirmed that knockdown of hll using RNA interference significantly decreased lipid stores. Importantly, genetically modifying bubblegum, cueball, or hll resulted in sleep rebound alterations following sleep deprivation compared to genetic background controls. Conclusions: We have identified a set of genes that may confer resilience/vulnerability to sleep deprivation and demonstrate that genes involved in lipid metabolism modulate sleep homeostasis. Citation: Thimgan MS

  17. Altered sleep-wake cycles and food intake: the Ramadan model.

    PubMed

    Reilly, Thomas; Waterhouse, Jim

    2007-02-28

    In this review the effects of diurnal fasting on normal physiological processes are considered. Ramadan is placed in a circadian context, food and fluid ingestion being displaced to the pre-sunrise and post-sunset hours. Over the holy month, negative energy balance is often experienced, though this deficit is not a universal finding. Responses to exercise during the day show influences consistent with hypohydration and an increased reliance on fat as a source of fuel for exercise. Muscle performance and psychomotor performance are impaired as the month of fasting progresses but it is not clear how circadian rhythms in responses to activity are altered. For some measures at rest there is a reduction in amplitude and a delay in acrophase. Health-related benefits are reflected in a rise in high-density lipoprotein cholesterol and individuals with predispositions for coronary heart disease are not at increased risk of cardiovascular disorders due to fasting. The physiological adjustments during the month have some similarities to the disturbances in circadian rhythms experienced in different circumstances. The Ramadan model provides an alternative to those for ageing, nocturnal shift-work and time-zone transitions in understanding the links between behaviour and endogenous circadian rhythms. PMID:17081572

  18. Altered sleep-wake cycles and food intake: the Ramadan model.

    PubMed

    Reilly, Thomas; Waterhouse, Jim

    2007-02-28

    In this review the effects of diurnal fasting on normal physiological processes are considered. Ramadan is placed in a circadian context, food and fluid ingestion being displaced to the pre-sunrise and post-sunset hours. Over the holy month, negative energy balance is often experienced, though this deficit is not a universal finding. Responses to exercise during the day show influences consistent with hypohydration and an increased reliance on fat as a source of fuel for exercise. Muscle performance and psychomotor performance are impaired as the month of fasting progresses but it is not clear how circadian rhythms in responses to activity are altered. For some measures at rest there is a reduction in amplitude and a delay in acrophase. Health-related benefits are reflected in a rise in high-density lipoprotein cholesterol and individuals with predispositions for coronary heart disease are not at increased risk of cardiovascular disorders due to fasting. The physiological adjustments during the month have some similarities to the disturbances in circadian rhythms experienced in different circumstances. The Ramadan model provides an alternative to those for ageing, nocturnal shift-work and time-zone transitions in understanding the links between behaviour and endogenous circadian rhythms.

  19. Chronic Alcohol Treatment in Rats Alters Sleep by Fragmenting Periods of Vigilance Cycling in the Light Period with Extended Wakenings

    PubMed Central

    Mukherjee, Sanjib; Simasko, Steven M.

    2009-01-01

    Studies have shown that disturbed sleep produced by chronic alcohol abuse in humans can predict relapse drinking after periods of abstinence. How alcohol produces disturbed sleep remains unknown. In this study we used a novel analysis of sleep to examine the effects of alcohol on sleep patterns in rats. This analysis separates waking into multiple components and defines a period labeled vigilance cycling (VC) in which the rat rapidly cycles through various vigilance states. These VC episodes are separated by long duration wake periods (LDW). We find that 6 weeks of alcohol (6% in a liquid diet) caused fragmentation of extended VC episodes that normally occur in the light period. However, total daily amounts of slow-wave sleep (SWS) and rapid-eye movement sleep (REMS) remained constant. The daily amount of wake, SWS, and REMS remained constant because the alcohol treated rats increased the amount of VC in the dark period, and the sleep nature of VC in the dark period became more intense. In addition, we observed more wake and less REMS early in the light period in alcohol treated rats. All effects completely reversed by day 16 of alcohol withdrawal. Comparison of the effects of chronic alcohol to acute alcohol exposure demonstrated the effects of chronic alcohol are due to adaptation and not the acute presence of alcohol. The effects of chronic alcohol treatment in rats mimic the effects reported in humans (REMS suppression, difficulty falling asleep, and difficulty remaining asleep). PMID:19014977

  20. Increased fragmentation of sleep-wake cycles in the 5XFAD mouse model of Alzheimer's disease.

    PubMed

    Sethi, M; Joshi, S S; Webb, R L; Beckett, T L; Donohue, K D; Murphy, M P; O'Hara, B F; Duncan, M J

    2015-04-01

    Sleep perturbations including fragmented sleep with frequent night-time awakenings and daytime naps are common in patients with Alzheimer's disease (AD), and these daily disruptions are a major factor for institutionalization. The objective of this study was to investigate if sleep-wake patterns are altered in 5XFAD mice, a well-characterized double transgenic mouse model of AD which exhibits an early onset of robust AD pathology and memory deficits. These mice have five distinct human mutations in two genes, the amyloid precursor protein (APP) and Presenilin1 (PS1) engineered into two transgenes driven by a neuron-specific promoter (Thy1), and thus develop severe amyloid deposition by 4 months of age. Age-matched (4-6.5 months old) male and female 5XFAD mice were monitored and compared to wild-type littermate controls for multiple sleep traits using a non-invasive, high throughput, automated piezoelectric system which detects breathing and gross body movements to characterize sleep and wake. Sleep-wake patterns were recorded continuously under baseline conditions (undisturbed) for 3 days and after sleep deprivation of 4h, which in mice produces a significant sleep debt and challenge to sleep homeostasis. Under baseline conditions, 5XFAD mice exhibited shorter bout lengths (14% lower values for males and 26% for females) as compared to controls (p<0.001). In females, the 5XFAD mice also showed 12% less total sleep than WT (p<0.01). Bout length reductions were greater during the night (the active phase for mice) than during the day, which does not model the human condition of disrupted sleep at night (the inactive period). However, the overall decrease in bout length suggests increased fragmentation and disruption in sleep consolidation that may be relevant to human sleep. The 5XFAD mice may serve as a useful model for testing therapeutic strategies to improve sleep consolidation in AD patients.

  1. The sleep-friendly ICU.

    PubMed

    Sareli, Aharon E; Schwab, Richard J

    2008-07-01

    Achieving restorative sleep in the ICU remains a challenge for most patients. Various environmental and nonenvironmental factors affect sleep patterns in the ICU. This article discusses the effects and relative importance of these factors on sleep patterns in the critical care setting. In addition, the implications of sleep pattern alteration on human physiology and homeostatic mechanisms are considered.

  2. Enhanced histaminergic neurotransmission and sleep-wake alterations, a study in histamine H3-receptor knock-out mice.

    PubMed

    Gondard, Elise; Anaclet, Christelle; Akaoka, Hidéo; Guo, Rui-Xian; Zhang, Mei; Buda, Colette; Franco, Patricia; Kotani, Hidehito; Lin, Jian-Sheng

    2013-05-01

    Long-term abolition of a brain arousal system impairs wakefulness (W), but little is known about the consequences of long-term enhancement. The brain histaminergic arousal system is under the negative control of H3-autoreceptors whose deletion results in permanent enhancement of histamine (HA) turnover. In order to determine the consequences of enhancement of the histaminergic system, we compared the cortical EEG and sleep-wake states of H3-receptor knockout (H3R-/-) and wild-type mouse littermates. We found that H3R-/-mice had rich phenotypes. On the one hand, they showed clear signs of enhanced HA neurotransmission and vigilance, i.e., a higher EEG θ power during spontaneous W and a greater extent of W or sleep restriction during behavioral tasks, including environmental change, locomotion, and motivation tests. On the other hand, during the baseline dark period, they displayed deficient W and signs of sleep deterioration, such as pronounced sleep fragmentation and reduced cortical slow activity during slow wave sleep (SWS), most likely due to a desensitization of postsynaptic histaminergic receptors as a result of constant HA release. Ciproxifan (H3-receptor inverse agonist) enhanced W in wild-type mice, but not in H3R-/-mice, indicating a functional deletion of H3-receptors, whereas triprolidine (postsynaptic H1-receptor antagonist) or α-fluoromethylhistidine (HA-synthesis inhibitor) caused a greater SWS increase in H3R-/- than in wild-type mice, consistent with enhanced HA neurotransmission. These sleep-wake characteristics and the obesity phenotypes previously reported in this animal model suggest that chronic enhancement of histaminergic neurotransmission eventually compromises the arousal system, leading to sleep-wake, behavioral, and metabolic disorders similar to those caused by voluntary sleep restriction in humans.

  3. Enhanced Histaminergic Neurotransmission and Sleep-Wake Alterations, a Study in Histamine H3-Receptor Knock-Out Mice

    PubMed Central

    Gondard, Elise; Anaclet, Christelle; Akaoka, Hidéo; Guo, Rui-Xian; Zhang, Mei; Buda, Colette; Franco, Patricia; Kotani, Hidehito; Lin, Jian-Sheng

    2013-01-01

    Long-term abolition of a brain arousal system impairs wakefulness (W), but little is known about the consequences of long-term enhancement. The brain histaminergic arousal system is under the negative control of H3-autoreceptors whose deletion results in permanent enhancement of histamine (HA) turnover. In order to determine the consequences of enhancement of the histaminergic system, we compared the cortical EEG and sleep-wake states of H3-receptor knockout (H3R−/−) and wild-type mouse littermates. We found that H3R−/−mice had rich phenotypes. On the one hand, they showed clear signs of enhanced HA neurotransmission and vigilance, i.e., a higher EEG θ power during spontaneous W and a greater extent of W or sleep restriction during behavioral tasks, including environmental change, locomotion, and motivation tests. On the other hand, during the baseline dark period, they displayed deficient W and signs of sleep deterioration, such as pronounced sleep fragmentation and reduced cortical slow activity during slow wave sleep (SWS), most likely due to a desensitization of postsynaptic histaminergic receptors as a result of constant HA release. Ciproxifan (H3-receptor inverse agonist) enhanced W in wild-type mice, but not in H3R−/−mice, indicating a functional deletion of H3-receptors, whereas triprolidine (postsynaptic H1-receptor antagonist) or α-fluoromethylhistidine (HA-synthesis inhibitor) caused a greater SWS increase in H3R−/− than in wild-type mice, consistent with enhanced HA neurotransmission. These sleep-wake characteristics and the obesity phenotypes previously reported in this animal model suggest that chronic enhancement of histaminergic neurotransmission eventually compromises the arousal system, leading to sleep-wake, behavioral, and metabolic disorders similar to those caused by voluntary sleep restriction in humans. PMID:23303066

  4. Associations between sleep loss and increased risk of obesity and diabetes

    PubMed Central

    Knutson, Kristen L.; Van Cauter, Eve

    2015-01-01

    During the past few decades, sleep curtailment has become a very common behavior in industrialized countries. This trend for shorter sleep duration has developed over the same time period as the dramatic increase in the prevalence of obesity and diabetes. There is rapidly accumulating evidence to indicate that chronic partial sleep loss may increase the risk of obesity and diabetes. Laboratory studies in healthy volunteers have shown that experimental sleep restriction is associated with an adverse impact on glucose homeostasis. Insulin sensitivity decreases rapidly and markedly without adequate compensation in beta cell function, resulting in an elevated risk of diabetes. Prospective epidemiologic studies in both children and adults are consistent with a causative role of short sleep in the increased risk of diabetes. Sleep curtailment is also associated with a dysregulation of the neuroendocrine control of appetite, with a reduction of the satiety factor leptin and an increase in the hunger-promoting hormone ghrelin. Thus, sleep loss may alter the ability of leptin and ghrelin to accurately signal caloric need, acting in concert to produce an internal misperception of insufficient energy availability. The adverse impact of sleep deprivation on appetite regulation is likely to be driven by increased activity in neuronal populations expressing the excitatory peptides orexins that promote both waling and feeding. Consistent with the laboratory evidence, multiple epidemiologic studies have shown an association between short sleep and higher body mass index after controlling for a variety of possible confounders. PMID:18591489

  5. Sleep, Circadian Rhythms, and Performance During Space Shuttle Missions

    NASA Technical Reports Server (NTRS)

    Neri, David F.; Czeisler, Charles A.; Dijk, Derk-Jan; Wyatt, James K.; Ronda, Joseph M.; Hughes, Rod J.

    2003-01-01

    Sleep and circadian rhythms may be disturbed during spaceflight, and these disturbances can affect crewmembers' performance during waking hours. The mechanisms underlying sleep and circadian rhythm disturbances in space are not well understood, and effective countermeasures are not yet available. We investigated sleep, circadian rhythms, cognitive performance, and light-dark cycles in five astronauts prior to, during, and after the 16-day STS-90 mission and the IO-day STS-95 mission. The efficacy of low-dose, alternative-night, oral melatonin administration as a countermeasure for sleep disturbances was evaluated. During these missions, scheduled rest activity cycles were 20-35 minutes shorter than 24 hours. Light levels on the middeck and in the Spacelab were very low; whereas on the flight deck (which has several windows), they were highly variable. Circadian rhythm abnormalities were observed. During the second half of the missions, the rhythm of urinary cortisol appeared to be delayed relative to the sleep-wake schedule. Performance during wakefulness was impaired. Astronauts slept only about 6.5 hours per day, and subjective sleep quality was lower in space. No beneficial effects of melatonin (0.3 mg administered prior to sleep episodes on alternate nights) were observed. A surprising finding was a marked increase in rapid eye movement (REM) sleep upon return to Earth. We conclude that these Space Shuttle missions were associated with circadian rhythm disturbances, sleep loss, decrements in neurobehavioral performance, and alterations in REM sleep homeostasis. Shorter than 24-hour rest-activity schedules and exposure to light-dark cycles inadequate for optimal circadian synchronization may have contributed to these disturbances.

  6. Sleep, Memory & Brain Rhythms

    PubMed Central

    Watson, Brendon O.; Buzsáki, György

    2015-01-01

    Sleep occupies roughly one-third of our lives, yet the scientific community is still not entirely clear on its purpose or function. Existing data point most strongly to its role in memory and homeostasis: that sleep helps maintain basic brain functioning via a homeostatic mechanism that loosens connections between overworked synapses, and that sleep helps consolidate and re-form important memories. In this review, we will summarize these theories, but also focus on substantial new information regarding the relation of electrical brain rhythms to sleep. In particular, while REM sleep may contribute to the homeostatic weakening of overactive synapses, a prominent and transient oscillatory rhythm called “sharp-wave ripple” seems to allow for consolidation of behaviorally relevant memories across many structures of the brain. We propose that a theory of sleep involving the division of labor between two states of sleep–REM and non-REM, the latter of which has an abundance of ripple electrical activity–might allow for a fusion of the two main sleep theories. This theory then postulates that sleep performs a combination of consolidation and homeostasis that promotes optimal knowledge retention as well as optimal waking brain function. PMID:26097242

  7. Overnight emotional adaptation to negative stimuli is altered by REM sleep deprivation and is correlated with intervening dream emotions.

    PubMed

    Lara-Carrasco, Jessica; Nielsen, Tore A; Solomonova, Elizaveta; Levrier, Katia; Popova, Ani

    2009-06-01

    Rapid eye movement (REM) sleep and dreaming may be implicated in cross-night adaptation to emotionally negative events. To evaluate the impact of REM sleep deprivation (REMD) and the presence of dream emotions on a possible emotional adaptation (EA) function, 35 healthy subjects randomly assigned to REMD (n = 17; mean age 26.4 +/- 4.3 years) and control (n = 18; mean age 23.7 +/- 4.4 years) groups underwent a partial REMD and control nights in the laboratory, respectively. In the evening preceding and morning following REMD, subjects rated neutral and negative pictures on scales of valence and arousal and EA scores were calculated. Subjects also rated dream emotions using the same scales and a 10-item emotions list. REMD was relatively successful in decreasing REM% on the experimental night, although a mean split procedure was applied to better differentiate subjects high and low in REM%. High and low groups differed - but in a direction contrary to expectations. Subjects high in REMD% showed greater adaptation to negative pictures on arousal ratings than did those low in REMD% (P < 0.05), even after statistically controlling sleep efficiency and awakening times. Subjects above the median on EA(valence) had less intense overall dream negativity (P < 0.005) and dream sadness (P < 0.004) than subjects below the median. A correlation between the emotional intensities of the morning dream and the morning picture ratings supports a possible emotional carry-over effect. REM sleep may enhance morning reactivity to negative emotional stimuli. Further, REM sleep and dreaming may be implicated in different dimensions of cross-night adaptation to negative emotions.

  8. Altered S-nitrosothiol homeostasis provides a survival advantage to breast cancer cells in HER2 tumors and reduces their sensitivity to trastuzumab.

    PubMed

    Cañas, Amanda; López-Sánchez, Laura M; Peñarando, Jon; Valverde, Araceli; Conde, Francisco; Hernández, Vanessa; Fuentes, Elena; López-Pedrera, Chary; de la Haba-Rodríguez, Juan R; Aranda, Enrique; Rodríguez-Ariza, Antonio

    2016-04-01

    The monoclonal antibody trastuzumab against HER2/neu, which is overexpressed in 15-20% of breast cancers, has clinical efficacy but many patients do not respond to initial treatment or develop resistance during treatment. Nitric oxide (NO) regulates cell signaling by targeting specific cysteine residues in proteins, forming S-nitrosothiols (SNO) in a process known as S-nitrosylation. We previously reported that molecular characteristics in breast cancer may dictate the tumor response to impaired SNO homeostasis. In the present study, we explored the role of SNO homeostasis in HER2 breast tumors. The antiproliferative action of trastuzumab in HER2-overexpressing BT-474 and SKBR-3 cells was suppressed when S-nitrosoglutathione reductase (GSNOR/ADH5) activity, which plays a key role in SNO homeostasis, was specifically inhibited with the pyrrole derivative compound N6022. Moreover, GSNOR inhibition restored the activation of survival signaling pathways involved in the resistance to anti-HER2 therapies (AKT, Src and c-Abl kinases and TrkA/NRTK1, TrkB/NRTK2, EphA1 and EphA3 receptors) and reduced the apoptotic effect of trastuzumab. Accordingly, GSNOR inhibition augmented the S-nitrosylation of apoptosis-related proteins, including Apaf-1, pSer73/63 c-Jun, calcineurin subunit α and HSF1. In agreement with in vitro data, immunohistochemical analyses of 51 breast tumors showed that HER2 expression was associated with lower expression of GSNOR protein. Moreover, gene expression analysis confirmed that high ADH5/GSNOR gene expression was associated with high patient survival rates in HER2 tumors. In conclusion, our data provide evidence of molecular mechanisms contributing to the progression of HER2+ breast cancers and could facilitate the development of therapeutic options to counteract resistance to anti-HER2 therapies. PMID:26854735

  9. Altered S-nitrosothiol homeostasis provides a survival advantage to breast cancer cells in HER2 tumors and reduces their sensitivity to trastuzumab.

    PubMed

    Cañas, Amanda; López-Sánchez, Laura M; Peñarando, Jon; Valverde, Araceli; Conde, Francisco; Hernández, Vanessa; Fuentes, Elena; López-Pedrera, Chary; de la Haba-Rodríguez, Juan R; Aranda, Enrique; Rodríguez-Ariza, Antonio

    2016-04-01

    The monoclonal antibody trastuzumab against HER2/neu, which is overexpressed in 15-20% of breast cancers, has clinical efficacy but many patients do not respond to initial treatment or develop resistance during treatment. Nitric oxide (NO) regulates cell signaling by targeting specific cysteine residues in proteins, forming S-nitrosothiols (SNO) in a process known as S-nitrosylation. We previously reported that molecular characteristics in breast cancer may dictate the tumor response to impaired SNO homeostasis. In the present study, we explored the role of SNO homeostasis in HER2 breast tumors. The antiproliferative action of trastuzumab in HER2-overexpressing BT-474 and SKBR-3 cells was suppressed when S-nitrosoglutathione reductase (GSNOR/ADH5) activity, which plays a key role in SNO homeostasis, was specifically inhibited with the pyrrole derivative compound N6022. Moreover, GSNOR inhibition restored the activation of survival signaling pathways involved in the resistance to anti-HER2 therapies (AKT, Src and c-Abl kinases and TrkA/NRTK1, TrkB/NRTK2, EphA1 and EphA3 receptors) and reduced the apoptotic effect of trastuzumab. Accordingly, GSNOR inhibition augmented the S-nitrosylation of apoptosis-related proteins, including Apaf-1, pSer73/63 c-Jun, calcineurin subunit α and HSF1. In agreement with in vitro data, immunohistochemical analyses of 51 breast tumors showed that HER2 expression was associated with lower expression of GSNOR protein. Moreover, gene expression analysis confirmed that high ADH5/GSNOR gene expression was associated with high patient survival rates in HER2 tumors. In conclusion, our data provide evidence of molecular mechanisms contributing to the progression of HER2+ breast cancers and could facilitate the development of therapeutic options to counteract resistance to anti-HER2 therapies.

  10. Muscle-specific inositide phosphatase (MIP/MTMR14) is reduced with age and its loss accelerates skeletal muscle aging process by altering calcium homeostasis

    PubMed Central

    Romero-Suarez, Sandra; Shen, Jinhua; Brotto, Leticia; Hall, Todd; Mo, ChengLin; Valdivia, Héctor H.; Andresen, Jon; Wacker, Michael; Nosek, Thomas M.; Qu, Cheng-Kui; Brotto, Marco

    2010-01-01

    We have recently reported that a novel muscle-specific inositide phosphatase (MIP/MTMR14) plays a critical role in [Ca2+]i homeostasis through dephosphorylation of sn-1-stearoyl-2-arachidonoyl phosphatidylinositol (3,5) bisphosphate (PI(3,5)P2). Loss of function mutations in MIP have been identified in human centronuclear myopathy. We developed a MIP knockout (MIPKO) animal model and found that MIPKO mice were more susceptible to exercise-induced muscle damage, a trademark of muscle functional changes in older subjects. We used wild-type (Wt) mice and MIPKO mice to elucidate the roles of MIP in muscle function during aging. We found MIP mRNA expression, MIP protein levels, and MIP phosphatase activity significantly decreased in old Wt mice. The mature MIPKO mice displayed phenotypes that closely resembled those seen in old Wt mice: i) decreased walking speed, ii) decreased treadmill activity, iii) decreased contractile force, and iv) decreased power generation, classical features of sarcopenia in rodents and humans. Defective Ca2+ homeostasis is also present in mature MIPKO and old Wt mice, suggesting a putative role of MIP in the decline of muscle function during aging. Our studies offer a new avenue for the investigation of MIP roles in skeletal muscle function and as a potential therapeutic target to treat aging sarcopenia. PMID:20817957

  11. Amygdala opioid receptors mediate the electroacupuncture-induced deterioration of sleep disruptions in epilepsy rats

    PubMed Central

    2013-01-01

    Background Clinical and experimental evidence demonstrates that sleep and epilepsy reciprocally affect each other. Previous studies indicated that epilepsy alters sleep homeostasis; in contrast, sleep disturbance deteriorates epilepsy. If a therapy possesses both epilepsy suppression and sleep improvement, it would be the priority choice for seizure control. Effects of acupuncture of Feng-Chi (GB20) acupoints on epilepsy suppression and insomnia treatment have been documented in the ancient Chinese literature, Lingshu Jing (Classic of the Miraculous Pivot). Therefore, this study was designed to investigate the effect of electroacupuncture (EA) stimulation of bilateral Feng-Chi acupoints on sleep disruptions in rats with focal epilepsy. Results Our result indicates that administration of pilocarpine into the left central nucleus of amygdala (CeA) induced focal epilepsy and decreased both rapid eye movement (REM) sleep and non-REM (NREM) sleep. High-frequency (100 Hz) EA stimulation of bilateral Feng-Chi acupoints, in which a 30-min EA stimulation was performed before the dark period of the light:dark cycle in three consecutive days, further deteriorated pilocarpine-induced sleep disruptions. The EA-induced exacerbation of sleep disruption was blocked by microinjection of naloxone, μ- (naloxonazine), κ- (nor-binaltorphimine) or δ-receptor antagonists (natrindole) into the CeA, suggesting the involvement of amygdaloid opioid receptors. Conclusion The present study suggests that high-frequency (100 Hz) EA stimulation of bilateral Feng-Chi acupoints exhibits no benefit in improving pilocarpine-induced sleep disruptions; in contrast, EA further deteriorated sleep disturbances. Opioid receptors in the CeA mediated EA-induced exacerbation of sleep disruptions in epileptic rats. PMID:24215575

  12. Estimating individual optimal sleep duration and potential sleep debt

    PubMed Central

    Kitamura, Shingo; Katayose, Yasuko; Nakazaki, Kyoko; Motomura, Yuki; Oba, Kentaro; Katsunuma, Ruri; Terasawa, Yuri; Enomoto, Minori; Moriguchi, Yoshiya; Hida, Akiko; Mishima, Kazuo

    2016-01-01

    In this study, we hypothesized that dynamics of sleep time obtained over consecutive days of extended sleep in a laboratory reflect an individual’s optimal sleep duration (OSD) and that the difference between OSD and habitual sleep duration (HSD) at home represents potential sleep debt (PSD). We found that OSD varies among individuals and PSD showed stronger correlation with subjective/objective sleepiness than actual sleep time, interacting with individual’s vulnerability of sleep loss. Furthermore, only 1 h of PSD takes four days to recover to their optimal level. Recovery from PSD was also associated with the improvement in glycometabolism, thyrotropic activity and hypothalamic-pituitary-adrenocortical axis. Additionally, the increase (rebound) in total sleep time from HSD at the first extended sleep would be a simple indicator of PSD. These findings confirmed self-evaluating the degree of sleep debt at home as a useful clinical marker. To establish appropriate sleep habits, it is necessary to evaluate OSD, vulnerability to sleep loss, and sleep homeostasis characteristics on an individual basis. PMID:27775095

  13. Differences in Insulin Secretion and Sensitivity in Short-Sleep Insomnia

    PubMed Central

    Vasisht, Kaveeta P.; Kessler, Lynn E.; Booth, John N.; Imperial, Jacqueline G.; Penev, Plamen D.

    2013-01-01

    Objective: Short-sleep insomnia is associated with increased risk of diabetes. The role of altered insulin secretion and action in this association is poorly understood. Design: Observational study. Setting: Academic clinical research center. Participants: Nondiabetic individuals with insomnia (mean [standard deviation] age 48 [9] y, body mass index 25.6 [3.9] kg/m2) with ≤ 6 h (short sleep, n = 14) and > 6 h of sleep (n = 14) during overnight laboratory polysomnography. Measurements and Results: Standard oral glucose testing was used to assess glucose tolerance, beta-cell function (homeostasis model assessment [HOMA-B]; second-phase insulin secretion) and insulin resistance (HOMA-IR; insulin sensitivity index). There was no significant difference in hemoglobin A1C and fasting or 2-h blood glucose concentrations between sleep groups. Short-sleep insomnia sufferers had lower fasting and postchallenge serum insulin concentrations associated with lower estimates of fasting and glucose-stimulated insulin secretion, and increased insulin sensitivity. Conclusions: Individuals with short-sleep insomnia appear to have higher indices of systemic insulin sensitivity and secrete less insulin without changes in overall glucose tolerance. Citation: Vasisht KP; Kessler LE; Booth JN; Imperial JG; Penev PD. Differences in insulin secretion and sensitivity in short-sleep insomnia. SLEEP 2013;36(6):955-957. PMID:23729940

  14. Monitoring dynamic alterations in calcium homeostasis by T1-mapping manganese-enhanced MRI (MEMRI) in the early stage of small intestinal ischemia-reperfusion injury.

    PubMed

    Zhao, Da-wei; Zhang, Le-tian; Cheng, Hai-yun; Zhang, Yu-long; Min, Jia-yan; Xiao, Hua-liang; Wang, Yi

    2015-08-01

    Manganese-enhanced MRI studies have proven to be useful in monitoring physiological activities associated with calcium ions (Ca(2+)) due to the paramagnetic property of the manganese ion (Mn(2+)), which makes it an excellent probe of Ca(2+) . In this study, we developed a method in which a Mn(2+)-enhanced T1 -map MRI could enable the monitoring of Ca(2+) influx during the early stages of intestinal ischemia-reperfusion (I/R) injury. The Mn(2+) infusion protocol was optimized by obtaining dose-dependent and time-course wash-out curves using a Mn(2+)-enhanced T1-map MRI of rabbit abdomens following an intravenous infusion of 50 mmol/l MnCl2 (5-10 nmol/g body weight (BW)). In the rabbit model of intestinal I/R injury, T1 values were derived from the T1 maps in the intestinal wall region and revealed a relationship between the dose of the infused MnCl2 and the intestinal wall relaxation time. Significant Mn(2+) clearance was also observed over time in control animals after the infusion of Mn(2+) at a dose of 10 nmol/g BW. This technique was also shown to be sensitive enough to monitor variations in calcium ion homeostasis in vivo after small intestinal I/R injury. The T1 values of the intestinal I/R group were significantly lower (P < 0.05) than that of the control group at 5, 10, and 15 min after Mn(2+) infusion. Our data suggest that MnCl2 has the potential to be an MRI contrast agent that can be effectively used to monitor changes in intracellular Ca(2+) homeostasis during the early stages of intestinal I/R injury.

  15. Sleep and Women

    MedlinePlus

    ... Benefits Side Effects Variations Tips Healthy Sleep Habits Sleep Disorders by Category Insomnias Insomnia Child Insomnia Short Sleeper ... Work SIDS Sleep apnea Sleep Debt Sleep Deprivation Sleep Disorders Sleep history Sleep hygiene sleep length Sleep Need ...

  16. [Sleep and biological clock in the elderly].

    PubMed

    Münch, Mirjam

    2014-11-01

    This article gives an overview of factors underlying age-related changes in sleep wake behavior in healthy older humans. The self-regulation of the sleep-wake cycle [sleep-wake homeostasis] and the circadian clock, represent primary factors responsible for changes in sleep with age. As a matter of fact older healthy adults have a more superficial and less consolidated sleep and go to bed earlier compared to younger ages. Furthermore, sleep in healthy older people is more vulnerable to disturbances such as circadian desynchronisation and the lack of zeitgebers [insufficient light during the day].

  17. [How does sleeping restore our brain?].

    PubMed

    Wigren, Henna-Kaisa; Stenberg, Tarja

    2015-01-01

    The central function of sleep is to keep our brain functional, but what is the restoration that sleep provides? Sleep after learning improves learning outcomes. According to the theory of synaptic homeostasis the total strength of synapses, having increased during the day, is restored during sleep, making room for the next day's experiences. According to the theory of active synaptic consolidation, repetition during sleep strengthens the synapses, and these strengthened synapses form a permanent engram. According to a recent study, removal of waste products from the brain may also be one of the functions of sleep. PMID:26237917

  18. REM sleep loss and recovery regulates blood-brain barrier function.

    PubMed

    Gómez-González, Beatriz; Hurtado-Alvarado, Gabriela; Esqueda-León, Enrique; Santana-Miranda, Rafael; Rojas-Zamorano, José Ángel; Velázquez-Moctezuma, Javier

    2013-08-01

    The functions of rapid eye movement (REM) sleep have remained elusive since more than 50 years. Previous reports have identified several independent processes affected by the loss and subsequent recovery of REM sleep (hippocampal neurogenesis, brain stem neuronal cell death, and neurotransmitter content in several brain regions); however, a common underlying mechanism has not been found. We propose that altered brain homeostasis secondary to blood-brain barrier breakdown may explain all those changes induced by REM sleep loss. Therefore, the present report aimed to study the consequences of REM sleep restriction upon blood-brain barrier permeability to Evans blue. REM sleep restriction was induced by the multiple platform technique; male rats were REM sleep restricted 20h daily (with 4h sleep opportunity) during 10 days; control groups included large platform and intact rats. To study blood-brain barrier permeability Evans blue was intracardially administered; stained brains were sliced and photographed for optical density quantification. An independent experiment was carried out to elucidate the mechanism of blood-brain breakdown by transmission electron microscopy. REM sleep restriction increased blood-brain barrier permeability to Evans blue in the whole brain as compared to both control groups. Brief periods of sleep recovery rapidly and effectively restored the severe alteration of blood-brain barrier function by reducing blood-to-brain transfer of Evans blue. The mechanism of blood-brain barrier breakdown involved increased caveolae formation at brain endothelial cells. In conclusion, our data suggest that REM sleep regulates the physical barrier properties of the blood-brain barrier.

  19. Sleep Loss and Inflammation

    PubMed Central

    Simpson, Norah S.; Meier-Ewert, Hans K.; Haack, Monika

    2012-01-01

    Controlled, experimental studies on the effects of acute sleep loss in humans have shown that mediators of inflammation are altered by sleep loss. Elevations in these mediators have been found to occur in healthy, rigorously screened individuals undergoing experimental vigils of more than 24 hours, and have also been seen in response to various durations of sleep restricted to between 25 and 50% of a normal 8 hour sleep amount. While these altered profiles represent small changes, such sub-clinical shifts in basal inflammatory cytokines are known to be associated with the future development of metabolic syndrome disease in healthy, asymptomatic individuals. Although the mechanism of this altered inflammatory status in humans undergoing experimental sleep loss is unknown, it is likely that autonomic activation and metabolic changes play key roles. PMID:21112025

  20. Differential Kinetics in Alteration and Recovery of Cognitive Processes from a Chronic Sleep Restriction in Young Healthy Men.

    PubMed

    Rabat, Arnaud; Gomez-Merino, Danielle; Roca-Paixao, Laura; Bougard, Clément; Van Beers, Pascal; Dispersyn, Garance; Guillard, Mathias; Bourrilhon, Cyprien; Drogou, Catherine; Arnal, Pierrick J; Sauvet, Fabien; Leger, Damien; Chennaoui, Mounir

    2016-01-01

    Chronic sleep restriction (CSR) induces neurobehavioral deficits in young and healthy people with a morning failure of sustained attention process. Testing both the kinetic of failure and recovery of different cognitive processes (i.e., attention, executive) under CSR and their potential links with subject's capacities (stay awake, baseline performance, age) and with some biological markers of stress and anabolism would be useful in order to understand the role of sleep debt on human behavior. Twelve healthy subjects spent 14 days in laboratory with 2 baseline days (B1 and B2, 8 h TIB) followed by 7 days of sleep restriction (SR1-SR7, 4 h TIB), 3 sleep recovery days (R1-R3, 8 h TIB) and two more ones 8 days later (R12-R13). Subjective sleepiness (KSS), maintenance of wakefulness latencies (MWT) were evaluated four times a day (10:00, 12:00 a.m. and 2:00, 4:00 p.m.) and cognitive tests were realized at morning (8:30 a.m.) and evening (6:30 p.m.) sessions during B2, SR1, SR4, SR7, R2, R3 and R13. Saliva (B2, SR7, R2, R13) and blood (B1, SR6, R1, R12) samples were collected in the morning. Cognitive processes were differently impaired and recovered with a more rapid kinetic for sustained attention process. Besides, a significant time of day effect was only evidenced for sustained attention failures that seemed to be related to subject's age and their morning capacity to stay awake. Executive processes were equally disturbed/recovered during the day and this failure/recovery process seemed to be mainly related to baseline subject's performance and to their capacity to stay awake. Morning concentrations of testosterone, cortisol and α-amylase were significantly decreased at SR6-SR7, but were either and respectively early (R1), tardily (after R2) and not at all (R13) recovered. All these results suggest a differential deleterious and restorative effect of CSR on cognition through biological changes of the stress pathway and subject's capacity (ClinicalTrials-NCT01989741

  1. Differential Kinetics in Alteration and Recovery of Cognitive Processes from a Chronic Sleep Restriction in Young Healthy Men

    PubMed Central

    Rabat, Arnaud; Gomez-Merino, Danielle; Roca-Paixao, Laura; Bougard, Clément; Van Beers, Pascal; Dispersyn, Garance; Guillard, Mathias; Bourrilhon, Cyprien; Drogou, Catherine; Arnal, Pierrick J.; Sauvet, Fabien; Leger, Damien; Chennaoui, Mounir

    2016-01-01

    Chronic sleep restriction (CSR) induces neurobehavioral deficits in young and healthy people with a morning failure of sustained attention process. Testing both the kinetic of failure and recovery of different cognitive processes (i.e., attention, executive) under CSR and their potential links with subject’s capacities (stay awake, baseline performance, age) and with some biological markers of stress and anabolism would be useful in order to understand the role of sleep debt on human behavior. Twelve healthy subjects spent 14 days in laboratory with 2 baseline days (B1 and B2, 8 h TIB) followed by 7 days of sleep restriction (SR1-SR7, 4 h TIB), 3 sleep recovery days (R1–R3, 8 h TIB) and two more ones 8 days later (R12–R13). Subjective sleepiness (KSS), maintenance of wakefulness latencies (MWT) were evaluated four times a day (10:00, 12:00 a.m. and 2:00, 4:00 p.m.) and cognitive tests were realized at morning (8:30 a.m.) and evening (6:30 p.m.) sessions during B2, SR1, SR4, SR7, R2, R3 and R13. Saliva (B2, SR7, R2, R13) and blood (B1, SR6, R1, R12) samples were collected in the morning. Cognitive processes were differently impaired and recovered with a more rapid kinetic for sustained attention process. Besides, a significant time of day effect was only evidenced for sustained attention failures that seemed to be related to subject’s age and their morning capacity to stay awake. Executive processes were equally disturbed/recovered during the day and this failure/recovery process seemed to be mainly related to baseline subject’s performance and to their capacity to stay awake. Morning concentrations of testosterone, cortisol and α-amylase were significantly decreased at SR6-SR7, but were either and respectively early (R1), tardily (after R2) and not at all (R13) recovered. All these results suggest a differential deleterious and restorative effect of CSR on cognition through biological changes of the stress pathway and subject’s capacity (Clinical

  2. A Thyroid Hormone Challenge in Hypothyroid Rats Identifies T3 Regulated Genes in the Hypothalamus and in Models with Altered Energy Balance and Glucose Homeostasis

    PubMed Central

    Herwig, Annika; Campbell, Gill; Mayer, Claus-Dieter; Boelen, Anita; Anderson, Richard A.; Ross, Alexander W.; Mercer, Julian G.

    2014-01-01

    Background: The thyroid hormone triiodothyronine (T3) is known to affect energy balance. Recent evidence points to an action of T3 in the hypothalamus, a key area of the brain involved in energy homeostasis, but the components and mechanisms are far from understood. The aim of this study was to identify components in the hypothalamus that may be involved in the action of T3 on energy balance regulatory mechanisms. Methods: Sprague Dawley rats were made hypothyroid by giving 0.025% methimazole (MMI) in their drinking water for 22 days. On day 21, half the MMI-treated rats received a saline injection, whereas the others were injected with T3. Food intake and body weight measurements were taken daily. Body composition was determined by magnetic resonance imaging, gene expression was analyzed by in situ hybridization, and T3-induced gene expression was determined by microarray analysis of MMI-treated compared to MMI-T3-injected hypothalamic RNA. Results: Post mortem serum thyroid hormone levels showed that MMI treatment decreased circulating thyroid hormones and increased thyrotropin (TSH). MMI treatment decreased food intake and body weight. Body composition analysis revealed reduced lean and fat mass in thyroidectomized rats from day 14 of the experiment. MMI treatment caused a decrease in circulating triglyceride concentrations, an increase in nonesterified fatty acids, and decreased insulin levels. A glucose tolerance test showed impaired glucose clearance in the thyroidectomized animals. In the brain, in situ hybridization revealed marked changes in gene expression, including genes such as Mct8, a thyroid hormone transporter, and Agrp, a key component in energy balance regulation. Microarray analysis revealed 110 genes to be up- or downregulated with T3 treatment (±1.3-fold change, p<0.05). Three genes chosen from the differentially expressed genes were verified by in situ hybridization to be activated by T3 in cells located at or close to the hypothalamic

  3. Neurocognitive Consequences of Sleep Deprivation

    PubMed Central

    Goel, Namni; Rao, Hengyi; Durmer, Jeffrey S.; Dinges, David F.

    2012-01-01

    Sleep deprivation is associated with considerable social, financial, and health-related costs, in large measure because it produces impaired cognitive performance due to increasing sleep propensity and instability of waking neurobehavioral functions. Cognitive functions particularly affected by sleep loss include psychomotor and cognitive speed, vigilant and executive attention, working memory, and higher cognitive abilities. Chronic sleep-restriction experiments—which model the kind of sleep loss experienced by many individuals with sleep fragmentation and premature sleep curtailment due to disorders and lifestyle—demonstrate that cognitive deficits accumulate to severe levels over time without full awareness by the affected individual. Functional neuroimaging has revealed that frequent and progressively longer cognitive lapses, which are a hallmark of sleep deprivation, involve distributed changes in brain regions including frontal and parietal control areas, secondary sensory processing areas, and thalamic areas. There are robust differences among individuals in the degree of their cognitive vulnerability to sleep loss that may involve differences in prefrontal and parietal cortices, and that may have a basis in genes regulating sleep homeostasis and circadian rhythms. Thus, cognitive deficits believed to be a function of the severity of clinical sleep disturbance may be a product of genetic alleles associated with differential cognitive vulnerability to sleep loss. PMID:19742409

  4. Sleep and metabolic function

    PubMed Central

    Morselli, Lisa L.; Guyon, Aurore; Spiegel, Karine

    2012-01-01

    Evidence for the role of sleep on metabolic and endocrine function has been reported more than four decades ago. In the past 30 years, the prevalence of obesity and diabetes has greatly increased in industrialized countries, and self-imposed sleep curtailment, now very common, is starting to be recognized as a contributing factor, alongside with increased caloric intake and decreased physical activity. Furthermore, obstructive sleep apnea, a chronic condition characterized by recurrent upper airway obstruction leading to intermittent hypoxemia and sleep fragmentation, has also become highly prevalent as a consequence of the epidemic of obesity and has been shown to contribute, in a vicious circle, to the metabolic disturbances observed in obese patients. In this article, we summarize the current data supporting the role of sleep in the regulation of glucose homeostasis and the hormones involved in the regulation of appetite. We also review the results of the epidemiologic and laboratory studies that investigated the impact of sleep duration and quality on the risk of developing diabetes and obesity, as well as the mechanisms underlying this increased risk. Finally, we discuss how obstructive sleep apnea affects glucose metabolism and the beneficial impact of its treatment, the continuous positive airway pressure. In conclusion, the data available in the literature highlight the importance of getting enough good sleep for metabolic health. PMID:22101912

  5. Transcriptomics Profiling of Alzheimer’s Disease Reveal Neurovascular Defects, Altered Amyloid-β Homeostasis, and Deregulated Expression of Long Noncoding RNAs

    PubMed Central

    Magistri, Marco; Velmeshev, Dmitry; Makhmutova, Madina; Faghihi, Mohammad Ali

    2015-01-01

    Abstract The underlying genetic variations of late-onset Alzheimer’s disease (LOAD) cases remain largely unknown. A combination of genetic variations with variable penetrance and lifetime epigenetic factors may converge on transcriptomic alterations that drive LOAD pathological process. Transcriptome profiling using deep sequencing technology offers insight into common altered pathways regardless of underpinning genetic or epigenetic factors and thus represents an ideal tool to investigate molecular mechanisms related to the pathophysiology of LOAD. We performed directional RNA sequencing on high quality RNA samples extracted from hippocampi of LOAD and age-matched controls. We further validated our data using qRT-PCR on a larger set of postmortem brain tissues, confirming downregulation of the gene encoding substance P (TAC1) and upregulation of the gene encoding the plasminogen activator inhibitor-1 (SERPINE1). Pathway analysis indicates dysregulation in neural communication, cerebral vasculature, and amyloid-β clearance. Beside protein coding genes, we identified several annotated and non-annotated long noncoding RNAs that are differentially expressed in LOAD brain tissues, three of them are activity-dependent regulated and one is induced by Aβ1 - 42 exposure of human neural cells. Our data provide a comprehensive list of transcriptomics alterations in LOAD hippocampi and warrant holistic approach including both coding and non-coding RNAs in functional studies aimed to understand the pathophysiology of LOAD. PMID:26402107

  6. Cardiovascular physiology and sleep.

    PubMed

    Murali, Narayana S; Svatikova, Anna; Somers, Virend K

    2003-05-01

    Sleep is a natural periodic suspension of consciousness during which processes of rest and restoration occur. The cognitive, reparative and regenerative accompaniments of sleep appear to be essential for maintenance of health and homeostasis. This brief overview will examine the cardiovascular responses to normal and disordered sleep, and their physiologic and pathologic implications. In the past, sleep was believed to be a passive state. The tableau of sleep as it unfolds is anything but a passive process. The brain's activity is as complex as wakefulness, never "resting" during sleep. Following the demise of the 'passive theory of sleep' (the reticular activating system is fatigued during the waking day and hence becomes inactive), there arose the 'active theory of sleep' (sleep is due to an active general inhibition of the brain) (1). Hess demonstrated the active nature of sleep in cats, inducing "physiological sleep" with electrical stimulation of the diencephalon (2). Classical experiments of transection of the cat brainstem (3) at midpontine level inhibited sleep completely, implying that centers below this level were involved in the induction of sleep (1, 4). For the first time, measurement of sleep depth without awakening the sleeper using the electroencephalogram (EEG) was demonstrated in animals by Caton and in humans, by Berger (1). This was soon followed by discovery of the rapid eye movement sleep periods (REM) by Aserinski and Kleitman (5), demonstration of periodical sleep cycles and their association with REM sleep (6, 7). Multiple studies and steady discoveries (4) made polysomnography, with its ability to perform simultaneous whole night recordings of EEG, electromyogram (EMG), and electrooculogram (EOC), a major diagnostic tool in study of sleep disorders. This facility has been of further critical importance in allowing evaluation of the interaction between sleep and changes in hemodynamics and autonomic cardiovascular control. Consequently the

  7. Exposure to bisphenol-A during pregnancy partially mimics the effects of a high-fat diet altering glucose homeostasis and gene expression in adult male mice.

    PubMed

    García-Arevalo, Marta; Alonso-Magdalena, Paloma; Rebelo Dos Santos, Junia; Quesada, Ivan; Carneiro, Everardo M; Nadal, Angel

    2014-01-01

    Bisphenol-A (BPA) is one of the most widespread EDCs used as a base compound in the manufacture of polycarbonate plastics. The aim of our research has been to study how the exposure to BPA during pregnancy affects weight, glucose homeostasis, pancreatic β-cell function and gene expression in the major peripheral organs that control energy flux: white adipose tissue (WAT), the liver and skeletal muscle, in male offspring 17 and 28 weeks old. Pregnant mice were treated with a subcutaneous injection of 10 µg/kg/day of BPA or a vehicle from day 9 to 16 of pregnancy. One month old offspring were divided into four different groups: vehicle treated mice that ate a normal chow diet (Control group); BPA treated mice that also ate a normal chow diet (BPA); vehicle treated animals that had a high fat diet (HFD) and BPA treated animals that were fed HFD (HFD-BPA). The BPA group started to gain weight at 18 weeks old and caught up to the HFD group before week 28. The BPA group as well as the HFD and HFD-BPA ones presented fasting hyperglycemia, glucose intolerance and high levels of non-esterified fatty acids (NEFA) in plasma compared with the Control one. Glucose stimulated insulin release was disrupted, particularly in the HFD-BPA group. In WAT, the mRNA expression of the genes involved in fatty acid metabolism, Srebpc1, Pparα and Cpt1β was decreased by BPA to the same extent as with the HFD treatment. BPA treatment upregulated Pparγ and Prkaa1 genes in the liver; yet it diminished the expression of Cd36. Hepatic triglyceride levels were increased in all groups compared to control. In conclusion, male offspring from BPA-treated mothers presented symptoms of diabesity. This term refers to a form of diabetes which typically develops in later life and is associated with obesity.

  8. Sleep Physiology, Abnormal States, and Therapeutic Interventions

    PubMed Central

    Wickboldt, Alvah T.; Bowen, Alex F.; Kaye, Aaron J.; Kaye, Adam M.; Rivera Bueno, Franklin; Kaye, Alan D.

    2012-01-01

    Sleep is essential. Unfortunately, a significant portion of the population experiences altered sleep states that often result in a multitude of health-related issues. The regulation of sleep and sleep-wake cycles is an area of intense research, and many options for treatment are available. The following review summarizes the current understanding of normal and abnormal sleep-related conditions and the available treatment options. All clinicians managing patients must recommend appropriate therapeutic interventions for abnormal sleep states. Clinicians' solid understanding of sleep physiology, abnormal sleep states, and treatments will greatly benefit patients regardless of their disease process. PMID:22778676

  9. Ovarian hormone level alterations during rat post-reproductive life-span influence CD8 + T-cell homeostasis

    PubMed Central

    Arsenović-Ranin, Nevena; Kosec, Duško; Nacka-Aleksić, Mirjana; Pilipović, Ivan; Stojić-Vukanić, Zorica; Djikić, Jasmina; Bufan, Biljana

    2015-01-01

    The study examined the putative role of ovarian hormones in shaping of rat peripheral T-cell compartment during post-reproductive period. In 20-month-old rats ovariectomized (Ox) at the very end of reproductive period, thymic output, cellularity and composition of major TCRαβ + peripheral blood lymphocyte and splenocyte subsets were analyzed. Ovariectomy led to the enlargement of CD8 + peripheral blood lymphocyte and splenocyte subpopulations. This reflected: (i) a more efficient thymic generation of CD8 + cells as indicated by increased number of CD4+CD8 + double positive and the most mature CD4-CD8+TCRαβhigh thymocytes and CD8 + recent thymic emigrants (RTEs) in peripheral blood, but not in the spleen of Ox rats, and (ii) the expansion of CD8 + memory/activated peripheral blood lymphocytes and splenocytes. The latter was consistent with a greater frequency of proliferating cells among freshly isolated memory/activated CD8 + peripheral blood lymphocytes and splenocytes and increased proliferative response of CD8 + splenocytes to stimulation with plate-bound anti-CD3 antibody. The former could be related to the rise in splenic IL-7 and IL-15 mRNA expression. Although ovariectomy affected the overall number of CD4 + T cells in none of the examined compartments, it increased CD4+FoxP3 + peripheral blood lymphocyte and splenocyte counts by enhancing their generation in periphery. Collectively, the results suggest that ovariectomy-induced long-lasting disturbances in ovarian hormone levels (mirrored in diminished progesterone serum level in 20-month-old rats) affects both thymic CD8 + cell generation and peripheral homeostasis and leads to the expansion of CD4+FoxP3 + cells in the periphery, thereby enhancing autoreactive cell control on account of immune system efficacy to combat infections and tumors. PMID:25716018

  10. Sleep Disorders

    MedlinePlus

    ... the day, even if you have had enough sleep? You might have a sleep disorder. The most common kinds are Insomnia - a hard time falling or staying asleep Sleep apnea - breathing interruptions during sleep Restless legs syndrome - ...

  11. Sleep Problems

    MedlinePlus

    ... For Consumers Consumer Information by Audience For Women Sleep Problems Share Tweet Linkedin Pin it More sharing ... PDF 474KB) En Español Medicines to Help You Sleep Tips for Better Sleep Basic Facts about Sleep ...

  12. Regulation of Potassium Homeostasis.

    PubMed

    Palmer, Biff F

    2015-06-01

    Potassium is the most abundant cation in the intracellular fluid, and maintaining the proper distribution of potassium across the cell membrane is critical for normal cell function. Long-term maintenance of potassium homeostasis is achieved by alterations in renal excretion of potassium in response to variations in intake. Understanding the mechanism and regulatory influences governing the internal distribution and renal clearance of potassium under normal circumstances can provide a framework for approaching disorders of potassium commonly encountered in clinical practice. This paper reviews key aspects of the normal regulation of potassium metabolism and is designed to serve as a readily accessible review for the well informed clinician as well as a resource for teaching trainees and medical students.

  13. Sleep Deprivation Influences Circadian Gene Expression in the Lateral Habenula.

    PubMed

    Zhang, Beilin; Gao, Yanxia; Li, Yang; Yang, Jing; Zhao, Hua

    2016-01-01

    Sleep is governed by homeostasis and the circadian clock. Clock genes play an important role in the generation and maintenance of circadian rhythms but are also involved in regulating sleep homeostasis. The lateral habenular nucleus (LHb) has been implicated in sleep-wake regulation, since LHb gene expression demonstrates circadian oscillation characteristics. This study focuses on the participation of LHb clock genes in regulating sleep homeostasis, as the nature of their involvement is unclear. In this study, we observed changes in sleep pattern following sleep deprivation in LHb-lesioned rats using EEG recording techniques. And then the changes of clock gene expression (Per1, Per2, and Bmal1) in the LHb after 6 hours of sleep deprivation were detected by using real-time quantitative PCR (qPCR). We found that sleep deprivation increased the length of Non-Rapid Eye Movement Sleep (NREMS) and decreased wakefulness. LHb-lesioning decreased the amplitude of reduced wake time and increased NREMS following sleep deprivation in rats. qPCR results demonstrated that Per2 expression was elevated after sleep deprivation, while the other two genes were unaffected. Following sleep recovery, Per2 expression was comparable to the control group. This study provides the basis for further research on the role of LHb Per2 gene in the regulation of sleep homeostasis. PMID:27413249

  14. Sleep Deprivation Influences Circadian Gene Expression in the Lateral Habenula

    PubMed Central

    Gao, Yanxia

    2016-01-01

    Sleep is governed by homeostasis and the circadian clock. Clock genes play an important role in the generation and maintenance of circadian rhythms but are also involved in regulating sleep homeostasis. The lateral habenular nucleus (LHb) has been implicated in sleep-wake regulation, since LHb gene expression demonstrates circadian oscillation characteristics. This study focuses on the participation of LHb clock genes in regulating sleep homeostasis, as the nature of their involvement is unclear. In this study, we observed changes in sleep pattern following sleep deprivation in LHb-lesioned rats using EEG recording techniques. And then the changes of clock gene expression (Per1, Per2, and Bmal1) in the LHb after 6 hours of sleep deprivation were detected by using real-time quantitative PCR (qPCR). We found that sleep deprivation increased the length of Non-Rapid Eye Movement Sleep (NREMS) and decreased wakefulness. LHb-lesioning decreased the amplitude of reduced wake time and increased NREMS following sleep deprivation in rats. qPCR results demonstrated that Per2 expression was elevated after sleep deprivation, while the other two genes were unaffected. Following sleep recovery, Per2 expression was comparable to the control group. This study provides the basis for further research on the role of LHb Per2 gene in the regulation of sleep homeostasis. PMID:27413249

  15. In vivo evidence of mitochondrial dysfunction and altered redox homeostasis in a genetic mouse model of propionic acidemia: Implications for the pathophysiology of this disorder.

    PubMed

    Gallego-Villar, L; Rivera-Barahona, A; Cuevas-Martín, C; Guenzel, A; Pérez, B; Barry, M A; Murphy, M P; Logan, A; Gonzalez-Quintana, A; Martín, M A; Medina, S; Gil-Izquierdo, A; Cuezva, J M; Richard, E; Desviat, L R

    2016-07-01

    Accumulation of toxic metabolites has been described to inhibit mitochondrial enzymes, thereby inducing oxidative stress in propionic acidemia (PA), an autosomal recessive metabolic disorder caused by the deficiency of mitochondrial propionyl-CoA carboxylase. PA patients exhibit neurological deficits and multiorgan complications including cardiomyopathy. To investigate the role of mitochondrial dysfunction in the development of these alterations we have used a hypomorphic mouse model of PA that mimics the biochemical and clinical hallmarks of the disease. We have studied the tissue-specific bioenergetic signature by Reverse Phase Protein Microarrays and analysed OXPHOS complex activities, mtDNA copy number, oxidative damage, superoxide anion and hydrogen peroxide levels. The results show decreased levels and/or activity of several OXPHOS complexes in different tissues of PA mice. An increase in mitochondrial mass and OXPHOS complexes was observed in brain, possibly reflecting a compensatory mechanism including metabolic reprogramming. mtDNA depletion was present in most tissues analysed. Antioxidant enzymes were also found altered. Lipid peroxidation was present along with an increase in hydrogen peroxide and superoxide anion production. These data support the hypothesis that oxidative damage may contribute to the pathophysiology of PA, opening new avenues in the identification of therapeutic targets and paving the way for in vivo evaluation of compounds targeting mitochondrial biogenesis or reactive oxygen species production. PMID:27083476

  16. Exposure to acute electromagnetic radiation of mobile phone exposure range alters transiently skin homeostasis of a model of pigmented reconstructed epidermis.

    PubMed

    Simon, D; Daubos, A; Pain, C; Fitoussi, R; Vié, K; Taieb, A; de Benetti, L; Cario-André, M

    2013-02-01

    Exposure to electromagnetic radiations (EMR) produced by mobile phone concerns half the world's population and raises the problem of their impact on human health. In this study, we looked at the effects of mobile phone exposure (GSM basic, 900 MHz, SAR 2 mW g(-1) , 6 h) on a model of pigmented skin. We have analysed the expression and localization of various markers of keratinocyte and melanocyte differentiation 2, 6, 18 and 24 h after EMR exposure of reconstructed epidermis containing either only keratinocytes or a combination of keratinocytes and melanocytes grown on dead de-epidermized dermis, using histology, immunohistochemistry and Western blot. No changes were found in epidermal architecture, localization of epidermal markers, presence of apoptotic cells and the induction of p53 in both types of epidermis (with or without melanocytes) after exposure to EMR. In pigmented reconstructs, no change in the location and dendricity of melanocytes and in melanin transfer to neighbouring keratinocytes was detected after EMR exposure. Loricrin, cytokeratin 14 were significantly decreased at 6 h. The level of all markers increased at 24 h as compared to 6 h post-EMR exposure, associated with a significant decrease of the 20S proteasome activity. Our data indicate that exposure to 900 MHz frequency induces a transient alteration of epidermal homoeostasis, which may alter the protective capacity of the skin against external factors. Presence or absence of melanocytes did not modify the behaviour of reconstructs after EMR exposure.

  17. Chronic sleep restriction during pregnancy--repercussion on cardiovascular and renal functioning of male offspring.

    PubMed

    Lima, Ingrid L B; Rodrigues, Aline F A C; Bergamaschi, Cássia T; Campos, Ruy R; Hirata, Aparecida E; Tufik, Sergio; Xylaras, Beatriz D P; Visniauskas, Bruna; Chagas, Jair R; Gomes, Guiomar N

    2014-01-01

    Changes in the maternal environment can induce fetal adaptations that result in the progression of chronic diseases in the offspring. The objective of the present study was to evaluate the effects of maternal chronic sleep restriction on blood pressure, renal function and cardiac baroreflex response on male offspring at adult age. Female 3-month-old Wistar rats were divided in two experimental groups: control (C) and chronic sleep restricted (CSR). Pregnancy was confirmed by vaginal smear. Chronic sleep restricted females were subjected to sleep restriction by the multiple platform technique for 20 h daily, between the 1st and 20th day of pregnancy. After birth, the litters were reduced to 6 rats per mother, and were designated as offspring from control (OC) and offspring from chronic sleep restricted (OCSR). Indirect blood pressure (BPi - tail cuff) was measured by plethysmography in male offspring at 3 months old. Following, the renal function and cardiac baroreflex response were analyzed. Values of BPi in OCSR were significantly higher compared to OC [OC: 127 ± 2.6 (19); OCSR: 144 ± 2.5 (17) mmHg]. The baroreflex sensitivity to the increase of blood pressure was reduced in OCSR [Slope: OC: -2.6 ± 0.15 (9); OCRS: -1.6 ± 0.13 (9)]. Hypothalamic activity of ACE2 was significantly reduced in OCSR compared to OC [OC: 97.4 ± 15 (18); OSR: 60.2 ± 3.6 (16) UAF/min/protein mg]. Renal function alteration was noticed by the increase in glomerular filtration rate (GFR) observed in OCSR [OC: 6.4 ± 0.2 (10); OCSR: 7.4 ± 0.3 (7)]. Chronic sleep restriction during pregnancy caused in the offspring hypertension, altered cardiac baroreflex response, reduced ACE-2 activity in the hypothalamus and renal alterations. Our data suggest that the reduction of sleeping time along the pregnancy is able to modify maternal homeostasis leading to functional alterations in offspring.

  18. Proteomic analysis of human bladder epithelial cells by 2D blue native SDS-PAGE reveals TCDD-induced alterations of calcium and iron homeostasis possibly mediated by nitric oxide.

    PubMed

    Verma, Nisha; Pink, Mario; Petrat, Frank; Rettenmeier, Albert W; Schmitz-Spanke, Simone

    2015-01-01

    A proteomic analysis of the interaction among multiprotein complexes involved in 2,3,7,8-dibenzo-p-dioxin (TCDD)-mediated toxicity in urinary bladder epithelial RT4 cells was performed using two-dimensional blue native SDS-PAGE (2D BN/SDS-PAGE). To enrich the protein complexes, unexposed and TCDD-exposed cells were fractionated. BN/SDS-PAGE of the resulting fractions led to an effective separation of proteins and protein complexes of various origins, including cell membrane, mitochondria, and other intracellular compartments. Major differences between the proteome of control and exposed cells involved the alteration of many calcium-regulated proteins (calmodulin, protein S100-A2, annexin A5, annexin A10, gelsolin isoform b) and iron-regulated proteins (ferritin, heme-binding protein 2, transferrin). On the basis of these findings, the intracellular calcium concentration was determined, revealing a significant increase after 24 h of exposure to TCDD. Moreover, the concentration of the labile iron pool (LIP) was also significantly elevated in TCDD-exposed cells. This increase was strongly inhibited by the calmodulin (CaM) antagonist W-7, which pointed toward a possible interaction between iron and calcium signaling. Because nitric oxide (NO) production was significantly enhanced in TCDD-exposed cells and was also inhibited by W-7, we hypothesize that alterations in calcium and iron homeostasis upon exposure to TCDD may be linked through NO generated by CaM-activated nitric oxide synthase. In our model, we propose that NO produced upon TCDD exposure interacts with the iron centers of iron-regulatory proteins (IRPs) that modulate the alteration of ferritin and transferrin, resulting in an augmented cellular LIP and, hence, increased toxicity.

  19. Sleep disordered breathing at the extremes of age: infancy

    PubMed Central

    Tan, Hui-Leng

    2016-01-01

    Educational aims The reader will be able to: Understand normal sleep patterns in infancyAppreciate disorders of breathing in infancyAppreciate disorders of respiratory control Normal sleep in infancy is a time of change with alterations in sleep architecture, sleep duration, sleep patterns and respiratory control as an infant grows older. Interactions between sleep and respiration are key to the mechanisms by which infants are vulnerable to sleep disordered breathing. This review discusses normal sleep in infancy, as well as normal sleep breathing in infancy. Sleep disordered breathing (obstructive and central) as well as disorders of ventilatory control and infant causes of hypoventilation are all reviewed in detail. PMID:27064478

  20. Nordihydroguaiaretic Acid Extends the Lifespan of Drosophila and Mice, Increases Mortality-Related Tumors and Hemorrhagic Diathesis, and Alters Energy Homeostasis in Mice.

    PubMed

    Spindler, Stephen R; Mote, Patricia L; Lublin, Alex L; Flegal, James M; Dhahbi, Joseph M; Li, Rui

    2015-12-01

    Mesonordihydroguaiaretic acid (NDGA) extends murine lifespan. The studies reported here describe its dose dependence, effects on body weight, toxicity-related clinical chemistries, and mortality-related pathologies. In flies, we characterized its effects on lifespan, food consumption, body weight, and locomotion. B6C3F1 mice were fed AIN-93M diet supplemented with 1.5, 2.5, 3.5, or 4.5 g NDGA/kg diet (1.59, 2.65, 3.71 and 4.77 mg/kg body weight/day) beginning at 12 months of age. Only the 3.5 mg/kg diet produced a highly significant increase in lifespan, as judged by either the Mantel-Cox log-rank test (p = .008) or the Gehan-Breslow-Wilcoxon test (p = .009). NDGA did not alter food intake, but dose-responsively reduced weight, suggesting it decreased the absorption or increased the utilization of calories. NDGA significantly increased the incidence of liver, lung, and thymus tumors, and peritoneal hemorrhagic diathesis found at necropsy. However, clinical chemistries found little evidence for overt toxicity. While NDGA was not overtly toxic at its therapeutic dosage, its association with severe end of life pathologies does not support the idea that NDGA consumption will increase human lifespan or health-span. The less toxic derivatives of NDGA which are under development should be explored as anti-aging therapeutics.

  1. Nordihydroguaiaretic Acid Extends the Lifespan of Drosophila and Mice, Increases Mortality-Related Tumors and Hemorrhagic Diathesis, and Alters Energy Homeostasis in Mice

    PubMed Central

    Spindler, Stephen R.; Mote, Patricia L.; Lublin, Alex L.; Flegal, James M.; Dhahbi, Joseph M.; Li, Rui

    2015-01-01

    Mesonordihydroguaiaretic acid (NDGA) extends murine lifespan. The studies reported here describe its dose dependence, effects on body weight, toxicity-related clinical chemistries, and mortality-related pathologies. In flies, we characterized its effects on lifespan, food consumption, body weight, and locomotion. B6C3F1 mice were fed AIN-93M diet supplemented with 1.5, 2.5, 3.5, or 4.5g NDGA/kg diet (1.59, 2.65, 3.71 and 4.77mg/kg body weight/day) beginning at 12 months of age. Only the 3.5mg/kg diet produced a highly significant increase in lifespan, as judged by either the Mantel–Cox log-rank test (p = .008) or the Gehan–Breslow–Wilcoxon test (p = .009). NDGA did not alter food intake, but dose-responsively reduced weight, suggesting it decreased the absorption or increased the utilization of calories. NDGA significantly increased the incidence of liver, lung, and thymus tumors, and peritoneal hemorrhagic diathesis found at necropsy. However, clinical chemistries found little evidence for overt toxicity. While NDGA was not overtly toxic at its therapeutic dosage, its association with severe end of life pathologies does not support the idea that NDGA consumption will increase human lifespan or health-span. The less toxic derivatives of NDGA which are under development should be explored as anti-aging therapeutics. PMID:25380600

  2. Selective REM sleep deprivation in narcolepsy.

    PubMed

    Vu, Manh Hoang; Hurni, Christoph; Mathis, Johannes; Roth, Corinne; Bassetti, Claudio L

    2011-03-01

    Narcolepsy is characterized by excessive daytime sleepiness and rapid eye movement (REM) sleep abnormalities, including cataplexy. The aim of this study was to assess REM sleep pressure and homeostasis in narcolepsy. Six patients with narcolepsy and six healthy controls underwent a REM sleep deprivation protocol, including one habituation, one baseline, two deprivation nights (D1, D2) and one recovery night. Multiple sleep latency tests (MSLTs) were performed during the day after baseline and after D2. During D1 and D2 REM sleep was prevented by awakening the subjects at the first polysomnographic signs of REM sleep for 2 min. Mean sleep latency and number of sleep-onset REM periods (SOREMs) were determined on all MSLT. More interventions were required to prevent REM sleep in narcoleptics compared with control subjects during D1 (57 ± 16 versus 24 ± 10) and D2 (87 ± 22 versus 35 ± 8, P = 0.004). Interventions increased from D1 to D2 by 46% in controls and by 53% in narcoleptics (P < 0.03). Selective REM sleep deprivation was successful in both controls (mean reduction of REM to 6% of baseline) and narcoleptics (11%). Both groups had a reduction of total sleep time during the deprivation nights (P = 0.03). Neither group had REM sleep rebound in the recovery night. Narcoleptics had, however, an increase in the number of SOREMs on MSLT (P = 0.005). There was no increase in the number of cataplexies after selective REM sleep deprivation. We conclude that: (i) REM sleep pressure is higher in narcoleptics; (ii) REM sleep homeostasis is similar in narcoleptics and controls; (iii) in narcoleptics selective REM sleep deprivation may have an effect on sleep propensity but not on cataplexy.

  3. Capsicum annuum tobacco mosaic virus-induced clone 1 expression perturbation alters the plant's response to ethylene and interferes with the redox homeostasis.

    PubMed

    Shin, Ryoung; An, Jong-Min; Park, Chang-Jin; Kim, Young Jin; Joo, Sunjoo; Kim, Woo Taek; Paek, Kyung-Hee

    2004-05-01

    Capsicum annuum tobacco mosaic virus (TMV)-induced clone 1 (CaTin1) gene was expressed early during incompatible interaction of hot pepper (Caspsicum annuum) plants with TMV and Xanthomonas campestris. RNA-blot analysis showed that CaTin1 gene was expressed only in roots in untreated plants and induced mainly in leaf in response to ethylene, NaCl, and methyl viologen but not by salicylic acid and methyl jasmonate. The ethylene dependence of CaTin1 induction upon TMV inoculation was demonstrated by the decrease of CaTin1 expression in response to several inhibitors of ethylene biosynthesis or its action. Transgenic tobacco (Nicotiana tabacum) plants expressing CaTin1 gene in sense- or antisense-orientation showed interesting characteristics such as the accelerated growth and the enhanced resistance to biotic as well as abiotic stresses. Such characteristics appear to be caused by the elevated level of ethylene and H2O2. Moreover, in transgenic plants expressing antisense CaTin1 gene, the expression of some pathogenesis-related genes was enhanced constitutively, which may be mainly due to the increased ethylene level. The promoter of CaTin1 has four GCC-boxes, two AT-rich regions, and an elicitor-inducible W-box. The induction of the promoter activity by ethylene depends on GCC-boxes and by TMV on W-box. Taken together, we propose that the CaTin1 up-regulation or down-regulation interferes with the redox balance of plants leading to the altered response to ethylene and biotic as well as abiotic stresses.

  4. Sleep smart-optimizing sleep for declarative learning and memory.

    PubMed

    Feld, Gordon B; Diekelmann, Susanne

    2015-01-01

    The last decade has witnessed a spurt of new publications documenting sleep's essential contribution to the brains ability to form lasting memories. For the declarative memory domain, slow wave sleep (the deepest sleep stage) has the greatest beneficial effect on the consolidation of memories acquired during preceding wakefulness. The finding that newly encoded memories become reactivated during subsequent sleep fostered the idea that reactivation leads to the strengthening and transformation of the memory trace. According to the active system consolidation account, trace reactivation leads to the redistribution of the transient memory representations from the hippocampus to the long-lasting knowledge networks of the cortex. Apart from consolidating previously learned information, sleep also facilitates the encoding of new memories after sleep, which probably relies on the renormalization of synaptic weights during sleep as suggested by the synaptic homeostasis theory. During wakefulness overshooting potentiation causes an imbalance in synaptic weights that is countered by synaptic downscaling during subsequent sleep. This review briefly introduces the basic concepts and central findings of the research on sleep and memory, and discusses implications of this lab-based work for everyday applications to make the best possible use of sleep's beneficial effect on learning and memory. PMID:26029150

  5. Deletion of Apoptosis Signal-Regulating Kinase 1 (ASK1) Protects Pancreatic Beta-Cells from Stress-Induced Death but Not from Glucose Homeostasis Alterations under Pro-Inflammatory Conditions

    PubMed Central

    Pepin, Emilie; Higa, Arisa; Schuster-Klein, Carole; Bernard, Catherine; Sulpice, Thierry; Guardiola, Beatrice; Chevet, Eric; Alquier, Thierry

    2014-01-01

    Background Type 2 diabetes is characterized by pancreatic beta-cell dysfunction and is associated with low-grade inflammation. Recent observations suggest that apoptosis signal-regulating kinase 1 (ASK1) is involved in beta-cell death in response to different stressors. In this study, we tested whether ASK1 deficiency protects beta-cells from glucolipotoxic conditions and cytokines treatment or from glucose homeostasis alteration induced by endotoxemia. Methodology/Principal Findings Insulin secretion was neither affected upon shRNA-mediated downregulation of ASK1 in MIN6 cells nor in islets from ASK1-deficient mice. ASK1 silencing in MIN6 cells and deletion in islets did not prevent the deleterious effect of glucolipotoxic conditions or cytokines on insulin secretion. However, it protected MIN6 cells from death induced by ER stress or palmitate and islets from short term caspase activation in response to cytokines. Moreover, endotoxemia induced by LPS infusion increased insulin secretion during hyperglycemic clamps but the response was similar in wild-type and ASK1-deficient mice. Finally, insulin sensitivity in the presence of LPS was not affected by ASK1-deficiency. Conclusions/Significance Our study demonstrates that ASK1 is not involved in beta-cell function and dysfunction but controls stress-induced beta-cell death. PMID:25383781

  6. C9orf72 Hexanucleotide Expansions Are Associated with Altered Endoplasmic Reticulum Calcium Homeostasis and Stress Granule Formation in Induced Pluripotent Stem Cell-Derived Neurons from Patients with Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.

    PubMed

    Dafinca, Ruxandra; Scaber, Jakub; Ababneh, Nida'a; Lalic, Tatjana; Weir, Gregory; Christian, Helen; Vowles, Jane; Douglas, Andrew G L; Fletcher-Jones, Alexandra; Browne, Cathy; Nakanishi, Mahito; Turner, Martin R; Wade-Martins, Richard; Cowley, Sally A; Talbot, Kevin

    2016-08-01

    An expanded hexanucleotide repeat in a noncoding region of the C9orf72 gene is a major cause of amyotrophic lateral sclerosis (ALS), accounting for up to 40% of familial cases and 7% of sporadic ALS in European populations. We have generated induced pluripotent stem cells (iPSCs) from fibroblasts of patients carrying C9orf72 hexanucleotide expansions, differentiated these to functional motor and cortical neurons, and performed an extensive phenotypic characterization. In C9orf72 iPSC-derived motor neurons, decreased cell survival is correlated with dysfunction in Ca(2+) homeostasis, reduced levels of the antiapoptotic protein Bcl-2, increased endoplasmic reticulum (ER) stress, and reduced mitochondrial membrane potential. Furthermore, C9orf72 motor neurons, and also cortical neurons, show evidence of abnormal protein aggregation and stress granule formation. This study is an extensive characterization of iPSC-derived motor neurons as cellular models of ALS carrying C9orf72 hexanucleotide repeats, which describes a novel pathogenic link between C9orf72 mutations, dysregulation of calcium signaling, and altered proteostasis and provides a potential pharmacological target for the treatment of ALS and the related neurodegenerative disease frontotemporal dementia. Stem Cells 2016;34:2063-2078.

  7. C9orf72 Hexanucleotide Expansions Are Associated with Altered Endoplasmic Reticulum Calcium Homeostasis and Stress Granule Formation in Induced Pluripotent Stem Cell‐Derived Neurons from Patients with Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

    PubMed Central

    Dafinca, Ruxandra; Scaber, Jakub; Ababneh, Nida'a; Lalic, Tatjana; Weir, Gregory; Christian, Helen; Vowles, Jane; Douglas, Andrew G.L.; Fletcher‐Jones, Alexandra; Browne, Cathy; Nakanishi, Mahito; Turner, Martin R.; Wade‐Martins, Richard

    2016-01-01

    Abstract An expanded hexanucleotide repeat in a noncoding region of the C9orf72 gene is a major cause of amyotrophic lateral sclerosis (ALS), accounting for up to 40% of familial cases and 7% of sporadic ALS in European populations. We have generated induced pluripotent stem cells (iPSCs) from fibroblasts of patients carrying C9orf72 hexanucleotide expansions, differentiated these to functional motor and cortical neurons, and performed an extensive phenotypic characterization. In C9orf72 iPSC‐derived motor neurons, decreased cell survival is correlated with dysfunction in Ca2+ homeostasis, reduced levels of the antiapoptotic protein Bcl‐2, increased endoplasmic reticulum (ER) stress, and reduced mitochondrial membrane potential. Furthermore, C9orf72 motor neurons, and also cortical neurons, show evidence of abnormal protein aggregation and stress granule formation. This study is an extensive characterization of iPSC‐derived motor neurons as cellular models of ALS carrying C9orf72 hexanucleotide repeats, which describes a novel pathogenic link between C9orf72 mutations, dysregulation of calcium signaling, and altered proteostasis and provides a potential pharmacological target for the treatment of ALS and the related neurodegenerative disease frontotemporal dementia. Stem Cells 2016;34:2063–2078 PMID:27097283

  8. Sleep and respiration in microgravity.

    PubMed

    Prisk, G K

    1998-01-01

    Sleep studies conducted during the STS-90 Neurolab mission are explored. The relationship between sleep, melatonin, and circadian phase is reviewed. The study contained both sleep and awake components. The objectives of the sleep component were to test five hypotheses: that circadian rhythms of core body temperature and urinary melatonin are synchronized to required sleep-wake schedules, that spaceflight results in substantial disruption of sleep, that the pattern of chest and abdominal wall motion alters during the different sleep stages in microgravity, that arterial oxygen saturation is reduced during some stages of sleep in microgravity, and that pre-sleep administration of melatonin during microgravity results in improved sleep quality. The awake component tested three hypotheses: that ventilatory response to carbon dioxide is increased during exposure to microgravity and that this exacerbates sleep disruption, that ventilatory response to hypoxia is increased by exposure to microgravity, and that the improved sleep resulting from the pre-sleep administration of melatonin enhances next day cognition when compared to placebo.

  9. Sleep and respiration in microgravity

    NASA Technical Reports Server (NTRS)

    Prisk, G. K.

    1998-01-01

    Sleep studies conducted during the STS-90 Neurolab mission are explored. The relationship between sleep, melatonin, and circadian phase is reviewed. The study contained both sleep and awake components. The objectives of the sleep component were to test five hypotheses: that circadian rhythms of core body temperature and urinary melatonin are synchronized to required sleep-wake schedules, that spaceflight results in substantial disruption of sleep, that the pattern of chest and abdominal wall motion alters during the different sleep stages in microgravity, that arterial oxygen saturation is reduced during some stages of sleep in microgravity, and that pre-sleep administration of melatonin during microgravity results in improved sleep quality. The awake component tested three hypotheses: that ventilatory response to carbon dioxide is increased during exposure to microgravity and that this exacerbates sleep disruption, that ventilatory response to hypoxia is increased by exposure to microgravity, and that the improved sleep resulting from the pre-sleep administration of melatonin enhances next day cognition when compared to placebo.

  10. Sleeping Worries Away or Worrying Away Sleep? Physiological Evidence on Sleep-Emotion Interactions

    PubMed Central

    Talamini, Lucia M.; Bringmann, Laura F.; de Boer, Marieke; Hofman, Winni F.

    2013-01-01

    Recent findings suggest that sleep might serve a role in emotional coping. However, most findings are based on subjective reports of sleep quality, while the relation with underlying sleep physiology is still largely unknown. In this study, the impact of an emotionally distressing experience on the EEG correlates of sleep was assessed. In addition, the association between sleep physiological parameters and the extent of emotional attenuation over sleep was determined. The experimental set up involved presentation of an emotionally neutral or distressing film fragment in the evening, followed by polysomnographic registration of undisturbed, whole-night sleep and assessment of emotional reactivity to film cues on the next evening. We found that emotional distress induced mild sleep deterioration, but also an increase in the proportion of slow wave sleep (SWS) and altered patterning of rapid eye movement (REM) sleep. Indeed, while REM sleep occurrence normally increases over the course of the night, emotional distress flattened this distribution and correlated with an increased number of REM periods. While sleep deterioration was negatively associated to emotional attenuation over sleep, the SWS response was positively related to such attenuation and may form part of a compensatory response to the stressor. Interestingly, trait-like SWS characteristics also correlated positively with the extent of emotion attenuation over sleep. The combined results provide strong evidence for an intimate reciprocal relation between sleep physiology and emotional processing. Moreover, individual differences in subjects' emotional and sleep responses suggest there may be a coupling of certain emotion and sleep traits into distinct emotional sleep types. PMID:23671601

  11. [Biological rhythm, sleep and jet lag].

    PubMed

    Zulley, Jürgen

    2014-11-01

    Sleep is an active recovery process, which is governed by biological rhythms. This rhythmic variation influences almost all bodily functions and dictates the optimal time for sleep. Sleep itself is an inconsistent state mainly characterized by the alteration between REM and NREM sleep. Vital regenerative processes occur during sleep. Sleep is a basic prerequisite for wellbeing, health and performance. If the synchronization between sleep and the biological rhythms is disturbed, malfunctions of the organism have to be expected. Such a state can be found by a sudden shift of local time by travelling across time zones (jet lag). Therapeutic strategies can reduce the symptoms associated with the state of jet lag.

  12. Sleep Quiz

    MedlinePlus

    Skip Navigation Bar Home Current Issue Past Issues Sleep Quiz Past Issues / Summer 2007 Table of Contents ... on. Photo: iStock Take the National Center on Sleep Disorders Research Sleep Quiz TRUE OR FALSE ? _____1. ...

  13. Sleep Quiz

    MedlinePlus

    ... Home » About the NHLBI » Organization » National Center on Sleep Disorders Research (NCSDR) » Patient & Public Information » Sleep Quiz National Center on Sleep Disorders Research Research Professional Education Patient & Public Information Communications ...

  14. [Sleep psychiatry].

    PubMed

    Chiba, Shigeru

    2013-01-01

    Sleep disorders are serious issues in modern society. There has been marked scientific interest in sleep for a century, with the discoveries of the electrical activity of the brain (EEG), sleep-wake system, rapid eye movement (REM) sleep, and circadian rhythm system. Additionally, the advent of video-polysomnography in clinical research has revealed some of the consequences of disrupted sleep and sleep deprivation in psychiatric disorders. Decades of clinical research have demonstrated that sleep disorders are intimately tied to not only physical disease (e. g., lifestyle-related disease) but psychiatric illness. According to The International Classification of Sleep Disorders (2005), sleep disorders are classified into 8 major categories: 1) insomnia, 2) sleep-related breathing disorders, 3) hypersomnias of central origin, 4) circadian rhythm sleep disorders, 5) parasomnias, 6) sleep-related movement disorders, 7) isolated symptoms, and 8) other sleep disorders. Several sleep disorders, including obstructive sleep apnea syndrome, restless legs syndrome, periodic limb movement disorder, sleepwalking, REM sleep behavior disorder, and narcolepsy, may be comorbid or possibly mimic numerous psychiatric disorders, and can even occur due to psychiatric pharmacotherapy. Moreover, sleep disorders may exacerbate underlying psychiatric disorders when left untreated. Therefore, psychiatrists should pay attention to the intimate relationship between sleep disorders and psychiatric symptoms. Sleep psychiatry is an academic field focusing on interrelations between sleep medicine and psychiatry. This mini-review summarizes recent findings in sleep psychiatry. Future research on the bidirectional relation between sleep disturbance and psychiatric symptoms will shed light on the pathophysiological view of psychiatric disorders and sleep disorders. PMID:24050022

  15. Metabolic consequences of sleep and circadian disorders

    PubMed Central

    Depner, Christopher M.; Stothard, Ellen R.; Wright, Kenneth P.

    2014-01-01

    Sleep and circadian rhythms modulate or control daily physiological patterns with importance for normal metabolic health. Sleep deficiencies associated with insufficient sleep schedules, insomnia with short-sleep duration, sleep apnea, narcolepsy, circadian misalignment, shift work, night eating syndrome and sleep-related eating disorder may all contribute to metabolic dysregulation. Sleep deficiencies and circadian disruption associated with metabolic dysregulation may contribute to weight gain, obesity, and type 2 diabetes potentially by altering timing and amount of food intake, disrupting energy balance, inflammation, impairing glucose tolerance and insulin sensitivity. Given the rapidly increasing prevalence of metabolic diseases, it is important to recognize the role of sleep and circadian disruption in the development, progression, and morbidity of metabolic disease. Some findings indicate sleep treatments and countermeasures improve metabolic health, but future clinical research investigating prevention and treatment of chronic metabolic disorders through treatment of sleep and circadian disruption is needed. PMID:24816752

  16. Metabolic consequences of sleep and circadian disorders.

    PubMed

    Depner, Christopher M; Stothard, Ellen R; Wright, Kenneth P

    2014-07-01

    Sleep and circadian rhythms modulate or control daily physiological patterns with importance for normal metabolic health. Sleep deficiencies associated with insufficient sleep schedules, insomnia with short-sleep duration, sleep apnea, narcolepsy, circadian misalignment, shift work, night eating syndrome, and sleep-related eating disorder may all contribute to metabolic dysregulation. Sleep deficiencies and circadian disruption associated with metabolic dysregulation may contribute to weight gain, obesity, and type 2 diabetes potentially by altering timing and amount of food intake, disrupting energy balance, inflammation, impairing glucose tolerance, and insulin sensitivity. Given the rapidly increasing prevalence of metabolic diseases, it is important to recognize the role of sleep and circadian disruption in the development, progression, and morbidity of metabolic disease. Some findings indicate sleep treatments and countermeasures improve metabolic health, but future clinical research investigating prevention and treatment of chronic metabolic disorders through treatment of sleep and circadian disruption is needed.

  17. Sleep Dysfunction and Gastrointestinal Diseases.

    PubMed

    Khanijow, Vikesh; Prakash, Pia; Emsellem, Helene A; Borum, Marie L; Doman, David B

    2015-12-01

    Sleep deprivation and impaired sleep quality have been associated with poor health outcomes. Many patients experience sleep disturbances, which can increase the risk of medical conditions such as hypertension, obesity, stroke, and heart disease as well as increase overall mortality. Recent studies have suggested that there is a strong association between sleep disturbances and gastrointestinal diseases. Proinflammatory cytokines, such as tumor necrosis factor, interleukin-1, and interleukin-6, have been associated with sleep dysfunction. Alterations in these cytokines have been seen in certain gastrointestinal diseases, such as gastroesophageal reflux disease, inflammatory bowel disease, liver disorders, and colorectal cancer. It is important for gastroenterologists to be aware of the relationship between sleep disorders and gastrointestinal illnesses to ensure good care for patients. This article reviews the current research on the interplay between sleep disorders, immune function, and gastrointestinal diseases. PMID:27134599

  18. Sleep Dysfunction and Gastrointestinal Diseases

    PubMed Central

    Khanijow, Vikesh; Prakash, Pia; Emsellem, Helene A.; Borum, Marie L.

    2015-01-01

    Sleep deprivation and impaired sleep quality have been associated with poor health outcomes. Many patients experience sleep disturbances, which can increase the risk of medical conditions such as hypertension, obesity, stroke, and heart disease as well as increase overall mortality. Recent studies have suggested that there is a strong association between sleep disturbances and gastrointestinal diseases. Proinflammatory cytokines, such as tumor necrosis factor, interleukin-1, and interleukin-6, have been associated with sleep dysfunction. Alterations in these cytokines have been seen in certain gastrointestinal diseases, such as gastroesophageal reflux disease, inflammatory bowel disease, liver disorders, and colorectal cancer. It is important for gastroenterologists to be aware of the relationship between sleep disorders and gastrointestinal illnesses to ensure good care for patients. This article reviews the current research on the interplay between sleep disorders, immune function, and gastrointestinal diseases. PMID:27134599

  19. Role of orexin in the central regulation of glucose and energy homeostasis.

    PubMed

    Tsuneki, Hiroshi; Wada, Tsutomu; Sasaoka, Toshiyasu

    2012-01-01

    Hypothalamic orexin neurons are known to regulate sleep/wake stability, feeding behavior, emotions, autonomic nerve activity, and whole-body energy metabolism. In addition, emerging evidence indicates that orexin contributes to central regulation of glucose homeostasis. Intriguingly, central administration of orexin is reported to cause blood glucose-elevating effect or blood glucose-lowering effect in rodents, depending on the experimental conditions. Here we reviewed the recent reports regarding the mode and mechanism of actions of orexin on these two opposing effects, and discuss the functional significance for the maintenance of glucose homeostasis. The fact that orexin exhibits biphasic effects on autonomic nerve activity and lipolysis suggests that orexin dually regulates the glucose appearance. In fact, orexin neurons are activated not only depending on the demand for glucose but also according to a circadian rhythm in the suprachiasmatic nucleus. The excited orexin neurons appear to alter the sympathetic or parasympathetic outflow to the periphery, and modulate the glucose production and utilization. Furthermore, deficiency of orexin action, particularly reduction of orexin 2 receptor-signaling, disrupts the mechanism for protection against insulin resistance associated with aging or induced by chronic high fat feeding in mice. Taken together, hypothalamic orexin system may manage multiple tasks to coordinate the interconnection among the arousal, feeding, circadian, and glucose homeostasis pathways. PMID:22293586

  20. Slow wave and rem sleep mechanisms are differently altered in hereditary pick disease associated with the TAU G389R mutation.

    PubMed

    Gemignani, A; Pietrini, P; Murrell, J R; Glazier, B S; Zolo, P; Guazzelli, M; Ghetti, B

    2005-02-01

    Sleep disturbances are found in the course of most dementing syndromes. We report a longitudinal polysomnographic and 18FDG-PET study in a 38-year-old male with FTDP17 carrying the Tau gene mutation G389R. All-night sleep EEG and wake cerebral glucose metabolism at rest (eyes/ears covered) of the preceding day were studied twice, eight months (Night 1; PET 1) and sixteen months (Night 2; PET 2) after the initial neurological evaluation. The Night 1 study showed sleep fragmentation associated to a short REM latency and a severe reduction of slow wave sleep, with relatively preserved NREM-REM sleep cycles; daytime PET 1 revealed severe cerebral glucose metabolic reductions in frontal and temporal areas, with relative preservation of remaining cortical regions and subcortical structures. On Night 2, the total sleep time was less than 5 hours, delta sleep and REM latency remained shortened and only two sleep cycles could be identified; daytime PET 2 exam revealed a greater cortical metabolic impairment and an involvement of subcortical brain regions as compared to PET 1. Post-mortem neuropathological data showed severe neuronal loss, spongiosis and gliosis that were mostly marked in cortical layers I, II, V and VI. In vivo, neurometabolic and post-mortem neuropathological data are consistent with and indicative of a severe dysfunction of intra- and trans-hemispheric regional connectivity and of cortico-thalamic circuits. These findings suggest that the decreased cortical and subcortical connectivity may have been the main pathophysiological mechanism responsible for delta sleep reduction and the cognitive decline.

  1. Sleep and Chronic Disease

    MedlinePlus

    ... CDC Cancel Submit Search The CDC Sleep and Sleep Disorders Note: Javascript is disabled or is not supported ... CDC.gov . Sleep About Us About Sleep Key Sleep Disorders Sleep and Chronic Disease How Much Sleep Do ...

  2. Sleeping on a problem: the impact of sleep disturbance on intensive care patients - a clinical review.

    PubMed

    Delaney, Lori J; Van Haren, Frank; Lopez, Violeta

    2015-01-01

    Sleep disturbance is commonly encountered amongst intensive care patients and has significant psychophysiological effects, which protract recovery and increases mortality. Bio-physiological monitoring of intensive care patients reveal alterations in sleep architecture, with reduced sleep quality and continuity. The etiological causes of sleep disturbance are considered to be multifactorial, although environmental stressors namely, noise, light and clinical care interactions have been frequently cited in both subjective and objective studies. As a result, interventions are targeted towards modifiable factors to ameliorate their impact. This paper reviews normal sleep physiology and the impact that sleep disturbance has on patient psychophysiological recovery, and the contribution that the clinical environment has on intensive care patients' sleep.

  3. Sleep in elite athletes and nutritional interventions to enhance sleep.

    PubMed

    Halson, Shona L

    2014-05-01

    Sleep has numerous important physiological and cognitive functions that may be particularly important to elite athletes. Recent evidence, as well as anecdotal information, suggests that athletes may experience a reduced quality and/or quantity of sleep. Sleep deprivation can have significant effects on athletic performance, especially submaximal, prolonged exercise. Compromised sleep may also influence learning, memory, cognition, pain perception, immunity and inflammation. Furthermore, changes in glucose metabolism and neuroendocrine function as a result of chronic, partial sleep deprivation may result in alterations in carbohydrate metabolism, appetite, food intake and protein synthesis. These factors can ultimately have a negative influence on an athlete's nutritional, metabolic and endocrine status and hence potentially reduce athletic performance. Research has identified a number of neurotransmitters associated with the sleep-wake cycle. These include serotonin, gamma-aminobutyric acid, orexin, melanin-concentrating hormone, cholinergic, galanin, noradrenaline, and histamine. Therefore, nutritional interventions that may act on these neurotransmitters in the brain may also influence sleep. Carbohydrate, tryptophan, valerian, melatonin and other nutritional interventions have been investigated as possible sleep inducers and represent promising potential interventions. In this review, the factors influencing sleep quality and quantity in athletic populations are examined and the potential impact of nutritional interventions is considered. While there is some research investigating the effects of nutritional interventions on sleep, future research may highlight the importance of nutritional and dietary interventions to enhance sleep. PMID:24791913

  4. Homeostasis and Biofeedback

    PubMed Central

    Kryspin, J.; Godfrey, C. M.

    1976-01-01

    Homeostasis of human organisms is the maintenance of a hierarchy of steady state conditions with little variation from, and prompt return to, a stabilized level during function. Any one of the information channels which informs the organism of the state of homeostasis can be used as ‘biofeedback’, i.e. to increase awareness of inadequate control and to teach new control mechanisms. If homeostasis is the basis of good health, disease may be considered a deviation from homeostasis. Through the use of biofeedback the subject may be made aware of poor health and learn to make adjustments to achieve homeostasis. Clinical application and results in several chronic disorders illustrate some successes and limitations of this approach. PMID:21304759

  5. Physiologically based quantitative modeling of unihemispheric sleep.

    PubMed

    Kedziora, D J; Abeysuriya, R G; Phillips, A J K; Robinson, P A

    2012-12-01

    Unihemispheric sleep has been observed in numerous species, including birds and aquatic mammals. While knowledge of its functional role has been improved in recent years, the physiological mechanisms that generate this behavior remain poorly understood. Here, unihemispheric sleep is simulated using a physiologically based quantitative model of the mammalian ascending arousal system. The model includes mutual inhibition between wake-promoting monoaminergic nuclei (MA) and sleep-promoting ventrolateral preoptic nuclei (VLPO), driven by circadian and homeostatic drives as well as cholinergic and orexinergic input to MA. The model is extended here to incorporate two distinct hemispheres and their interconnections. It is postulated that inhibitory connections between VLPO nuclei in opposite hemispheres are responsible for unihemispheric sleep, and it is shown that contralateral inhibitory connections promote unihemispheric sleep while ipsilateral inhibitory connections promote bihemispheric sleep. The frequency of alternating unihemispheric sleep bouts is chiefly determined by sleep homeostasis and its corresponding time constant. It is shown that the model reproduces dolphin sleep, and that the sleep regimes of humans, cetaceans, and fur seals, the latter both terrestrially and in a marine environment, require only modest changes in contralateral connection strength and homeostatic time constant. It is further demonstrated that fur seals can potentially switch between their terrestrial bihemispheric and aquatic unihemispheric sleep patterns by varying just the contralateral connection strength. These results provide experimentally testable predictions regarding the differences between species that sleep bihemispherically and unihemispherically. PMID:22960411

  6. Sleep inertia, sleep homeostatic and circadian influences on higher-order cognitive functions.

    PubMed

    Burke, Tina M; Scheer, Frank A J L; Ronda, Joseph M; Czeisler, Charles A; Wright, Kenneth P

    2015-08-01

    Sleep inertia, sleep homeostatic and circadian processes modulate cognition, including reaction time, memory, mood and alertness. How these processes influence higher-order cognitive functions is not well known. Six participants completed a 73-day-long study that included two 14-day-long 28-h forced desynchrony protocols to examine separate and interacting influences of sleep inertia, sleep homeostasis and circadian phase on higher-order cognitive functions of inhibitory control and selective visual attention. Cognitive performance for most measures was impaired immediately after scheduled awakening and improved during the first ~2-4 h of wakefulness (decreasing sleep inertia); worsened thereafter until scheduled bedtime (increasing sleep homeostasis); and was worst at ~60° and best at ~240° (circadian modulation, with worst and best phases corresponding to ~09:00 and ~21:00 hours, respectively, in individuals with a habitual wake time of 07:00 hours). The relative influences of sleep inertia, sleep homeostasis and circadian phase depended on the specific higher-order cognitive function task examined. Inhibitory control appeared to be modulated most strongly by circadian phase, whereas selective visual attention for a spatial-configuration search task was modulated most strongly by sleep inertia. These findings demonstrate that some higher-order cognitive processes are differentially sensitive to different sleep-wake regulatory processes. Differential modulation of cognitive functions by different sleep-wake regulatory processes has important implications for understanding mechanisms contributing to performance impairments during adverse circadian phases, sleep deprivation and/or upon awakening from sleep. PMID:25773686

  7. Sleep inertia, sleep homeostatic and circadian influences on higher-order cognitive functions.

    PubMed

    Burke, Tina M; Scheer, Frank A J L; Ronda, Joseph M; Czeisler, Charles A; Wright, Kenneth P

    2015-08-01

    Sleep inertia, sleep homeostatic and circadian processes modulate cognition, including reaction time, memory, mood and alertness. How these processes influence higher-order cognitive functions is not well known. Six participants completed a 73-day-long study that included two 14-day-long 28-h forced desynchrony protocols to examine separate and interacting influences of sleep inertia, sleep homeostasis and circadian phase on higher-order cognitive functions of inhibitory control and selective visual attention. Cognitive performance for most measures was impaired immediately after scheduled awakening and improved during the first ~2-4 h of wakefulness (decreasing sleep inertia); worsened thereafter until scheduled bedtime (increasing sleep homeostasis); and was worst at ~60° and best at ~240° (circadian modulation, with worst and best phases corresponding to ~09:00 and ~21:00 hours, respectively, in individuals with a habitual wake time of 07:00 hours). The relative influences of sleep inertia, sleep homeostasis and circadian phase depended on the specific higher-order cognitive function task examined. Inhibitory control appeared to be modulated most strongly by circadian phase, whereas selective visual attention for a spatial-configuration search task was modulated most strongly by sleep inertia. These findings demonstrate that some higher-order cognitive processes are differentially sensitive to different sleep-wake regulatory processes. Differential modulation of cognitive functions by different sleep-wake regulatory processes has important implications for understanding mechanisms contributing to performance impairments during adverse circadian phases, sleep deprivation and/or upon awakening from sleep.

  8. Tensional homeostasis in single fibroblasts.

    PubMed

    Webster, Kevin D; Ng, Win Pin; Fletcher, Daniel A

    2014-07-01

    Adherent cells generate forces through acto-myosin contraction to move, change shape, and sense the mechanical properties of their environment. They are thought to maintain defined levels of tension with their surroundings despite mechanical perturbations that could change tension, a concept known as tensional homeostasis. Misregulation of tensional homeostasis has been proposed to drive disorganization of tissues and promote progression of diseases such as cancer. However, whether tensional homeostasis operates at the single cell level is unclear. Here, we directly test the ability of single fibroblast cells to regulate tension when subjected to mechanical displacements in the absence of changes to spread area or substrate elasticity. We use a feedback-controlled atomic force microscope to measure and modulate forces and displacements of individual contracting cells as they spread on a fibronectin-patterned atomic-force microscope cantilever and coverslip. We find that the cells reach a steady-state contraction force and height that is insensitive to stiffness changes as they fill the micropatterned areas. Rather than maintaining a constant tension, the fibroblasts altered their contraction force in response to mechanical displacement in a strain-rate-dependent manner, leading to a new and stable steady-state force and height. This response is influenced by overexpression of the actin crosslinker α-actinin, and rheology measurements reveal that changes in cell elasticity are also strain- rate-dependent. Our finding of tensional buffering, rather than homeostasis, allows cells to transition between different tensional states depending on how they are displaced, permitting distinct responses to slow deformations during tissue growth and rapid deformations associated with injury.

  9. ASICs and cardiovascular homeostasis.

    PubMed

    Abboud, François M; Benson, Christopher J

    2015-07-01

    In this review we address primarily the role of ASICs in determining sensory signals from arterial baroreceptors, peripheral chemoreceptors, and cardiopulmonary and somatic afferents. Alterations in these sensory signals during acute cardiovascular stresses result in changes in sympathetic and parasympathetic activities that restore cardiovascular homeostasis. In pathological states, however, chronic dysfunctions of these afferents result in serious sympatho-vagal imbalances with significant increases in mortality and morbidity. We identified a role for ASIC2 in the mechano-sensitivity of aortic baroreceptors and of ASIC3 in the pH sensitivity of carotid bodies. In spontaneously hypertensive rats, we reported decreased expression of ASIC2 in nodose ganglia neurons and overexpression of ASIC3 in carotid bodies. This reciprocal expression of ASIC2 and ASIC3 results in reciprocal changes in sensory sensitivity of baro- and chemoreceptors and a consequential synergistic exaggeration sympathetic nerve activity. A similar reciprocal sensory dysautonomia prevails in heart failure and increases the risk of mortality. There is also evidence that ASIC heteromers in skeletal muscle afferents contribute significantly to the exercise pressor reflex. In cardiac muscle afferents of the dorsal root ganglia, they contribute to nociception and to the detrimental sympathetic activation during ischemia. Finally, we report that an inhibitory influence of ASIC2-mediated baroreceptor activity suppresses the sympatho-excitatory reflexes of the chemoreceptors and skeletal muscle afferents, as well as the ASIC1a-mediated excitation of central neurons during fear, threat, or panic. The translational potential of activation of ASIC2 in cardiovascular disease states may be a beneficial sympatho-inhibition and parasympathetic activation. This article is part of the Special Issue entitled 'Acid-Sensing Ion Channels in the Nervous System'.

  10. Effects of Sleep Deprivation on Brain Bioenergetics, Sleep, and Cognitive Performance in Cocaine-Dependent Individuals

    PubMed Central

    Trksak, George H.; Bracken, Bethany K.; Jensen, J. Eric; Plante, David T.; Penetar, David M.; Tartarini, Wendy L.; Maywalt, Melissa A.; Dorsey, Cynthia M.; Renshaw, Perry F.; Lukas, Scott E.

    2013-01-01

    In cocaine-dependent individuals, sleep is disturbed during cocaine use and abstinence, highlighting the importance of examining the behavioral and homeostatic response to acute sleep loss in these individuals. The current study was designed to identify a differential effect of sleep deprivation on brain bioenergetics, cognitive performance, and sleep between cocaine-dependent and healthy control participants. 14 healthy control and 8 cocaine-dependent participants experienced consecutive nights of baseline, total sleep deprivation, and recovery sleep in the research laboratory. Participants underwent [31]P magnetic resonance spectroscopy (MRS) brain imaging, polysomnography, Continuous Performance Task, and Digit Symbol Substitution Task. Following recovery sleep, [31]P MRS scans revealed that cocaine-dependent participants exhibited elevated global brain β-NTP (direct measure of adenosine triphosphate), α-NTP, and total NTP levels compared to those of healthy controls. Cocaine-dependent participants performed worse on the Continuous Performance Task and Digit Symbol Substitution Task at baseline compared to healthy control participants, but sleep deprivation did not worsen cognitive performance in either group. Enhancements of brain ATP levels in cocaine dependent participants following recovery sleep may reflect a greater impact of sleep deprivation on sleep homeostasis, which may highlight the importance of monitoring sleep during abstinence and the potential influence of sleep loss in drug relapse. PMID:24250276

  11. Effects of sleep deprivation on brain bioenergetics, sleep, and cognitive performance in cocaine-dependent individuals.

    PubMed

    Trksak, George H; Bracken, Bethany K; Jensen, J Eric; Plante, David T; Penetar, David M; Tartarini, Wendy L; Maywalt, Melissa A; Dorsey, Cynthia M; Renshaw, Perry F; Lukas, Scott E

    2013-01-01

    In cocaine-dependent individuals, sleep is disturbed during cocaine use and abstinence, highlighting the importance of examining the behavioral and homeostatic response to acute sleep loss in these individuals. The current study was designed to identify a differential effect of sleep deprivation on brain bioenergetics, cognitive performance, and sleep between cocaine-dependent and healthy control participants. 14 healthy control and 8 cocaine-dependent participants experienced consecutive nights of baseline, total sleep deprivation, and recovery sleep in the research laboratory. Participants underwent ³¹P magnetic resonance spectroscopy (MRS) brain imaging, polysomnography, Continuous Performance Task, and Digit Symbol Substitution Task. Following recovery sleep, ³¹P MRS scans revealed that cocaine-dependent participants exhibited elevated global brain β-NTP (direct measure of adenosine triphosphate), α-NTP, and total NTP levels compared to those of healthy controls. Cocaine-dependent participants performed worse on the Continuous Performance Task and Digit Symbol Substitution Task at baseline compared to healthy control participants, but sleep deprivation did not worsen cognitive performance in either group. Enhancements of brain ATP levels in cocaine dependent participants following recovery sleep may reflect a greater impact of sleep deprivation on sleep homeostasis, which may highlight the importance of monitoring sleep during abstinence and the potential influence of sleep loss in drug relapse. PMID:24250276

  12. Effects of Sleep Deprivation on Mice Bone Marrow and Spleen B Lymphopoiesis.

    PubMed

    Lungato, Lisandro; Nogueira-Pedro, Amanda; Carvalho Dias, Carolina; Paredes-Gamero, Edgar Julian; Tufik, Sergio; D'Almeida, Vânia

    2016-06-01

    B lymphocytes are immune cells crucial for the maintenance and viability of the humoral response. Sleep is an essential event for the maintenance and integrity of all systems, including the immune system (IS). Thus, sleep deprivation (SD) causes problems in metabolism and homeostasis in many cell systems, including the IS. In this study, our goal was to determine changes in B lymphocytes from the bone marrow (BM) and spleen after SD. Three-month-old male Swiss mice were used. These mice were sleep deprived through the modified multiple platform method for different periods (24, 48, and 72 h), whereas another group was allowed to sleep for 24 h after 72 h of SD (rebound group) and a third group was allowed to sleep normally during the entire experiment. After this, the spleen and BM were collected, and cell analyses were performed. The numbers of B lymphocytes in the BM and spleen were reduced by SD. Additionally, reductions in the percentage of lymphocyte progenitors and their ability to form colonies were observed. Moreover, an increase in the death of B lymphocytes from the BM and spleen was associated with an increase in oxidative stress indicators, such as DCFH-DA, CAT, and mitochondrial SOD. Rebound was not able to reverse most of the alterations elicited by SD. The reduction in B lymphocytes and their progenitors by cell death, with a concomitant increase in oxidative stress, showed that SD promoted a failure in B lymphopoiesis.

  13. Effects of Sleep Deprivation on Mice Bone Marrow and Spleen B Lymphopoiesis.

    PubMed

    Lungato, Lisandro; Nogueira-Pedro, Amanda; Carvalho Dias, Carolina; Paredes-Gamero, Edgar Julian; Tufik, Sergio; D'Almeida, Vânia

    2016-06-01

    B lymphocytes are immune cells crucial for the maintenance and viability of the humoral response. Sleep is an essential event for the maintenance and integrity of all systems, including the immune system (IS). Thus, sleep deprivation (SD) causes problems in metabolism and homeostasis in many cell systems, including the IS. In this study, our goal was to determine changes in B lymphocytes from the bone marrow (BM) and spleen after SD. Three-month-old male Swiss mice were used. These mice were sleep deprived through the modified multiple platform method for different periods (24, 48, and 72 h), whereas another group was allowed to sleep for 24 h after 72 h of SD (rebound group) and a third group was allowed to sleep normally during the entire experiment. After this, the spleen and BM were collected, and cell analyses were performed. The numbers of B lymphocytes in the BM and spleen were reduced by SD. Additionally, reductions in the percentage of lymphocyte progenitors and their ability to form colonies were observed. Moreover, an increase in the death of B lymphocytes from the BM and spleen was associated with an increase in oxidative stress indicators, such as DCFH-DA, CAT, and mitochondrial SOD. Rebound was not able to reverse most of the alterations elicited by SD. The reduction in B lymphocytes and their progenitors by cell death, with a concomitant increase in oxidative stress, showed that SD promoted a failure in B lymphopoiesis. PMID:26517012

  14. Predictability of Sleep in Patients with Insomnia

    PubMed Central

    Vallières, Annie; Ivers, Hans; Beaulieu-Bonneau, Simon; Morin, Charles M.

    2011-01-01

    Study Objectives: To evaluate whether the night-to-night variability in insomnia follows specific predictable patterns and to characterize sleep patterns using objective sleep and clinical variables. Design: Prospective observational study. Setting: University-affiliated sleep disorders center. Participants: 146 participants suffering from chronic and primary insomnia. Measurements and Results: Daily sleep diaries were completed for an average of 48 days and self-reported questionnaires once. Three nights were spent in the sleep laboratory for polysomnographic (PSG) assessment. Sleep efficiency, sleep onset latency, wake after sleep onset, and total sleep time were derived from sleep diaries and PSG. Time-series diary data were used to compute conditional probabilities of having an insomnia night after 1, 2, or 3 consecutive insomnia night(s). Conditional probabilities were submitted to a k-means cluster analysis. A 3-cluster solution was retained. One cluster included 38 participants exhibiting an unpredictable insomnia pattern. Another included 30 participants with a low and decreasing probability to have an insomnia night. The last cluster included 49 participants exhibiting a high probability to have insomnia every night. Clusters differed on age, insomnia severity, and mental fatigue, and on subjective sleep variables, but not on PSG sleep variables. Conclusion: These findings replicate our previous study and provide additional evidence that unpredictability is a less prevalent feature of insomnia than suggested previously in the literature. The presence of the 3 clusters is discussed in term of sleep perception and sleep homeostasis dysregulation. Citation: Vallières A; Ivers H; Beaulieu-Bonneau S; Morin CM. Predictability of sleep in patients with insomnia. SLEEP 2011;34(5):609-617. PMID:21532954

  15. Disruption of iron homeostasis in mesothelial cells following talc pleurodesis

    EPA Science Inventory

    The mechanism for biological effect following particle exposure is incompletely understood. One postulate proposed to explain biological effect after particles is an altered iron homeostasis in the host. The fibro-inflammatory properties of particles are exploited therapeutically...

  16. Oxygen Sensing and Homeostasis.

    PubMed

    Prabhakar, Nanduri R; Semenza, Gregg L

    2015-09-01

    The discovery of carotid bodies as sensory receptors for detecting arterial blood oxygen levels, and the identification and elucidation of the roles of hypoxia-inducible factors (HIFs) in oxygen homeostasis have propelled the field of oxygen biology. This review highlights the gas-messenger signaling mechanisms associated with oxygen sensing, as well as transcriptional and non-transcriptional mechanisms underlying the maintenance of oxygen homeostasis by HIFs and their relevance to physiology and pathology.

  17. Sleep Eduction: Treatment & Therapy

    MedlinePlus

    ... Benefits Side Effects Variations Tips Healthy Sleep Habits Sleep Disorders by Category Insomnias Insomnia Child Insomnia Short Sleeper Hypersomnias Narcolepsy Insufficient Sleep Syndrome Long Sleeper Sleep Breathing Disorders Sleep Apnea Snoring Central Sleep Apnea Overview & Facts ...

  18. Sleep Talking (Somniloquy)

    MedlinePlus

    ... Benefits Side Effects Variations Tips Healthy Sleep Habits Sleep Disorders by Category Insomnias Insomnia Child Insomnia Short Sleeper Hypersomnias Narcolepsy Insufficient Sleep Syndrome Long Sleeper Sleep Breathing Disorders Sleep Apnea Snoring Central Sleep Apnea Overview & Facts ...

  19. Sleep Apnea Information Page

    MedlinePlus

    ... is Sleep Apnea? Sleep apnea is a common sleep disorder characterized by brief interruptions of breathing during sleep. ... better ways to prevent, treat, and ultimately cure sleep disorders, such as sleep apnea. NIH Patient Recruitment for ...

  20. Healthy Sleep Habits

    MedlinePlus

    ... Benefits Side Effects Variations Tips Healthy Sleep Habits Sleep Disorders by Category Insomnias Insomnia Child Insomnia Short Sleeper Hypersomnias Narcolepsy Insufficient Sleep Syndrome Long Sleeper Sleep Breathing Disorders Sleep Apnea Snoring Central Sleep Apnea Overview & Facts ...

  1. Percentage of REM sleep is associated with overnight change in leptin.

    PubMed

    Olson, Christy A; Hamilton, Nancy A; Somers, Virend K

    2016-08-01

    Sleep contributes importantly to energy homeostasis, and may impact hormones regulating appetite, such as leptin, an adipocyte-derived hormone. There is increasing evidence that sleep duration, and reduced rapid eye movement sleep, are linked to obesity. Leptin has central neural effects beyond modulation of appetite alone. As sleep is not a unifrom process, interactions between leptin and sleep stages including rapid eye movement sleep may play a role in the relationship between sleep and obesity. This study examined the relationship between serum leptin and rapid eye movement sleep in a sample of healthy adults. Participants were 58 healthy adults who underwent polysomnography. Leptin was measured before and after sleep. It was hypothesized that a lower percentage of rapid eye movement sleep would be related to lower leptin levels during sleep. The relationship between percentage of rapid eye movement sleep and leptin was analysed using hierarchical linear regression. An increased percentage of rapid eye movement sleep was related to a greater reduction in leptin during sleep even when controlling for age, gender, percent body fat and total sleep time. A greater percentage of rapid eye movement sleep was accompanied by more marked reductions in leptin. Studies examining the effects of selective rapid eye movement sleep deprivation on leptin levels, and hence on energy homeostasis in humans, are needed. PMID:26919408

  2. Glycogen metabolism and the homeostatic regulation of sleep.

    PubMed

    Petit, Jean-Marie; Burlet-Godinot, Sophie; Magistretti, Pierre J; Allaman, Igor

    2015-02-01

    In 1995 Benington and Heller formulated an energy hypothesis of sleep centered on a key role of glycogen. It was postulated that a major function of sleep is to replenish glycogen stores in the brain that have been depleted during wakefulness which is associated to an increased energy demand. Astrocytic glycogen depletion participates to an increase of extracellular adenosine release which influences sleep homeostasis. Here, we will review some evidence obtained by studies addressing the question of a key role played by glycogen metabolism in sleep regulation as proposed by this hypothesis or by an alternative hypothesis named "glycogenetic" hypothesis as well as the importance of the confounding effect of glucocorticoïds. Even though actual collected data argue in favor of a role of sleep in brain energy balance-homeostasis, they do not support a critical and direct involvement of glycogen metabolism on sleep regulation. For instance, glycogen levels during the sleep-wake cycle are driven by different physiological signals and therefore appear more as a marker-integrator of brain energy status than a direct regulator of sleep homeostasis. In support of this we provide evidence that blockade of glycogen mobilization does not induce more sleep episodes during the active period while locomotor activity is reduced. These observations do not invalidate the energy hypothesis of sleep but indicate that underlying cellular mechanisms are more complex than postulated by Benington and Heller.

  3. Sleep and olfactory cortical plasticity

    PubMed Central

    Barnes, Dylan C.; Wilson, Donald A.

    2014-01-01

    In many systems, sleep plays a vital role in memory consolidation and synaptic homeostasis. These processes together help store information of biological significance and reset synaptic circuits to facilitate acquisition of information in the future. In this review, we describe recent evidence of sleep-dependent changes in olfactory system structure and function which contribute to odor memory and perception. During slow-wave sleep, the piriform cortex becomes hypo-responsive to odor stimulation and instead displays sharp-wave activity similar to that observed within the hippocampal formation. Furthermore, the functional connectivity between the piriform cortex and other cortical and limbic regions is enhanced during slow-wave sleep compared to waking. This combination of conditions may allow odor memory consolidation to occur during a state of reduced external interference and facilitate association of odor memories with stored hedonic and contextual cues. Evidence consistent with sleep-dependent odor replay within olfactory cortical circuits is presented. These data suggest that both the strength and precision of odor memories is sleep-dependent. The work further emphasizes the critical role of synaptic plasticity and memory in not only odor memory but also basic odor perception. The work also suggests a possible link between sleep disturbances that are frequently co-morbid with a wide range of pathologies including Alzheimer’s disease, schizophrenia and depression and the known olfactory impairments associated with those disorders. PMID:24795585

  4. Pathophysiology of Sleep Apnea

    PubMed Central

    Veasey, Sigrid C.; Morgan, Barbara J.; O'Donnell, Christopher P.

    2010-01-01

    Sleep-induced apnea and disordered breathing refers to intermittent, cyclical cessations or reductions of airflow, with or without obstructions of the upper airway (OSA). In the presence of an anatomically compromised, collapsible airway, the sleep-induced loss of compensatory tonic input to the upper airway dilator muscle motor neurons leads to collapse of the pharyngeal airway. In turn, the ability of the sleeping subject to compensate for this airway obstruction will determine the degree of cycling of these events. Several of the classic neurotransmitters and a growing list of neuromodulators have now been identified that contribute to neurochemical regulation of pharyngeal motor neuron activity and airway patency. Limited progress has been made in developing pharmacotherapies with acceptable specificity for the treatment of sleep-induced airway obstruction. We review three types of major long-term sequelae to severe OSA that have been assessed in humans through use of continuous positive airway pressure (CPAP) treatment and in animal models via long-term intermittent hypoxemia (IH): 1) cardiovascular. The evidence is strongest to support daytime systemic hypertension as a consequence of severe OSA, with less conclusive effects on pulmonary hypertension, stroke, coronary artery disease, and cardiac arrhythmias. The underlying mechanisms mediating hypertension include enhanced chemoreceptor sensitivity causing excessive daytime sympathetic vasoconstrictor activity, combined with overproduction of superoxide ion and inflammatory effects on resistance vessels. 2) Insulin sensitivity and homeostasis of glucose regulation are negatively impacted by both intermittent hypoxemia and sleep disruption, but whether these influences of OSA are sufficient, independent of obesity, to contribute significantly to the “metabolic syndrome” remains unsettled. 3) Neurocognitive effects include daytime sleepiness and impaired memory and concentration. These effects reflect

  5. Sleep Apnea

    MedlinePlus

    Sleep apnea is a common disorder that causes your breathing to stop or get very shallow. Breathing ... an hour. The most common type is obstructive sleep apnea. It causes your airway to collapse or ...

  6. Role of sleep quality in the metabolic syndrome

    PubMed Central

    Koren, Dorit; Dumin, Magdalena; Gozal, David

    2016-01-01

    Emerging evidence has assigned an important role to sleep as a modulator of metabolic homeostasis. The impact of variations in sleep duration, sleep-disordered breathing, and chronotype to cardiometabolic function encompasses a wide array of perturbations spanning from obesity, insulin resistance, type 2 diabetes, the metabolic syndrome, and cardiovascular disease risk and mortality in both adults and children. Here, we critically and extensively review the published literature on such important issues and provide a comprehensive overview of the most salient pathophysiologic pathways underlying the links between sleep, sleep disorders, and cardiometabolic functioning.

  7. Role of sleep quality in the metabolic syndrome

    PubMed Central

    Koren, Dorit; Dumin, Magdalena; Gozal, David

    2016-01-01

    Emerging evidence has assigned an important role to sleep as a modulator of metabolic homeostasis. The impact of variations in sleep duration, sleep-disordered breathing, and chronotype to cardiometabolic function encompasses a wide array of perturbations spanning from obesity, insulin resistance, type 2 diabetes, the metabolic syndrome, and cardiovascular disease risk and mortality in both adults and children. Here, we critically and extensively review the published literature on such important issues and provide a comprehensive overview of the most salient pathophysiologic pathways underlying the links between sleep, sleep disorders, and cardiometabolic functioning. PMID:27601926

  8. Role of sleep quality in the metabolic syndrome.

    PubMed

    Koren, Dorit; Dumin, Magdalena; Gozal, David

    2016-01-01

    Emerging evidence has assigned an important role to sleep as a modulator of metabolic homeostasis. The impact of variations in sleep duration, sleep-disordered breathing, and chronotype to cardiometabolic function encompasses a wide array of perturbations spanning from obesity, insulin resistance, type 2 diabetes, the metabolic syndrome, and cardiovascular disease risk and mortality in both adults and children. Here, we critically and extensively review the published literature on such important issues and provide a comprehensive overview of the most salient pathophysiologic pathways underlying the links between sleep, sleep disorders, and cardiometabolic functioning. PMID:27601926

  9. Effects of CPAP-therapy on brain electrical activity in obstructive sleep apneic patients: a combined EEG study using LORETA and Omega complexity : reversible alterations of brain activity in OSAS.

    PubMed

    Toth, Marton; Faludi, Bela; Kondakor, Istvan

    2012-10-01

    Effects of initiation of continuous positive airway pressure (CPAP) therapy on EEG background activity were investigated in patients with obstructive sleep apnea syndrome (OSAS, N = 25) to test possible reversibility of alterations of brain electrical activity caused by chronic hypoxia. Normal control group (N = 14) was also examined. Two EEG examinations were done in each groups: at night and in the next morning. Global and regional (left vs. right, anterior vs. posterior) measures of spatial complexity (Omega complexity) were used to characterize the degree of spatial synchrony of EEG. Low resolution electromagnetic tomography (LORETA) was used to localize generators of EEG activity in separate frequency bands. Before CPAP-treatment, a significantly lower Omega complexity was found globally and over the right hemisphere. Due to CPAP-treatment, these significant differences vanished. Significantly decreased Omega complexity was found in the anterior region after treatment. LORETA showed a decreased activity in all of the beta bands after therapy in the right hippocampus, premotor and temporo-parietal cortex, and bilaterally in the precuneus, paracentral and posterior cingulate cortex. No significant changes were seen in control group. Comparing controls and patients before sleep, an increased alpha2 band activity was seen bilaterally in the precuneus, paracentral and posterior cingulate cortex, while in the morning an increased beta3 band activity in the left precentral and bilateral premotor cortex and a decreased delta band activity in the right temporo-parietal cortex and insula were observed. These findings indicate that effect of sleep on EEG background activity is different in OSAS patients and normal controls. In OSAS patients, significant changes lead to a more normal EEG after a night under CPAP-treatment. Compensatory alterations of brain electrical activity in regions associated with influencing sympathetic outflow, visuospatial abilities, long

  10. Graph Theoretical Analysis of BOLD Functional Connectivity during Human Sleep without EEG Monitoring

    PubMed Central

    Lv, Jun; Liu, Dongdong; Ma, Jing; Wang, Xiaoying; Zhang, Jue

    2015-01-01

    Background Functional brain networks of human have been revealed to have small-world properties by both analyzing electroencephalogram (EEG) and functional magnetic resonance imaging (fMRI) time series. Methods & Results In our study, by using graph theoretical analysis, we attempted to investigate the changes of paralimbic-limbic cortex between wake and sleep states. Ten healthy young people were recruited to our experiment. Data from 2 subjects were excluded for the reason that they had not fallen asleep during the experiment. For each subject, blood oxygen level dependency (BOLD) images were acquired to analyze brain network, and peripheral pulse signals were obtained continuously to identify if the subject was in sleep periods. Results of fMRI showed that brain networks exhibited stronger small-world characteristics during sleep state as compared to wake state, which was in consistent with previous studies using EEG synchronization. Moreover, we observed that compared with wake state, paralimbic-limbic cortex had less connectivity with neocortical system and centrencephalic structure in sleep. Conclusions In conclusion, this is the first study, to our knowledge, has observed that small-world properties of brain functional networks altered when human sleeps without EEG synchronization. Moreover, we speculate that paralimbic-limbic cortex organization owns an efficient defense mechanism responsible for suppressing the external environment interference when humans sleep, which is consistent with the hypothesis that the paralimbic-limbic cortex may be functionally disconnected from brain regions which directly mediate their interactions with the external environment. Our findings also provide a reasonable explanation why stable sleep exhibits homeostasis which is far less susceptible to outside world. PMID:26360464

  11. The role of sleep in bipolar disorder.

    PubMed

    Gold, Alexandra K; Sylvia, Louisa G

    2016-01-01

    Bipolar disorder is a serious mental illness characterized by alternating periods of elevated and depressed mood. Sleep disturbances in bipolar disorder are present during all stages of the condition and exert a negative impact on overall course, quality of life, and treatment outcomes. We examine the partnership between circadian system (process C) functioning and sleep-wake homeostasis (process S) on optimal sleep functioning and explore the role of disruptions in both systems on sleep disturbances in bipolar disorder. A convergence of evidence suggests that sleep problems in bipolar disorder result from dysregulation across both process C and process S systems. Biomarkers of depressive episodes include heightened fragmentation of rapid eye movement (REM) sleep, reduced REM latency, increased REM density, and a greater percentage of awakenings, while biomarkers of manic episodes include reduced REM latency, greater percentage of stage I sleep, increased REM density, discontinuous sleep patterns, shortened total sleep time, and a greater time awake in bed. These findings highlight the importance of targeting novel treatments for sleep disturbance in bipolar disorder. PMID:27418862

  12. The role of sleep in bipolar disorder.

    PubMed

    Gold, Alexandra K; Sylvia, Louisa G

    2016-01-01

    Bipolar disorder is a serious mental illness characterized by alternating periods of elevated and depressed mood. Sleep disturbances in bipolar disorder are present during all stages of the condition and exert a negative impact on overall course, quality of life, and treatment outcomes. We examine the partnership between circadian system (process C) functioning and sleep-wake homeostasis (process S) on optimal sleep functioning and explore the role of disruptions in both systems on sleep disturbances in bipolar disorder. A convergence of evidence suggests that sleep problems in bipolar disorder result from dysregulation across both process C and process S systems. Biomarkers of depressive episodes include heightened fragmentation of rapid eye movement (REM) sleep, reduced REM latency, increased REM density, and a greater percentage of awakenings, while biomarkers of manic episodes include reduced REM latency, greater percentage of stage I sleep, increased REM density, discontinuous sleep patterns, shortened total sleep time, and a greater time awake in bed. These findings highlight the importance of targeting novel treatments for sleep disturbance in bipolar disorder.

  13. Sleep disorder or simple sleep ontogeny? Tendency for morningness is associated with worse sleep quality in the elderly

    PubMed Central

    Barbosa, A.A.; Miguel, M.A.L.; Tufik, S.; Sabino, F.C.; Cendoroglo, M.S.; Pedrazzoli, M.

    2016-01-01

    The objective of this study was to evaluate the alterations in sleep and circadian parameters during the aging process. The study sample comprises volunteers older than 18 up to 90 years of age that answered the Pittsburgh Sleep Quality Index (PSQI) and the Horne and Östberg circadian preference questionnaire. We observed that the shift to morningness with increasing age is associated with a significant worsening in sleep quality. We discuss that this sleep profile characterized by morningness and worse sleep quality observed in elderly, when compared to younger people, reflects not necessarily a pathological state, but an expected profile for this age group. PMID:27737315

  14. The Neurobiological Mechanisms and Treatments of REM Sleep Disturbances in Depression

    PubMed Central

    Wang, Yi-Qun; Li, Rui; Zhang, Meng-Qi; Zhang, Ze; Qu, Wei-Min; Huang, Zhi-Li

    2015-01-01

    Most depressed patients suffer from sleep abnormalities, which are one of the critical symptoms of depression. They are robust risk factors for the initiation and development of depression. Studies about sleep electroencephalograms have shown characteristic changes in depression such as reductions in non-rapid eye movement sleep production, disruptions of sleep continuity and disinhibition of rapid eye movement (REM) sleep. REM sleep alterations include a decrease in REM sleep latency, an increase in REM sleep duration and REM sleep density with respect to depressive episodes. Emotional brain processing dependent on the normal sleep-wake regulation seems to be failed in depression, which also promotes the development of clinical depression. Also, REM sleep alterations have been considered as biomarkers of depression. The disturbances of norepinephrine and serotonin systems may contribute to REM sleep abnormalities in depression. Lastly, this review also discusses the effects of different antidepressants on REM sleep disturbances in depression. PMID:26412074

  15. The Neurobiological Mechanisms and Treatments of REM Sleep Disturbances in Depression.

    PubMed

    Wang, Yi-Qun; Li, Rui; Zhang, Meng-Qi; Zhang, Ze; Qu, Wei-Min; Huang, Zhi-Li

    2015-01-01

    Most depressed patients suffer from sleep abnormalities, which are one of the critical symptoms of depression. They are robust risk factors for the initiation and development of depression. Studies about sleep electroencephalograms have shown characteristic changes in depression such as reductions in non-rapid eye movement sleep production, disruptions of sleep continuity and disinhibition of rapid eye movement (REM) sleep. REM sleep alterations include a decrease in REM sleep latency, an increase in REM sleep duration and REM sleep density with respect to depressive episodes. Emotional brain processing dependent on the normal sleep-wake regulation seems to be failed in depression, which also promotes the development of clinical depression. Also, REM sleep alterations have been considered as biomarkers of depression. The disturbances of norepinephrine and serotonin systems may contribute to REM sleep abnormalities in depression. Lastly, this review also discusses the effects of different antidepressants on REM sleep disturbances in depression.

  16. Operation of a homeostatic sleep switch.

    PubMed

    Pimentel, Diogo; Donlea, Jeffrey M; Talbot, Clifford B; Song, Seoho M; Thurston, Alexander J F; Miesenböck, Gero

    2016-08-18

    Sleep disconnects animals from the external world, at considerable risks and costs that must be offset by a vital benefit. Insight into this mysterious benefit will come from understanding sleep homeostasis: to monitor sleep need, an internal bookkeeper must track physiological changes that are linked to the core function of sleep. In Drosophila, a crucial component of the machinery for sleep homeostasis is a cluster of neurons innervating the dorsal fan-shaped body (dFB) of the central complex. Artificial activation of these cells induces sleep, whereas reductions in excitability cause insomnia. dFB neurons in sleep-deprived flies tend to be electrically active, with high input resistances and long membrane time constants, while neurons in rested flies tend to be electrically silent. Correlative evidence thus supports the simple view that homeostatic sleep control works by switching sleep-promoting neurons between active and quiescent states. Here we demonstrate state switching by dFB neurons, identify dopamine as a neuromodulator that operates the switch, and delineate the switching mechanism. Arousing dopamine caused transient hyperpolarization of dFB neurons within tens of milliseconds and lasting excitability suppression within minutes. Both effects were transduced by Dop1R2 receptors and mediated by potassium conductances. The switch to electrical silence involved the downregulation of voltage-gated A-type currents carried by Shaker and Shab, and the upregulation of voltage-independent leak currents through a two-pore-domain potassium channel that we term Sandman. Sandman is encoded by the CG8713 gene and translocates to the plasma membrane in response to dopamine. dFB-restricted interference with the expression of Shaker or Sandman decreased or increased sleep, respectively, by slowing the repetitive discharge of dFB neurons in the ON state or blocking their entry into the OFF state. Biophysical changes in a small population of neurons are thus linked to the

  17. Operation of a homeostatic sleep switch.

    PubMed

    Pimentel, Diogo; Donlea, Jeffrey M; Talbot, Clifford B; Song, Seoho M; Thurston, Alexander J F; Miesenböck, Gero

    2016-08-18

    Sleep disconnects animals from the external world, at considerable risks and costs that must be offset by a vital benefit. Insight into this mysterious benefit will come from understanding sleep homeostasis: to monitor sleep need, an internal bookkeeper must track physiological changes that are linked to the core function of sleep. In Drosophila, a crucial component of the machinery for sleep homeostasis is a cluster of neurons innervating the dorsal fan-shaped body (dFB) of the central complex. Artificial activation of these cells induces sleep, whereas reductions in excitability cause insomnia. dFB neurons in sleep-deprived flies tend to be electrically active, with high input resistances and long membrane time constants, while neurons in rested flies tend to be electrically silent. Correlative evidence thus supports the simple view that homeostatic sleep control works by switching sleep-promoting neurons between active and quiescent states. Here we demonstrate state switching by dFB neurons, identify dopamine as a neuromodulator that operates the switch, and delineate the switching mechanism. Arousing dopamine caused transient hyperpolarization of dFB neurons within tens of milliseconds and lasting excitability suppression within minutes. Both effects were transduced by Dop1R2 receptors and mediated by potassium conductances. The switch to electrical silence involved the downregulation of voltage-gated A-type currents carried by Shaker and Shab, and the upregulation of voltage-independent leak currents through a two-pore-domain potassium channel that we term Sandman. Sandman is encoded by the CG8713 gene and translocates to the plasma membrane in response to dopamine. dFB-restricted interference with the expression of Shaker or Sandman decreased or increased sleep, respectively, by slowing the repetitive discharge of dFB neurons in the ON state or blocking their entry into the OFF state. Biophysical changes in a small population of neurons are thus linked to the

  18. Oxygen sensing and metabolic homeostasis.

    PubMed

    Palmer, Biff F; Clegg, Deborah J

    2014-11-01

    Oxygen-sensing mechanisms have evolved to maintain cell and tissue homeostasis since the ability to sense and respond to changes in oxygen is essential for survival. The primary site of oxygen sensing occurs at the level of the carotid body which in response to hypoxia signals increased ventilation without the need for new protein synthesis. Chronic hypoxia activates cellular sensing mechanisms which lead to protein synthesis designed to alter cellular metabolism so cells can adapt to the low oxygen environment without suffering toxicity. The master regulator of the cellular response is hypoxia-inducible factor (HIF). Activation of this system under condition of hypobaric hypoxia leads to weight loss accompanied by increased basal metabolic rate and suppression of appetite. These effects are dose dependent, gender and genetic specific, and results in adverse effects if the exposure is extreme. Hypoxic adipose tissue may represent a unified cellular mechanism for variety of metabolic disorders, and insulin resistance in patients with metabolic syndrome.

  19. [Sleep disorders in dementia patients].

    PubMed

    Savaskan, E

    2015-06-01

    Dementia is characterized by cognitive and also behavioral and psychological symptoms of dementia (BPSD). The most prominent BPSD are depression and apathy but sleep disorders also complicate the clinical course of dementia. These symptoms are a severe burden for patients and caregivers and are difficult to treat partly due to comorbidities. Common sleep disorders in dementia are insomnia, hypersomnia, circadian rhythm alterations and aberrant nocturnal motor behavior. Sleep duration and rapid eye movement (REM) sleep are reduced. The diagnostic assessment of sleep disorders should include an evaluation of the underlying risk factors and a detailed sleep history for which several assessment instruments are available. The therapy of sleep disorders of dementia is primarily nonpharmacological: sleep counseling, sleep hygiene regulation, relaxation and psychotherapy techniques are given priority. Pharmacological treatment often has severe side effects in this elderly, vulnerable population and can only be considered if other nonpharmacological options have been unsuccessful. The application of medication should be limited in time and dosage. The pharmacological therapeutic options are critically discussed in detail.

  20. Altered Electroencephalographic Activity Associated with Changes in the Sleep-Wakefulness Cycle of C57BL/6J Mice in Response to a Photoperiod Shortening

    PubMed Central

    Rozov, Stanislav V.; Zant, Janneke C.; Gurevicius, Kestutis; Porkka-Heiskanen, Tarja; Panula, Pertti

    2016-01-01

    Aim: Under natural conditions diurnal rhythms of biological processes of the organism are synchronized with each other and to the environmental changes by means of the circadian system. Disturbances of the latter affect hormonal levels, sleep-wakefulness cycle and cognitive performance. To study mechanisms of such perturbations animal models subjected to artificial photoperiods are often used. The goal of current study was to understand the effects of circadian rhythm disruption, caused by a short light-dark cycle regime, on activity of the cerebral cortex in rodents. Methods: We used electroencephalogram to assess the distribution of vigilance states, perform spectral analysis, and estimate the homeostatic sleep drive. In addition, we analyzed spontaneous locomotion of C57BL/6J mice under symmetric, 22-, 21-, and 20-h-long light–dark cycles using video recording and tracking methods. Results and Conclusions: We found that shortening of photoperiod caused a significant increase of slow wave activity during non-rapid eye movement sleep suggesting an elevation of sleep pressure under such conditions. While the rhythm of spontaneous locomotion was completely entrained by all light–dark cycles tested, periodic changes in the power of the θ- and γ-frequency ranges during wakefulness gradually disappeared under 22- and 21-h-long light–dark cycles. This was associated with a significant increase in the θ–γ phase-amplitude coupling during wakefulness. Our results thus provide deeper understanding of the mechanisms underlying the impairment of learning and memory retention, which is associated with disturbed circadian regulation.

  1. Altered Electroencephalographic Activity Associated with Changes in the Sleep-Wakefulness Cycle of C57BL/6J Mice in Response to a Photoperiod Shortening

    PubMed Central

    Rozov, Stanislav V.; Zant, Janneke C.; Gurevicius, Kestutis; Porkka-Heiskanen, Tarja; Panula, Pertti

    2016-01-01

    Aim: Under natural conditions diurnal rhythms of biological processes of the organism are synchronized with each other and to the environmental changes by means of the circadian system. Disturbances of the latter affect hormonal levels, sleep-wakefulness cycle and cognitive performance. To study mechanisms of such perturbations animal models subjected to artificial photoperiods are often used. The goal of current study was to understand the effects of circadian rhythm disruption, caused by a short light-dark cycle regime, on activity of the cerebral cortex in rodents. Methods: We used electroencephalogram to assess the distribution of vigilance states, perform spectral analysis, and estimate the homeostatic sleep drive. In addition, we analyzed spontaneous locomotion of C57BL/6J mice under symmetric, 22-, 21-, and 20-h-long light–dark cycles using video recording and tracking methods. Results and Conclusions: We found that shortening of photoperiod caused a significant increase of slow wave activity during non-rapid eye movement sleep suggesting an elevation of sleep pressure under such conditions. While the rhythm of spontaneous locomotion was completely entrained by all light–dark cycles tested, periodic changes in the power of the θ- and γ-frequency ranges during wakefulness gradually disappeared under 22- and 21-h-long light–dark cycles. This was associated with a significant increase in the θ–γ phase-amplitude coupling during wakefulness. Our results thus provide deeper understanding of the mechanisms underlying the impairment of learning and memory retention, which is associated with disturbed circadian regulation. PMID:27630549

  2. Sleep Spindles Characteristics in Insomnia Sufferers and Their Relationship with Sleep Misperception.

    PubMed

    Normand, Marie-Pier; St-Hilaire, Patrick; Bastien, Célyne H

    2016-01-01

    Cortical hyperarousal is higher in insomnia sufferers (INS) than in good sleepers (GS) and could be related to an alteration in sleep protection mechanisms, like reduced density or altered characteristics in sleep spindles. The deficient sleep protection mechanisms might in turn enhance underestimation of sleep. This study's objective was to document sleep spindles characteristics in INS compared with GS and to investigate their potential role in sleep consolidation and misperception. Seventeen individuals with paradoxical insomnia (PARA-I), 24 individuals with psychophysiological insomnia (PSY-I), and 29 GS completed four consecutive polysomnographic nights in laboratory. Sleep spindles were detected automatically during stage 2 and SWS (3-4) on night 3. Number, density, duration, frequency, and amplitude of sleep spindles were calculated. A misperception index was used to determine the degree of discrepancy between subjective and objective total sleep times. Kruskal-Wallis H tests and post hoc tests revealed that PARA-I had significantly shorter sleep spindles than GS but that PSY-I and GS did not differ on spindles length. A standard multiple regression model revealed that neither sleep spindles characteristics nor objective sleep measures were predictive of sleep misperception. A longer duration of spindles could reflect a higher gating process but this hypothesis still needs to be confirmed in replication studies. PMID:27478648

  3. Sleep Spindles Characteristics in Insomnia Sufferers and Their Relationship with Sleep Misperception

    PubMed Central

    2016-01-01

    Cortical hyperarousal is higher in insomnia sufferers (INS) than in good sleepers (GS) and could be related to an alteration in sleep protection mechanisms, like reduced density or altered characteristics in sleep spindles. The deficient sleep protection mechanisms might in turn enhance underestimation of sleep. This study's objective was to document sleep spindles characteristics in INS compared with GS and to investigate their potential role in sleep consolidation and misperception. Seventeen individuals with paradoxical insomnia (PARA-I), 24 individuals with psychophysiological insomnia (PSY-I), and 29 GS completed four consecutive polysomnographic nights in laboratory. Sleep spindles were detected automatically during stage 2 and SWS (3-4) on night 3. Number, density, duration, frequency, and amplitude of sleep spindles were calculated. A misperception index was used to determine the degree of discrepancy between subjective and objective total sleep times. Kruskal-Wallis H tests and post hoc tests revealed that PARA-I had significantly shorter sleep spindles than GS but that PSY-I and GS did not differ on spindles length. A standard multiple regression model revealed that neither sleep spindles characteristics nor objective sleep measures were predictive of sleep misperception. A longer duration of spindles could reflect a higher gating process but this hypothesis still needs to be confirmed in replication studies. PMID:27478648

  4. Sleep and Epilepsy: Strange Bedfellows No More.

    PubMed

    St Louis, Erik K

    2011-09-01

    Ancient philosophers and theologians believed that altered consciousness freed the mind to prophesy the future, equating sleep with seizures. Only recently has the bidirectional influences of epilepsy and sleep upon one another received more substantive analysis. This article reviews the complex and increasingly recognized interrelationships between sleep and epilepsy. NREM sleep differentially activates interictal epileptiform discharges during slow wave (N3) sleep, while ictal seizure events occur more frequently during light NREM stages N1 and N2. The most commonly encountered types of sleep-related epilepsies (those with preferential occurrence during sleep or following arousal) include frontal and temporal lobe partial epilepsies in adults, and benign epilepsy of childhood with centrotemporal spikes (benign rolandic epilepsy) and juvenile myoclonic epilepsy in children and adolescents. Comorbid sleep disorders are frequent in patients with epilepsy, particularly obstructive sleep apnea in refractory epilepsy patients which may aggravate seizure burden, while treatment with nasal continuous positive airway pressure often improves seizure frequency. Distinguishing nocturnal events such as NREM parasomnias (confusional arousals, sleep walking, and night terrors), REM parasomnias including REM sleep behavior disorder, and nocturnal seizures if frequently difficult and benefits from careful history taking and video-EEG-polysomnography in selected cases. Differentiating nocturnal seizures from primary sleep disorders is essential for determining appropriate therapy, and recognizing co-existent sleep disorders in patients with epilepsy may improve their seizure burden and quality of life. PMID:23539488

  5. Neurobiological linkage between stress and sleep

    NASA Astrophysics Data System (ADS)

    Sanford, Larry D.; Wellman, Laurie L.

    2012-10-01

    Stress can have a significant negative impact on health and stress-induced alterations in sleep are implicated in both human sleep disorders and in psychiatric disorders in which sleep is affected. We have demonstrated that the amygdala, a region critical for regulating emotion, is a key modulator of sleep. Our current research is focused on understanding how the amygdala and stressful emotion affect sleep and on the role sleep plays in recovery from stress. We have implemented animal models to examine the how stress and stress-related memories impact sleep. Experiencing uncontrollable stress and reminders of uncontrollable stress can produce significant reductions in sleep, in particular rapid eye movement sleep. We are using these models to explore the neurobiology linking stress-related emotion and sleep. This research is relevant for sleep disorders such as insomnia and into mental disorders in which sleep is affected such as post-traumatic stress disorder (PTSD), which is typically characterized by a prominent sleep disturbance in the aftermath of exposure to a psychologically traumatic event.

  6. Sleep and Respiration in Microgravity

    NASA Technical Reports Server (NTRS)

    West, John B.; Elliott, Ann R.; Prisk, G. Kim; Paiva, Manuel

    2003-01-01

    Sleep is often reported to be of poor quality in microgravity, and studies on the ground have shown a strong relationship between sleep-disordered breathing and sleep disruption. During the 16-day Neurolab mission, we studied the influence of possible changes in respiratory function on sleep by performing comprehensive sleep recordings on the payload crew on four nights during the mission. In addition, we measured the changes in the ventilatory response to low oxygen and high carbon dioxide in the same subjects during the day, hypothesizing that changes in ventilatory control might affect respiration during sleep. Microgravity caused a large reduction in the ventilatory response to reduced oxygen. This is likely the result of an increase in blood pressure at the peripheral chemoreceptors in the neck that occurs when the normally present hydrostatic pressure gradient between the heart and upper body is abolished. This reduction was similar to that seen when the subjects were placed acutely in the supine position in one-G. In sharp contrast to low oxygen, the ventilatory response to elevated carbon dioxide was unaltered by microgravity or the supine position. Because of the similarities of the findings in microgravity and the supine position, it is unlikely that changes in ventilatory control alter respiration during sleep in microgravity. During sleep on the ground, there were a small number of apneas (cessation of breathing) and hypopneas (reduced breathing) in these normal subjects. During sleep in microgravity, there was a reduction in the number of apneas and hypopneas per hour compared to preflight. Obstructive apneas virtually disappeared in microgravity, suggesting that the removal of gravity prevents the collapse of upper airways during sleep. Arousals from sleep were reduced in microgravity compared to preflight, and virtually all of this reduction was as a result of a reduction in the number of arousals from apneas and hypopneas. We conclude that any sleep

  7. Mammalian sleep

    NASA Astrophysics Data System (ADS)

    Staunton, Hugh

    2005-05-01

    This review examines the biological background to the development of ideas on rapid eye movement sleep (REM sleep), so-called paradoxical sleep (PS), and its relation to dreaming. Aspects of the phenomenon which are discussed include physiological changes and their anatomical location, the effects of total and selective sleep deprivation in the human and animal, and REM sleep behavior disorder, the latter with its clinical manifestations in the human. Although dreaming also occurs in other sleep phases (non-REM or NREM sleep), in the human, there is a contingent relation between REM sleep and dreaming. Thus, REM is taken as a marker for dreaming and as REM is distributed ubiquitously throughout the mammalian class, it is suggested that other mammals also dream. It is suggested that the overall function of REM sleep/dreaming is more important than the content of the individual dream; its function is to place the dreamer protagonist/observer on the topographical world. This has importance for the developing infant who needs to develop a sense of self and separateness from the world which it requires to navigate and from which it is separated for long periods in sleep. Dreaming may also serve to maintain a sense of ‘I’ness or “self” in the adult, in whom a fragility of this faculty is revealed in neurological disorders.

  8. Total sleep deprivation, chronic sleep restriction and sleep disruption.

    PubMed

    Reynolds, Amy C; Banks, Siobhan

    2010-01-01

    Sleep loss may result from total sleep deprivation (such as a shift worker might experience), chronic sleep restriction (due to work, medical conditions or lifestyle) or sleep disruption (which is common in sleep disorders such as sleep apnea or restless legs syndrome). Total sleep deprivation has been widely researched, and its effects have been well described. Chronic sleep restriction and sleep disruption (also known as sleep fragmentation) have received less experimental attention. Recently, there has been increasing interest in sleep restriction and disruption as it has been recognized that they have a similar impact on cognitive functioning as a period of total sleep deprivation. Sleep loss causes impairments in cognitive performance and simulated driving and induces sleepiness, fatigue and mood changes. This review examines recent research on the effects of sleep deprivation, restriction and disruption on cognition and neurophysiologic functioning in healthy adults, and contrasts the similarities and differences between these three modalities of sleep loss.

  9. Loss of promoter IV-driven BDNF expression impacts oscillatory activity during sleep, sensory information processing and fear regulation

    PubMed Central

    Hill, J L; Hardy, N F; Jimenez, D V; Maynard, K R; Kardian, A S; Pollock, C J; Schloesser, R J; Martinowich, K

    2016-01-01

    Posttraumatic stress disorder is characterized by hyperarousal, sensory processing impairments, sleep disturbances and altered fear regulation; phenotypes associated with changes in brain oscillatory activity. Molecules associated with activity-dependent plasticity, including brain-derived neurotrophic factor (BDNF), may regulate neural oscillations by controlling synaptic activity. BDNF synthesis includes production of multiple Bdnf transcripts, which contain distinct 5′ noncoding exons. We assessed arousal, sensory processing, fear regulation and sleep in animals where BDNF expression from activity-dependent promoter IV is disrupted (Bdnf-e4 mice). Bdnf-e4 mice display sensory hyper-reactivity and impaired electrophysiological correlates of sensory information processing as measured by event-related potentials (ERP). Utilizing electroencephalogram, we identified a decrease in slow-wave activity during non-rapid eye movement sleep, suggesting impaired sleep homeostasis. Fear extinction is controlled by hippocampal–prefrontal cortical BDNF signaling, and neurophysiological communication patterns between the hippocampus (HPC) and medial prefrontal cortex (mPFC) correlate with behavioral performance during extinction. Impaired fear extinction in Bdnf-e4 mice is accompanied by increased HPC activation and decreased HPC–mPFC theta phase synchrony during early extinction, as well as increased mPFC activation during extinction recall. These results suggest that activity-dependent BDNF signaling is critical for regulating oscillatory activity, which may contribute to altered behavior. PMID:27552586

  10. Loss of promoter IV-driven BDNF expression impacts oscillatory activity during sleep, sensory information processing and fear regulation.

    PubMed

    Hill, J L; Hardy, N F; Jimenez, D V; Maynard, K R; Kardian, A S; Pollock, C J; Schloesser, R J; Martinowich, K

    2016-01-01

    Posttraumatic stress disorder is characterized by hyperarousal, sensory processing impairments, sleep disturbances and altered fear regulation; phenotypes associated with changes in brain oscillatory activity. Molecules associated with activity-dependent plasticity, including brain-derived neurotrophic factor (BDNF), may regulate neural oscillations by controlling synaptic activity. BDNF synthesis includes production of multiple Bdnf transcripts, which contain distinct 5' noncoding exons. We assessed arousal, sensory processing, fear regulation and sleep in animals where BDNF expression from activity-dependent promoter IV is disrupted (Bdnf-e4 mice). Bdnf-e4 mice display sensory hyper-reactivity and impaired electrophysiological correlates of sensory information processing as measured by event-related potentials (ERP). Utilizing electroencephalogram, we identified a decrease in slow-wave activity during non-rapid eye movement sleep, suggesting impaired sleep homeostasis. Fear extinction is controlled by hippocampal-prefrontal cortical BDNF signaling, and neurophysiological communication patterns between the hippocampus (HPC) and medial prefrontal cortex (mPFC) correlate with behavioral performance during extinction. Impaired fear extinction in Bdnf-e4 mice is accompanied by increased HPC activation and decreased HPC-mPFC theta phase synchrony during early extinction, as well as increased mPFC activation during extinction recall. These results suggest that activity-dependent BDNF signaling is critical for regulating oscillatory activity, which may contribute to altered behavior. PMID:27552586

  11. Changing your sleep habits

    MedlinePlus

    Insomnia - sleep habits; Sleep disorder - sleep habits; Problems falling asleep; Sleep hygiene ... Philadelphia, PA: Elsevier; 2017:chap 86. Vaughn BV. Disorders of sleep. In: Goldman L, Schafer AI, eds. Goldman's Cecil ...

  12. Sleep disorders - overview

    MedlinePlus

    Insomnia; Narcolepsy; Hypersomina; Daytime sleepiness; Sleep rhythm; Sleep disruptive behaviors; Jet lag ... excessive daytime sleepiness) Problems sticking to a regular sleep schedule (sleep rhythm problem) Unusual behaviors during sleep ( ...

  13. Sleep-disordered breathing, type 2 diabetes and the metabolic syndrome.

    PubMed

    Seetho, Ian W; Wilding, John P H

    2014-11-01

    Sleep-disordered breathing (SDB) encompasses a spectrum of conditions that can lead to altered sleep homeostasis. In particular, obstructive sleep apnoea (OSA) is the most common form of SDB and is associated with adverse cardiometabolic manifestations including hypertension, metabolic syndrome and type 2 diabetes, ultimately increasing the risk of cardiovascular disease. The pathophysiological basis of these associations may relate to repeated intermittent hypoxia and fragmented sleep episodes that characterize OSA which drive further mechanisms with adverse metabolic and cardiovascular consequences. The associations of OSA with type 2 diabetes and the metabolic syndrome have been described in studies ranging from epidemiological and observational studies to controlled trials investigating the effects of OSA therapy with continuous positive airway pressure (CPAP). In recent years, there have been rising prevalence rates of diabetes and obesity worldwide. Given the established links between SDB (in particular OSA) with both conditions, understanding the potential influence of OSA on the components of the metabolic syndrome and diabetes and the underlying mechanisms by which such interactions may contribute to metabolic dysregulation are important in order to effectively and holistically manage patients with SDB, type 2 diabetes or the metabolic syndrome. In this article, we review the literature describing the associations, the possible underlying pathophysiological mechanisms linking these conditions and the effects of interventions including CPAP treatment and weight loss.

  14. Brain iron homeostasis.

    PubMed

    Moos, Torben

    2002-11-01

    Iron is essential for virtually all types of cells and organisms. The significance of the iron for brain function is reflected by the presence of receptors for transferrin on brain capillary endothelial cells. The transport of iron into the brain from the circulation is regulated so that the extraction of iron by brain capillary endothelial cells is low in iron-replete conditions and the reverse when the iron need of the brain is high as in conditions with iron deficiency and during development of the brain. Whereas there is good agreement that iron is taken up by means of receptor-mediated uptake of iron-transferrin at the brain barriers, there are contradictory views on how iron is transported further on from the brain barriers and into the brain extracellular space. The prevailing hypothesis for transport of iron across the BBB suggests a mechanism that involves detachment of iron from transferrin within barrier cells followed by recycling of apo-transferrin to blood plasma and release of iron as non-transferrin-bound iron into the brain interstitium from where the iron is taken up by neurons and glial cells. Another hypothesis claims that iron-transferrin is transported into the brain by means of transcytosis through the BBB. This thesis deals with the topic "brain iron homeostasis" defined as the attempts to maintain constant concentrations of iron in the brain internal environment via regulation of iron transport through brain barriers, cellular iron uptake by neurons and glia, and export of iron from brain to blood. The first part deals with transport of iron-transferrin complexes from blood to brain either by transport across the brain barriers or by uptake and retrograde axonal transport in motor neurons projecting beyond the blood-brain barrier. The transport of iron and transport into the brain was examined using radiolabeled iron-transferrin. Intravenous injection of [59Fe-125]transferrin led to an almost two-fold higher accumulation of 59Fe than of

  15. Chronic Sleep Restriction during Pregnancy - Repercussion on Cardiovascular and Renal Functioning of Male Offspring

    PubMed Central

    Lima, Ingrid L. B.; Rodrigues, Aline F. A. C.; Bergamaschi, Cássia T.; Campos, Ruy R.; Hirata, Aparecida E.; Tufik, Sergio; Xylaras, Beatriz D. P.; Visniauskas, Bruna; Chagas, Jair R.; Gomes, Guiomar N.

    2014-01-01

    Changes in the maternal environment can induce fetal adaptations that result in the progression of chronic diseases in the offspring. The objective of the present study was to evaluate the effects of maternal chronic sleep restriction on blood pressure, renal function and cardiac baroreflex response on male offspring at adult age. Female 3-month-old Wistar rats were divided in two experimental groups: control (C) and chronic sleep restricted (CSR). Pregnancy was confirmed by vaginal smear. Chronic sleep restricted females were subjected to sleep restriction by the multiple platform technique for 20 h daily, between the 1st and 20th day of pregnancy. After birth, the litters were reduced to 6 rats per mother, and were designated as offspring from control (OC) and offspring from chronic sleep restricted (OCSR). Indirect blood pressure (BPi – tail cuff) was measured by plethysmography in male offspring at 3 months old. Following, the renal function and cardiac baroreflex response were analyzed. Values of BPi in OCSR were significantly higher compared to OC [OC: 127±2.6 (19); OCSR: 144±2.5 (17) mmHg]. The baroreflex sensitivity to the increase of blood pressure was reduced in OCSR [Slope: OC: −2.6±0.15 (9); OCRS: −1.6±0.13 (9)]. Hypothalamic activity of ACE2 was significantly reduced in OCSR compared to OC [OC: 97.4±15 (18); OSR: 60.2±3.6 (16) UAF/min/protein mg]. Renal function alteration was noticed by the increase in glomerular filtration rate (GFR) observed in OCSR [OC: 6.4±0.2 (10); OCSR: 7.4±0.3 (7)]. Chronic sleep restriction during pregnancy caused in the offspring hypertension, altered cardiac baroreflex response, reduced ACE-2 activity in the hypothalamus and renal alterations. Our data suggest that the reduction of sleeping time along the pregnancy is able to modify maternal homeostasis leading to functional alterations in offspring. PMID:25405471

  16. The role of sleep in bipolar disorder

    PubMed Central

    Gold, Alexandra K; Sylvia, Louisa G

    2016-01-01

    Bipolar disorder is a serious mental illness characterized by alternating periods of elevated and depressed mood. Sleep disturbances in bipolar disorder are present during all stages of the condition and exert a negative impact on overall course, quality of life, and treatment outcomes. We examine the partnership between circadian system (process C) functioning and sleep–wake homeostasis (process S) on optimal sleep functioning and explore the role of disruptions in both systems on sleep disturbances in bipolar disorder. A convergence of evidence suggests that sleep problems in bipolar disorder result from dysregulation across both process C and process S systems. Biomarkers of depressive episodes include heightened fragmentation of rapid eye movement (REM) sleep, reduced REM latency, increased REM density, and a greater percentage of awakenings, while biomarkers of manic episodes include reduced REM latency, greater percentage of stage I sleep, increased REM density, discontinuous sleep patterns, shortened total sleep time, and a greater time awake in bed. These findings highlight the importance of targeting novel treatments for sleep disturbance in bipolar disorder. PMID:27418862

  17. Heart failure and sleep disorders.

    PubMed

    Parati, Gianfranco; Lombardi, Carolina; Castagna, Francesco; Mattaliano, Paola; Filardi, Pasquale Perrone; Agostoni, Piergiuseppe

    2016-07-01

    Awareness of the importance of sleep-related disorders in patients with cardiovascular diseases is growing. In particular, sleep-disordered breathing, short sleep time, and low sleep quality are frequently reported by patients with heart failure (HF). Sleep-disordered breathing, which includes obstructive sleep apnoea (OSA) and central sleep apnoea (CSA), is common in patients with HF and has been suggested to increase the morbidity and mortality in these patients. Both OSA and CSA are associated with increased sympathetic activation, vagal withdrawal, altered haemodynamic loading conditions, and hypoxaemia. Moreover, OSA is strongly associated with arterial hypertension, the most common risk factor for cardiac hypertrophy and failure. Intrathoracic pressure changes are also associated with OSA, contributing to haemodynamic alterations and potentially affecting overexpression of genes involved in ventricular remodelling. HF treatment can decrease the severity of both OSA and CSA. Indeed, furosemide and spironolactone administration, exercise training, cardiac resynchronization therapy, and eventually heart transplantation have shown a positive effect on OSA and CSA in patients with HF. At present, whether CSA should be treated and, if so, which is the optimal therapy is still debated. By contrast, more evidence is available on the beneficial effects of OSA treatment in patients with HF.

  18. Sleep, immunity and inflammation in gastrointestinal disorders.

    PubMed

    Ali, Tauseef; Choe, James; Awab, Ahmed; Wagener, Theodore L; Orr, William C

    2013-12-28

    Sleep disorders have become a global issue, and discovering their causes and consequences are the focus of many research endeavors. An estimated 70 million Americans suffer from some form of sleep disorder. Certain sleep disorders have been shown to cause neurocognitive impairment such as decreased cognitive ability, slower response times and performance detriments. Recent research suggests that individuals with sleep abnormalities are also at greater risk of serious adverse health, economic consequences, and most importantly increased all-cause mortality. Several research studies support the associations among sleep, immune function and inflammation. Here, we review the current research linking sleep, immune function, and gastrointestinal diseases and discuss the interdependent relationship between sleep and these gastrointestinal disorders. Different physiologic processes including immune system and inflammatory cytokines help regulate the sleep. The inflammatory cytokines such as tumor necrosis factor, interleukin-1 (IL-1), and IL-6 have been shown to be a significant contributor of sleep disturbances. On the other hand, sleep disturbances such as sleep deprivation have been shown to up regulate these inflammatory cytokines. Alterations in these cytokine levels have been demonstrated in certain gastrointestinal diseases such as inflammatory bowel disease, gastro-esophageal reflux, liver disorders and colorectal cancer. In turn, abnormal sleep brought on by these diseases is shown to contribute to the severity of these same gastrointestinal diseases. Knowledge of these relationships will allow gastroenterologists a great opportunity to enhance the care of their patients.

  19. Sleep, immunity and inflammation in gastrointestinal disorders

    PubMed Central

    Ali, Tauseef; Choe, James; Awab, Ahmed; Wagener, Theodore L; Orr, William C

    2013-01-01

    Sleep disorders have become a global issue, and discovering their causes and consequences are the focus of many research endeavors. An estimated 70 million Americans suffer from some form of sleep disorder. Certain sleep disorders have been shown to cause neurocognitive impairment such as decreased cognitive ability, slower response times and performance detriments. Recent research suggests that individuals with sleep abnormalities are also at greater risk of serious adverse health, economic consequences, and most importantly increased all-cause mortality. Several research studies support the associations among sleep, immune function and inflammation. Here, we review the current research linking sleep, immune function, and gastrointestinal diseases and discuss the interdependent relationship between sleep and these gastrointestinal disorders. Different physiologic processes including immune system and inflammatory cytokines help regulate the sleep. The inflammatory cytokines such as tumor necrosis factor, interleukin-1 (IL-1), and IL-6 have been shown to be a significant contributor of sleep disturbances. On the other hand, sleep disturbances such as sleep deprivation have been shown to up regulate these inflammatory cytokines. Alterations in these cytokine levels have been demonstrated in certain gastrointestinal diseases such as inflammatory bowel disease, gastro-esophageal reflux, liver disorders and colorectal cancer. In turn, abnormal sleep brought on by these diseases is shown to contribute to the severity of these same gastrointestinal diseases. Knowledge of these relationships will allow gastroenterologists a great opportunity to enhance the care of their patients. PMID:24409051

  20. Sleep, immunity and inflammation in gastrointestinal disorders.

    PubMed

    Ali, Tauseef; Choe, James; Awab, Ahmed; Wagener, Theodore L; Orr, William C

    2013-12-28

    Sleep disorders have become a global issue, and discovering their causes and consequences are the focus of many research endeavors. An estimated 70 million Americans suffer from some form of sleep disorder. Certain sleep disorders have been shown to cause neurocognitive impairment such as decreased cognitive ability, slower response times and performance detriments. Recent research suggests that individuals with sleep abnormalities are also at greater risk of serious adverse health, economic consequences, and most importantly increased all-cause mortality. Several research studies support the associations among sleep, immune function and inflammation. Here, we review the current research linking sleep, immune function, and gastrointestinal diseases and discuss the interdependent relationship between sleep and these gastrointestinal disorders. Different physiologic processes including immune system and inflammatory cytokines help regulate the sleep. The inflammatory cytokines such as tumor necrosis factor, interleukin-1 (IL-1), and IL-6 have been shown to be a significant contributor of sleep disturbances. On the other hand, sleep disturbances such as sleep deprivation have been shown to up regulate these inflammatory cytokines. Alterations in these cytokine levels have been demonstrated in certain gastrointestinal diseases such as inflammatory bowel disease, gastro-esophageal reflux, liver disorders and colorectal cancer. In turn, abnormal sleep brought on by these diseases is shown to contribute to the severity of these same gastrointestinal diseases. Knowledge of these relationships will allow gastroenterologists a great opportunity to enhance the care of their patients. PMID:24409051

  1. Sleep and obsessive-compulsive disorder (OCD).

    PubMed

    Paterson, Jessica L; Reynolds, Amy C; Ferguson, Sally A; Dawson, Drew

    2013-12-01

    Obsessive-compulsive disorder (OCD) is a chronic mental illness that can have a debilitating effect on daily functioning. A body of research reveals altered sleep behaviour in OCD sufferers; however, findings are inconsistent and there is no consensus on the nature of this relationship. Understanding sleep disturbance in OCD is of critical importance given the known negative consequences of disturbed sleep for mood and emotional wellbeing. A systematic literature search was conducted of five databases for studies assessing sleep in adults diagnosed with OCD. Fourteen studies met inclusion criteria and qualitative data analysis methods were used to identify common themes. There was some evidence of reduced total sleep time and sleep efficiency in OCD patients. Many of the sleep disturbances noted were characteristic of depression. However, some OCD sufferers displayed delayed sleep onset and offset and an increased prevalence of delayed sleep phase disorder (DSPD). Severe OCD symptoms were consistently associated with greater sleep disturbance. While the sleep of OCD patients has not been a major focus to date, the existing literature suggests that addressing sleep disturbance in OCD patients may ensure a holistic approach to treatment, enhance treatment efficacy, mitigate relapse and protect against the onset of co-morbid psychiatric illnesses.

  2. Redox regulated peroxisome homeostasis.

    PubMed

    Wang, Xiaofeng; Li, Shuo; Liu, Yu; Ma, Changle

    2015-01-01

    Peroxisomes are ubiquitous organelles present in nearly all eukaryotic cells. Conserved functions of peroxisomes encompass beta-oxidation of fatty acids and scavenging of reactive oxygen species generated from diverse peroxisomal metabolic pathways. Peroxisome content, number, and size can change quickly in response to environmental and/or developmental cues. To achieve efficient peroxisome homeostasis, peroxisome biogenesis and degradation must be orchestrated. We review the current knowledge on redox regulated peroxisome biogenesis and degradation with an emphasis on yeasts and plants.

  3. Redox regulated peroxisome homeostasis.

    PubMed

    Wang, Xiaofeng; Li, Shuo; Liu, Yu; Ma, Changle

    2015-01-01

    Peroxisomes are ubiquitous organelles present in nearly all eukaryotic cells. Conserved functions of peroxisomes encompass beta-oxidation of fatty acids and scavenging of reactive oxygen species generated from diverse peroxisomal metabolic pathways. Peroxisome content, number, and size can change quickly in response to environmental and/or developmental cues. To achieve efficient peroxisome homeostasis, peroxisome biogenesis and degradation must be orchestrated. We review the current knowledge on redox regulated peroxisome biogenesis and degradation with an emphasis on yeasts and plants. PMID:25545794

  4. Sleeping to fuel the immune system: mammalian sleep and resistance to parasites.

    PubMed

    Opp, Mark R

    2009-01-09

    Sleep is an enigma. Why animals forgo eating and reproducing, while potentially increasing their risk of predation remains unknown. Although some may question whether all animals sleep, it is clear that all living organisms possess defenses against attack by pathogens. Immune responses of humans and animals are impaired by sleep loss, and responses to immune challenge include altered sleep. Thus, sleep is hypothesized to be a component of the acute phase response to infection and to function in host defense. Examining phylogenetic relationships among sleep parameters, components of the mammalian immune system and resistance to infection may provide insight into the evolution of sleep and lead to a greater appreciation for the role of sleep in host defense.

  5. Why does serotonergic activity drastically decrease during REM sleep?

    PubMed

    Sato, Kohji

    2013-10-01

    Here, I postulate two hypotheses that can explain the missing link between sleep and the serotonergic system in terms of spine homeostasis and memory consolidation. As dendritic spines contain many kinds of serotonin receptors, and the activation of serotonin receptors generally increases the number of spines in the cortex and hippocampus, I postulate that serotonin neurons are down-regulated during sleep to decrease spine number, which consequently maintains the total spine number at a constant level. Furthermore, since synaptic consolidation during REM sleep needs long-term potentiation (LTP), and serotonin is reported to inhibit LTP in the cortex, I postulate that serotonergic activity must drastically decrease during REM sleep to induce LTP and do memory consolidation. Until now, why serotonergic neurons show these dramatic changes in the sleep-wake cycle remains unexplained; however, making these hypotheses, I can confer physiological meanings on these dramatic changes of serotonergic neurons in terms of spine homeostasis and memory consolidation.

  6. Sleep and the processing of emotions.

    PubMed

    Deliens, Gaétane; Gilson, Médhi; Peigneux, Philippe

    2014-05-01

    How emotions interact with cognitive processes has been a topic of growing interest in the last decades, as well as studies investigating the role of sleep in cognition. We review here evidence showing that sleep and emotions entertain privileged relationships. The literature indicates that exposure to stressful and emotional experiences can induce changes in the post-exposure sleep architecture, whereas emotional disturbances are likely to develop following sleep alterations. In addition, post-training sleep appears particularly beneficial for the consolidation of intrinsically emotional memories, suggesting that emotions modulate the off-line brain activity patterns subtending memory consolidation processes. Conversely, sleep contributes unbinding core memories from their affective blanket and removing the latter, eventually participating to habituation processes and reducing aversive reactions to stressful stimuli. Taken together, these data suggest that sleep plays an important role in the regulation and processing of emotions, which highlight its crucial influence on human's abilities to manage and respond to emotional information.

  7. The Role of Sleep in Emotional Brain Function

    PubMed Central

    Goldstein, Andrea N.; Walker, Matthew P.

    2014-01-01

    Rapidly emerging evidence continues to describe an intimate and causal relationship between sleep and emotional brain function. These findings are mirrored by longstanding clinical observations demonstrating that nearly all mood and anxiety disorders co-occur with one or more sleep abnormalities. This review aims to (1) provide a synthesis of recent findings describing the emotional brain and behavioral benefits triggered by sleep, and conversely, the detrimental impairments following a lack of sleep, (2) outline a proposed framework in which sleep, and specifically rapid-eye movement (REM) sleep, supports a process of affective brain homeostasis, optimally preparing the organism for next-day social and emotional functioning, and (3) describe how this hypothesized framework can explain the prevalent relationships between sleep and psychiatric disorders, with a particular focus on post-traumatic stress disorder and major depression. PMID:24499013

  8. Developmental changes in sleep biology and potential effects on adolescent behavior and caffeine use.

    PubMed

    Carskadon, Mary A; Tarokh, Leila

    2014-10-01

    Adolescent development includes changes in the biological regulatory processes for the timing of sleep. Circadian rhythm changes and changes to the sleep-pressure system (sleep homeostasis) during adolescence both favor later timing of sleep. These changes, combined with prevailing social pressures, are responsible for most teens sleeping too late and too little; those who sleep least report consuming more caffeine. Although direct research findings are scarce, the likelihood of use and abuse of caffeine-laden products grows across the adolescent years due, in part, to excessive sleepiness.

  9. Human homeostasis in high-latitude environment.

    PubMed

    Panin, L E

    2007-01-01

    Profound changes occur in human metabolism in high-latitude environments under the action of climatic, industrial, and social factors. These changes involve protein, fat, carbohydrate, vitamin, and macro and microelement metabolism. This allowed us to state that "a polar metabolic type" is formed in the Arctic and Antarctic regions. The most pronounced alterations are found in energy metabolism. They can be characterized as "the change-over from carbohydrate-type metabolism to the lipid one." Metabolic changes are reflected in the chemical composition of internal medium (blood) of the human organism and its homeostasis. However, homeostasis in high-latitude environments depends not only on natural, but also on various conditioning factors, in particular, prolonged emotional stress and inactual nutritional pattern. These two factors exert a pronounced effect on adaptive changes in human metabolism and its homeostasis. Both factors often act concurrently and result in sustained and persistent changes of homeostasis, which lead directly to obesity and development of endocrine and cardiovascular pathology. This is observed not only for newcomers, but also for the indigenous population of the Asian North.

  10. Functional Anatomy of Non-REM Sleep

    PubMed Central

    de Andrés, Isabel; Garzón, Miguel; Reinoso-Suárez, Fernando

    2011-01-01

    The state of non-REM sleep (NREM), or slow wave sleep, is associated with a synchronized EEG pattern in which sleep spindles and/or K complexes and high-voltage slow wave activity (SWA) can be recorded over the entire cortical surface. In humans, NREM is subdivided into stages 2 and 3–4 (presently named N3) depending on the proportions of each of these polygraphic events. NREM is necessary for normal physical and intellectual performance and behavior. An overview of the brain structures involved in NREM generation shows that the thalamus and the cerebral cortex are absolutely necessary for the most significant bioelectric and behavioral events of NREM to be expressed; other structures like the basal forebrain, anterior hypothalamus, cerebellum, caudal brain stem, spinal cord and peripheral nerves contribute to NREM regulation and modulation. In NREM stage 2, sustained hyperpolarized membrane potential levels resulting from interaction between thalamic reticular and projection neurons gives rise to spindle oscillations in the membrane potential; the initiation and termination of individual spindle sequences depends on corticothalamic activities. Cortical and thalamic mechanisms are also involved in the generation of EEG delta SWA that appears in deep stage 3–4 (N3) NREM; the cortex has classically been considered to be the structure that generates this activity, but delta oscillations can also be generated in thalamocortical neurons. NREM is probably necessary to normalize synapses to a sustainable basal condition that can ensure cellular homeostasis. Sleep homeostasis depends not only on the duration of prior wakefulness but also on its intensity, and sleep need increases when wakefulness is associated with learning. NREM seems to ensure cell homeostasis by reducing the number of synaptic connections to a basic level; based on simple energy demands, cerebral energy economizing during NREM sleep is one of the prevalent hypotheses to explain NREM homeostasis

  11. Sleep at high altitude: guesses and facts.

    PubMed

    Bloch, Konrad E; Buenzli, Jana C; Latshang, Tsogyal D; Ulrich, Silvia

    2015-12-15

    Lowlanders commonly report a poor sleep quality during the first few nights after arriving at high altitude. Polysomnographic studies reveal that reductions in slow wave sleep are the most consistent altitude-induced changes in sleep structure identified by visual scoring. Quantitative spectral analyses of the sleep electroencephalogram have confirmed an altitude-related reduction in the low-frequency power (0.8-4.6 Hz). Although some studies suggest an increase in arousals from sleep at high altitude, this is not a consistent finding. Whether sleep instability at high altitude is triggered by periodic breathing or vice versa is still uncertain. Overnight changes in slow wave-derived encephalographic measures of neuronal synchronization in healthy subjects were less pronounced at moderately high (2,590 m) compared with low altitude (490 m), and this was associated with a decline in sleep-related memory consolidation. Correspondingly, exacerbation of breathing and sleep disturbances experienced by lowlanders with obstructive sleep apnea during a stay at 2,590 m was associated with poor performance in driving simulator tests. These findings suggest that altitude-related alterations in sleep may adversely affect daytime performance. Despite recent advances in our understanding of sleep at altitude, further research is required to better establish the role of gender and age in alterations of sleep at different altitudes, to determine the influence of acclimatization and of altitude-related illness, and to uncover the characteristics of sleep in highlanders that may serve as a study paradigm of sleep in patients exposed to chronic hypoxia due to cardiorespiratory disease.

  12. Sleep and Inflammatory Bowel Disease: Exploring the Relationship Between Sleep Disturbances and Inflammation

    PubMed Central

    Kinnucan, Jami A.; Rubin, David T.

    2013-01-01

    Sleep disturbances are associated with a greater risk of serious adverse health events, economic consequences, and, most importantly, increased all-cause mortality. Several studies support the associations among sleep, immune function, and inflammation. The relationship between sleep disturbances and inflammatory conditions is complex and not completely understood. Sleep deprivation can lead to increased levels of inflammatory cytokines, including interleukin (IL)-1β IL-6, tumor necrosis factor-α and C-reactive protein, which can lead to further activation of the inflammatory cascade. The relevance of sleep in inflammatory bowel disease (IBD), a chronic immune-mediated inflammatory disease of the gastrointestinal tract, has recently received more attention. Several studies have shown that patients with both inactive and active IBD have self-reported sleep disturbances. Here, we present a concise review of sleep and its association with the immune system and the process of inflammation. We discuss the studies that have evaluated sleep in patients with IBD as well as possible treatment options for those patients with sleep disturbances. An algorithm for evaluating sleep disturbances in the IBD population is also proposed. Further research is still needed to better characterize sleep disturbances in the IBD population as well as to assess the effects of various therapeutic interventions to improve sleep quality. It is possible that the diagnosis and treatment of sleep disturbances in this population may provide an opportunity to alter disease outcomes. PMID:24764789

  13. In Vivo Imaging of the Central and Peripheral Effects of Sleep Deprivation and Suprachiasmatic Nuclei Lesion on PERIOD-2 Protein in Mice

    PubMed Central

    Curie, Thomas; Maret, Stephanie; Emmenegger, Yann; Franken, Paul

    2015-01-01

    Study Objectives: That sleep deprivation increases the brain expression of various clock genes has been well documented. Based on these and other findings we hypothesized that clock genes not only underlie circadian rhythm generation but are also implicated in sleep homeostasis. However, long time lags have been reported between the changes in the clock gene messenger RNA levels and their encoded proteins. It is therefore crucial to establish whether also protein levels increase within the time frame known to activate a homeostatic sleep response. We report on the central and peripheral effects of sleep deprivation on PERIOD-2 (PER2) protein both in intact and suprachiasmatic nuclei-lesioned mice. Design: In vivo and in situ PER2 imaging during baseline, sleep deprivation, and recovery. Settings: Mouse sleep-recording facility. Participants: Per2::Luciferase knock-in mice. Interventions: N/A. Measurements and Results: Six-hour sleep deprivation increased PER2 not only in the brain but also in liver and kidney. Remarkably, the effects in the liver outlasted those observed in the brain. Within the brain the increase in PER2 concerned the cerebral cortex mainly, while leaving suprachiasmatic nuclei (SCN) levels unaffected. Against expectation, sleep deprivation did not increase PER2 in the brain of arrhythmic SCN-lesioned mice because of higher PER2 levels in baseline. In contrast, liver PER2 levels did increase in these mice similar to the sham and partially lesioned controls. Conclusions: Our results stress the importance of considering both sleep-wake dependent and circadian processes when quantifying clock-gene levels. Because sleep deprivation alters PERIOD-2 in the brain as well as in the periphery, it is tempting to speculate that clock genes constitute a common pathway mediating the shared and well-known adverse effects of both chronic sleep loss and disrupted circadian rhythmicity on metabolic health. Citation: Curie T, Maret S, Emmenegger Y, Franken P. In

  14. Sleep and Aging

    MedlinePlus

    ... There are two types of sleep: non-rapid eye movement -- or NREM sleep -- and rapid eye movement -- or REM sleep. NREM sleep includes four stages, ranging from light to deep sleep. Then we go into REM sleep, the most active ... During REM sleep, the eyes move back and forth beneath the eyelids and ...

  15. Sleep Disorders in Children: Collaboration for School-Based Intervention

    ERIC Educational Resources Information Center

    Everhart, D. Erik

    2011-01-01

    The effects of sleep disturbance on children are wide ranging and include alterations in behavior, mood, cognition, and academic performance. Screening and intervention for pediatric sleep disorders within the schools are not widely implemented, and the concept of integrating school personnel into the multidisciplinary sleep team has yet to be…

  16. Sleep Enhances a Spatially Mediated Generalization of Learned Values

    ERIC Educational Resources Information Center

    Javadi, Amir-Homayoun; Tolat, Anisha; Spiers, Hugo J.

    2015-01-01

    Sleep is thought to play an important role in memory consolidation. Here we tested whether sleep alters the subjective value associated with objects located in spatial clusters that were navigated to in a large-scale virtual town. We found that sleep enhances a generalization of the value of high-value objects to the value of locally clustered…

  17. Medicines for sleep

    MedlinePlus

    Benzodiazepines; Sedatives; Hypnotics; Sleeping pills; Insomnia - medicines; Sleep disorder - medicines ... the-counter (OTC) sleeping pills contain antihistamines. These medicines are commonly used to treat allergies. While these ...

  18. Sleep restriction acutely impairs glucose tolerance in rats.

    PubMed

    Jha, Pawan K; Foppen, Ewout; Kalsbeek, Andries; Challet, Etienne

    2016-06-01

    Chronic sleep curtailment in humans has been related to impairment of glucose metabolism. To better understand the underlying mechanisms, the purpose of the present study was to investigate the effect of acute sleep deprivation on glucose tolerance in rats. A group of rats was challenged by 4-h sleep deprivation in the early rest period, leading to prolonged (16 h) wakefulness. Another group of rats was allowed to sleep during the first 4 h of the light period and sleep deprived in the next 4 h. During treatment, food was withdrawn to avoid a postmeal rise in plasma glucose. An intravenous glucose tolerance test (IVGTT) was performed immediately after the sleep deprivation period. Sleep deprivation at both times of the day similarly impaired glucose tolerance and reduced the early-phase insulin responses to a glucose challenge. Basal concentrations of plasma glucose, insulin, and corticosterone remained unchanged after sleep deprivation. Throughout IVGTTs, plasma corticosterone concentrations were not different between the control and sleep-deprived group. Together, these results demonstrate that independent of time of day and sleep pressure, short sleep deprivation during the resting phase favors glucose intolerance in rats by attenuating the first-phase insulin response to a glucose load. In conclusion, this study highlights the acute adverse effects of only a short sleep restriction on glucose homeostasis. PMID:27354542

  19. CFTR and lung homeostasis.

    PubMed

    Collawn, James F; Matalon, Sadis

    2014-12-15

    CFTR is a cAMP-activated chloride and bicarbonate channel that is critical for lung homeostasis. Decreases in CFTR expression have dire consequences in cystic fibrosis (CF) and have been suggested to be a component of the lung pathology in chronic obstructive pulmonary disease. Decreases or loss of channel function often lead to mucus stasis, chronic bacterial infections, and the accompanying chronic inflammatory responses that promote progressive lung destruction, and, eventually in CF, lung failure. Here we discuss CFTR's functional role airway surface liquid hydration and pH, in regulation of other channels such as the epithelial sodium channel, and in regulating inflammatory responses in the lung. PMID:25381027

  20. A single night of partial sleep loss impairs fasting insulin sensitivity but does not affect cephalic phase insulin release in young men.

    PubMed

    Cedernaes, Jonathan; Lampola, Lauri; Axelsson, Emil K; Liethof, Lisanne; Hassanzadeh, Sara; Yeganeh, Adine; Broman, Jan-Erik; Schiöth, Helgi B; Benedict, Christian

    2016-02-01

    The present study sought to investigate whether a single night of partial sleep deprivation (PSD) would alter fasting insulin sensitivity and cephalic phase insulin release (CPIR) in humans. A rise in circulating insulin in response to food-related sensory stimulation may prepare tissues to break down ingested glucose, e.g. by stimulating rate-limiting glycolytic enzymes. In addition, given insulin's anorexigenic properties once it reaches the brain, the CPIR may serve as an early peripheral satiety signal. Against this background, in the present study 16 men participated in two separate sessions: one night of PSD (4.25 h sleep) versus one night of full sleep (8.5 h sleep). In the morning following each sleep condition, subjects' oral cavities were rinsed with a 1-molar sucrose solution for 45 s, preceded and followed by blood sampling for repeated determination of plasma glucose and serum insulin concentrations (-3, +3, +5, +7, +10 and +20 min). Our main result was that PSD, compared with full sleep, was associated with significantly higher peripheral insulin resistance, as indicated by a higher fasting homeostasis model assessment of insulin resistance index (+16%, P = 0.025). In contrast, no CPIR was observed in any of the two sleep conditions. Our findings indicate that a single night of PSD is already sufficient to impair fasting insulin sensitivity in healthy men. In contrast, brief oral cavity rinsing with sucrose solution did not change serum insulin concentrations, suggesting that a blunted CPIR is an unlikely mechanism through which acute sleep loss causes metabolic perturbations during morning hours in humans. PMID:26361380

  1. A role for cryptochromes in sleep regulation

    PubMed Central

    Wisor, Jonathan P; O'Hara, Bruce F; Terao, Akira; Selby, Chris P; Kilduff, Thomas S; Sancar, Aziz; Edgar, Dale M; Franken, Paul

    2002-01-01

    Background The cryptochrome 1 and 2 genes (cry1 and cry2) are necessary for the generation of circadian rhythms, as mice lacking both of these genes (cry1,2-/-) lack circadian rhythms. We studied sleep in cry1,2-/- mice under baseline conditions as well as under conditions of constant darkness and enforced wakefulness to determine whether cryptochromes influence sleep regulatory processes. Results Under all three conditions, cry1,2-/- mice exhibit the hallmarks of high non-REM sleep (NREMS) drive (i.e., increases in NREMS time, NREMS consolidation, and EEG delta power during NREMS). This unexpected phenotype was associated with elevated brain mRNA levels of period 1 and 2 (per1,2), and albumin d-binding protein (dbp), which are known to be transcriptionally inhibited by CRY1,2. To further examine the relationship between circadian genes and sleep homeostasis, we examined wild type mice and rats following sleep deprivation and found increased levels of per1,2 mRNA and decreased levels of dbp mRNA specifically in the cerebral cortex; these changes subsided with recovery sleep. The expression of per3, cry1,2, clock, npas2, bmal1, and casein-kinase-1ε did not change with sleep deprivation. Conclusions These results indicate that mice lacking cryptochromes are not simply a genetic model of circadian arrhythmicity in rodents and functionally implicate cryptochromes in the homeostatic regulation of sleep. PMID:12495442

  2. Effects of Diet on Sleep Quality.

    PubMed

    St-Onge, Marie-Pierre; Mikic, Anja; Pietrolungo, Cara E

    2016-09-01

    There is much emerging information surrounding the impact of sleep duration and quality on food choice and consumption in both children and adults. However, less attention has been paid to the effects of dietary patterns and specific foods on nighttime sleep. Early studies have shown that certain dietary patterns may affect not only daytime alertness but also nighttime sleep. In this review, we surveyed the literature to describe the role of food consumption on sleep. Research has focused on the effects of mixed meal patterns, such as high-carbohydrate plus low-fat or low-carbohydrate diets, over the short term on sleep. Such studies highlight a potential effect of macronutrient intakes on sleep variables, particularly alterations in slow wave sleep and rapid eye movement sleep with changes in carbohydrate and fat intakes. Other studies instead examined the intake of specific foods, consumed at a fixed time relative to sleep, on sleep architecture and quality. Those foods, specifically milk, fatty fish, tart cherry juice, and kiwifruit, are reviewed here. Studies provide some evidence for a role of certain dietary patterns and foods in the promotion of high-quality sleep, but more studies are necessary to confirm those preliminary findings. PMID:27633109

  3. Effects of Diet on Sleep Quality.

    PubMed

    St-Onge, Marie-Pierre; Mikic, Anja; Pietrolungo, Cara E

    2016-09-01

    There is much emerging information surrounding the impact of sleep duration and quality on food choice and consumption in both children and adults. However, less attention has been paid to the effects of dietary patterns and specific foods on nighttime sleep. Early studies have shown that certain dietary patterns may affect not only daytime alertness but also nighttime sleep. In this review, we surveyed the literature to describe the role of food consumption on sleep. Research has focused on the effects of mixed meal patterns, such as high-carbohydrate plus low-fat or low-carbohydrate diets, over the short term on sleep. Such studies highlight a potential effect of macronutrient intakes on sleep variables, particularly alterations in slow wave sleep and rapid eye movement sleep with changes in carbohydrate and fat intakes. Other studies instead examined the intake of specific foods, consumed at a fixed time relative to sleep, on sleep architecture and quality. Those foods, specifically milk, fatty fish, tart cherry juice, and kiwifruit, are reviewed here. Studies provide some evidence for a role of certain dietary patterns and foods in the promotion of high-quality sleep, but more studies are necessary to confirm those preliminary findings.

  4. The nature of spontaneous sleep across adulthood.

    PubMed

    Campbell, Scott S; Murphy, Patricia J

    2007-03-01

    The decline in sleep quality that often accompanies aging is thought to be the consequence of alterations in both circadian and homeostatic processes widely assumed to be responsible for sleep/wake regulation. A number of experimental approaches have been used to examine various aspects of age-related sleep changes, but none has examined spontaneous sleep across the entire 24-h day. Using the 'disentrainment' protocol, we studied such sleep in young, middle-aged and older adults. All subjects exhibited polyphasic sleep patterns, characterized by relatively short intervals of both sleep and waking. Whereas, the average duration of major nighttime sleep was significantly shorter in middle-aged and older subjects than in young adults, daytime napping was essentially unaffected by age. Comparisons of sleep and circadian variables between age groups suggest differential effects on sleep of the two regulatory processes, with changes in homeostatic drive preceding those of the circadian component. These findings add to a surprisingly scant literature on the longitudinal decline in sleep quality associated with aging. PMID:17309760

  5. Endocannabinoid Signaling Regulates Sleep Stability

    PubMed Central

    Pava, Matthew J.; Makriyannis, Alexandros; Lovinger, David M.

    2016-01-01

    The hypnogenic properties of cannabis have been recognized for centuries, but endogenous cannabinoid (endocannabinoid) regulation of vigilance states is poorly characterized. We report findings from a series of experiments in mice measuring sleep with polysomnography after various systemic pharmacological manipulations of the endocannabinoid system. Rapid, unbiased scoring of vigilance states was achieved using an automated algorithm that we devised and validated. Increasing endocannabinoid tone with a selective inhibitor of monoacyglycerol lipase (JZL184) or fatty acid amide hydrolase (AM3506) produced a transient increase in non-rapid eye movement (NREM) sleep due to an augmentation of the length of NREM bouts (NREM stability). Similarly, direct activation of type 1 cannabinoid (CB1) receptors with CP47,497 increased NREM stability, but both CP47,497 and JZL184 had a secondary effect that reduced NREM sleep time and stability. This secondary response to these drugs was similar to the early effect of CB1 blockade with the antagonist/inverse agonist AM281, which fragmented NREM sleep. The magnitude of the effects produced by JZL184 and AM281 were dependent on the time of day this drug was administered. While activation of CB1 resulted in only a slight reduction in gamma power, CB1 blockade had dramatic effects on broadband power in the EEG, particularly at low frequencies. However, CB1 blockade did not significantly reduce the rebound in NREM sleep following total sleep deprivation. These results support the hypothesis that endocannabinoid signaling through CB1 is necessary for NREM stability but it is not necessary for sleep homeostasis. PMID:27031992

  6. Endocannabinoid Signaling Regulates Sleep Stability.

    PubMed

    Pava, Matthew J; Makriyannis, Alexandros; Lovinger, David M

    2016-01-01

    The hypnogenic properties of cannabis have been recognized for centuries, but endogenous cannabinoid (endocannabinoid) regulation of vigilance states is poorly characterized. We report findings from a series of experiments in mice measuring sleep with polysomnography after various systemic pharmacological manipulations of the endocannabinoid system. Rapid, unbiased scoring of vigilance states was achieved using an automated algorithm that we devised and validated. Increasing endocannabinoid tone with a selective inhibitor of monoacyglycerol lipase (JZL184) or fatty acid amide hydrolase (AM3506) produced a transient increase in non-rapid eye movement (NREM) sleep due to an augmentation of the length of NREM bouts (NREM stability). Similarly, direct activation of type 1 cannabinoid (CB1) receptors with CP47,497 increased NREM stability, but both CP47,497 and JZL184 had a secondary effect that reduced NREM sleep time and stability. This secondary response to these drugs was similar to the early effect of CB1 blockade with the antagonist/inverse agonist AM281, which fragmented NREM sleep. The magnitude of the effects produced by JZL184 and AM281 were dependent on the time of day this drug was administered. While activation of CB1 resulted in only a slight reduction in gamma power, CB1 blockade had dramatic effects on broadband power in the EEG, particularly at low frequencies. However, CB1 blockade did not significantly reduce the rebound in NREM sleep following total sleep deprivation. These results support the hypothesis that endocannabinoid signaling through CB1 is necessary for NREM stability but it is not necessary for sleep homeostasis. PMID:27031992

  7. Endocannabinoid Signaling Regulates Sleep Stability.

    PubMed

    Pava, Matthew J; Makriyannis, Alexandros; Lovinger, David M

    2016-01-01

    The hypnogenic properties of cannabis have been recognized for centuries, but endogenous cannabinoid (endocannabinoid) regulation of vigilance states is poorly characterized. We report findings from a series of experiments in mice measuring sleep with polysomnography after various systemic pharmacological manipulations of the endocannabinoid system. Rapid, unbiased scoring of vigilance states was achieved using an automated algorithm that we devised and validated. Increasing endocannabinoid tone with a selective inhibitor of monoacyglycerol lipase (JZL184) or fatty acid amide hydrolase (AM3506) produced a transient increase in non-rapid eye movement (NREM) sleep due to an augmentation of the length of NREM bouts (NREM stability). Similarly, direct activation of type 1 cannabinoid (CB1) receptors with CP47,497 increased NREM stability, but both CP47,497 and JZL184 had a secondary effect that reduced NREM sleep time and stability. This secondary response to these drugs was similar to the early effect of CB1 blockade with the antagonist/inverse agonist AM281, which fragmented NREM sleep. The magnitude of the effects produced by JZL184 and AM281 were dependent on the time of day this drug was administered. While activation of CB1 resulted in only a slight reduction in gamma power, CB1 blockade had dramatic effects on broadband power in the EEG, particularly at low frequencies. However, CB1 blockade did not significantly reduce the rebound in NREM sleep following total sleep deprivation. These results support the hypothesis that endocannabinoid signaling through CB1 is necessary for NREM stability but it is not necessary for sleep homeostasis.

  8. [Sleep disturbances in children with autistic spectrum disorders].

    PubMed

    Kelmanson, I A

    2015-01-01

    An association between sleep disorders and autistic spectrum disorders in children is considered. Characteristic variants of sleep disorders, including resistance to going to bed, frequent night awakenings, parasomnias, changes in sleep structure, primarily, the decrease in the percentage of rapid eye movement sleep, are presented. Attention is focused on the possibility of the direct relationship between sleep disturbance and the pathogenesis of autistic spectrum disorders. A role of pathological alterations in the production of neuromediators and morphological changes in the brain structures characteristic of autistic spectrum disorders in the genesis of sleep disorders in children is discussed. Possible non-pharmacological and pharmacological approaches are suggested.

  9. The Synergistic Relationship between Alzheimer's Disease and Sleep Disorders: An Update.

    PubMed

    Villa, Chiara; Ferini-Strambi, Luigi; Combi, Romina

    2015-01-01

    Sleep disorders are frequently reported in Alzheimer's disease (AD), with a significant impact on patients and caregivers and a major risk factor for early institutionalization. Although changes in sleep organization are a hallmark of the normal aging processes, sleep macro- and micro-architectural alterations are more evident in patients affected by AD. Degeneration of neural pathways regulating sleep-wake patterns and sleep architecture may contribute to sleep alterations. In return, several recent studies suggested that common sleep disorders may precede clinical symptoms of dementia and represent risk factors for cognitive decline, through impairment of sleep-dependent memory consolidation processes. Thus, a close relationship between sleep disorders and AD has been largely hypothesized. Here, sleep alterations in AD and its pre-dementia stage, mild cognitive impairment, and their complex interactions are reviewed.

  10. [Correlation between eating disorders and sleep disturbances].

    PubMed

    Eiber, R; Friedman, S

    2001-01-01

    Anorectics and bulimics often complain sleep onset insomnia and disrupted sleep. During awakenings bulimics can have binges. Conversely, eating disorders can be a clinical expression of a concomitantly occurring sleep disorder. Two clinical entities have been recently described: the Night Eating Syndrome (NES) and the Sleep Related Eating Disorders. The main goal of this literature review was to better characterize the relationships between eating disorders and sleep disturbances. No specific EEG sleep pattern emerges in anorectic and bulimic patients. However, all studies include several methodological limitations: a few number of patients, heterogeneous patient groups, various diagnostic criteria. The results of studies evaluating the impact of depression on sleep EEG in eating disorder patients are also subject to controversy. The only study examining the relationship between sleep EEG and morphological alterations in anorectics and normal weight bulimics shows that patients with enlarged cerebrospinal fluid spaces spent more time in slow wave sleep and that the duration of rapid eye movement (REM) sleep was reduced. The ventricular brain ratio was negatively correlated with REM sleep. The Night Eating Syndrome consists in insomnia, binge eating and morning anorexia. Other criteria are proposed to characterize the NES: more than 50% of the daily energy intake is consumed after the last evening meal, awakenings at least once a night, repetition of the provisional criteria for more than 3 months, subjects do not meet criteria for bulimia nervosa or binge eating disorder. Patients have no amnesia nor alteration of alertness, and no other sleep disorder. There is no modification of sleep EEG except sleep maintenance. The prevalence of the NES is 1.5% in the general population. Some neuroendocrine disturbances have been found in the NES. The delimitation with eating disorders is not yet clearly established. If it shares the compulsive features with eating disorders

  11. Iron Homeostasis in Health and Disease

    PubMed Central

    Gozzelino, Raffaella; Arosio, Paolo

    2016-01-01

    Iron is required for the survival of most organisms, including bacteria, plants, and humans. Its homeostasis in mammals must be fine-tuned to avoid iron deficiency with a reduced oxygen transport and diminished activity of Fe-dependent enzymes, and also iron excess that may catalyze the formation of highly reactive hydroxyl radicals, oxidative stress, and programmed cell death. The advance in understanding the main players and mechanisms involved in iron regulation significantly improved since the discovery of genes responsible for hemochromatosis, the IRE/IRPs machinery, and the hepcidin-ferroportin axis. This review provides an update on the molecular mechanisms regulating cellular and systemic Fe homeostasis and their roles in pathophysiologic conditions that involve alterations of iron metabolism, and provides novel therapeutic strategies to prevent the deleterious effect of its deficiency/overload. PMID:26805813

  12. Acid-Base Homeostasis.

    PubMed

    Hamm, L Lee; Nakhoul, Nazih; Hering-Smith, Kathleen S

    2015-12-01

    Acid-base homeostasis and pH regulation are critical for both normal physiology and cell metabolism and function. The importance of this regulation is evidenced by a variety of physiologic derangements that occur when plasma pH is either high or low. The kidneys have the predominant role in regulating the systemic bicarbonate concentration and hence, the metabolic component of acid-base balance. This function of the kidneys has two components: reabsorption of virtually all of the filtered HCO3(-) and production of new bicarbonate to replace that consumed by normal or pathologic acids. This production or generation of new HCO3(-) is done by net acid excretion. Under normal conditions, approximately one-third to one-half of net acid excretion by the kidneys is in the form of titratable acid. The other one-half to two-thirds is the excretion of ammonium. The capacity to excrete ammonium under conditions of acid loads is quantitatively much greater than the capacity to increase titratable acid. Multiple, often redundant pathways and processes exist to regulate these renal functions. Derangements in acid-base homeostasis, however, are common in clinical medicine and can often be related to the systems involved in acid-base transport in the kidneys.

  13. Homeostasis in anorexia nervosa

    PubMed Central

    Södersten, Per; Bergh, Cecilia; Zandian, Modjtaba; Ioakimidis, Ioannis

    2014-01-01

    Brainstem and hypothalamic “orexigenic/anorexigenic” networks are thought to maintain body weight homeostasis in response to hormonal and metabolic feedback from peripheral sites. This approach has not been successful in managing over- and underweight patients. It is suggested that concept of homeostasis has been misinterpreted; rather than exerting control, the brain permits eating in proportion to the amount of physical activity necessary to obtain food. In support, animal experiments have shown that while a hypothalamic “orexigen” excites eating when food is abundant, it inhibits eating and stimulates foraging when food is in short supply. As the physical price of food approaches zero, eating and body weight increase without constraints. Conversely, in anorexia nervosa body weight is homeostatically regulated, the high level of physical activity in anorexia is displaced hoarding for food that keeps body weight constantly low. A treatment based on this point of view, providing patients with computerized mealtime support to re-establish normal eating behavior, has brought 75% of patients with eating disorders into remission, reduced the rate of relapse to 10%, and eliminated mortality. PMID:25147496

  14. Ageing and water homeostasis

    NASA Technical Reports Server (NTRS)

    Robertson, David; Jordan, Jens; Jacob, Giris; Ketch, Terry; Shannon, John R.; Biaggioni, Italo

    2002-01-01

    This review outlines current knowledge concerning fluid intake and volume homeostasis in ageing. The physiology of vasopressin is summarized. Studies have been carried out to determine orthostatic changes in plasma volume and to assess the effect of water ingestion in normal subjects, elderly subjects, and patients with dysautonomias. About 14% of plasma volume shifts out of the vasculature within 30 minutes of upright posture. Oral ingestion of water raises blood pressure in individuals with impaired autonomic reflexes and is an important source of noise in blood pressure trials in the elderly. On the average, oral ingestion of 16 ounces (473ml) of water raises blood pressure 11 mmHg in elderly normal subjects. In patients with autonomic impairment, such as multiple system atrophy, strikingly exaggerated pressor effects of water have been seen with blood pressure elevations greater than 75 mmHg not at all uncommon. Ingestion of water is a major determinant of blood pressure in the elderly population. Volume homeostasis is importantly affected by posture and large changes in plasma volume may occur within 30 minutes when upright posture is assumed.

  15. Essential Roles of GABA Transporter-1 in Controlling Rapid Eye Movement Sleep and in Increased Slow Wave Activity after Sleep Deprivation

    PubMed Central

    Xu, Xin-Hong; Qu, Wei-Min; Bian, Min-Juan; Huang, Fang; Fei, Jian; Urade, Yoshihiro; Huang, Zhi-Li

    2013-01-01

    GABA is the major inhibitory neurotransmitter in the mammalian central nervous system that has been strongly implicated in the regulation of sleep. GABA transporter subtype 1 (GAT1) constructs high affinity reuptake sites for GABA and regulates GABAergic transmission in the brain. However, the role of GAT1 in sleep-wake regulation remains elusive. In the current study, we characterized the spontaneous sleep-wake cycle and responses to sleep deprivation in GAT1 knock-out (KO) mice. GAT1 KO mice exhibited dominant theta-activity and a remarkable reduction of EEG power in low frequencies across all vigilance stages. Under baseline conditions, spontaneous rapid eye movement (REM) sleep of KO mice was elevated both during the light and dark periods, and non-REM (NREM) sleep was reduced during the light period only. KO mice also showed more state transitions from NREM to REM sleep and from REM sleep to wakefulness, as well as more number of REM and NREM sleep bouts than WT mice. During the dark period, KO mice exhibited more REM sleep bouts only. Six hours of sleep deprivation induced rebound increases in NREM and REM sleep in both genotypes. However, slow wave activity, the intensity component of NREM sleep was briefly elevated in WT mice but remained completely unchanged in KO mice, compared with their respective baselines. These results indicate that GAT1 plays a critical role in the regulation of REM sleep and homeostasis of NREM sleep. PMID:24155871

  16. Essential roles of GABA transporter-1 in controlling rapid eye movement sleep and in increased slow wave activity after sleep deprivation.

    PubMed

    Xu, Xin-Hong; Qu, Wei-Min; Bian, Min-Juan; Huang, Fang; Fei, Jian; Urade, Yoshihiro; Huang, Zhi-Li

    2013-01-01

    GABA is the major inhibitory neurotransmitter in the mammalian central nervous system that has been strongly implicated in the regulation of sleep. GABA transporter subtype 1 (GAT1) constructs high affinity reuptake sites for GABA and regulates GABAergic transmission in the brain. However, the role of GAT1 in sleep-wake regulation remains elusive. In the current study, we characterized the spontaneous sleep-wake cycle and responses to sleep deprivation in GAT1 knock-out (KO) mice. GAT1 KO mice exhibited dominant theta-activity and a remarkable reduction of EEG power in low frequencies across all vigilance stages. Under baseline conditions, spontaneous rapid eye movement (REM) sleep of KO mice was elevated both during the light and dark periods, and non-REM (NREM) sleep was reduced during the light period only. KO mice also showed more state transitions from NREM to REM sleep and from REM sleep to wakefulness, as well as more number of REM and NREM sleep bouts than WT mice. During the dark period, KO mice exhibited more REM sleep bouts only. Six hours of sleep deprivation induced rebound increases in NREM and REM sleep in both genotypes. However, slow wave activity, the intensity component of NREM sleep was briefly elevated in WT mice but remained completely unchanged in KO mice, compared with their respective baselines. These results indicate that GAT1 plays a critical role in the regulation of REM sleep and homeostasis of NREM sleep.

  17. Tau protein role in sleep-wake cycle.

    PubMed

    Cantero, Jose L; Hita-Yañez, Eva; Moreno-Lopez, Bernardo; Portillo, Federico; Rubio, Alicia; Avila, Jesus

    2010-01-01

    Evidence has shown that the lack of tau produces subtle changes in neuronal structure and modest impairment in complex behaviors, suggesting compensatory mechanisms carried out by other neuronal microtubule-associated proteins. Here we show major abnormalities in sleep-wake cycle of tau-deficient animals including increased wakefulness duration and decreased non-rapid eye movement (NREM) sleep time, a higher number of state transitions between NREM and wake, and shortened sleep bouts. Altered sleep structure in tau-/- mice was accompanied by a significant decline in delta power together with an enhanced spectral density of sleep spindles during NREM sleep. No significant differences were observed in rapid eye movement (REM) sleep between the two mouse strains. Taken together, these results suggest that tau indirectly participates in the regulation of the sleep-wake cycle modulating not only the control and maintenance of global brain states but also the cerebral oscillatory patterns underlying sleep-wake states.

  18. Sleep and orexins in nonmammalian vertebrates.

    PubMed

    Volkoff, Hélène

    2012-01-01

    Although a precise definition of "sleep" has yet to be established, sleep-like behaviors have been observed in all animals studied to date including mammals and nonmammalian vertebrates. Orexins are hypothalamic neuropeptides that are involved in the regulation of many physiological functions, including feeding, thermoregulation, cardiovascular control, as well as the control of the sleep-wakefulness cycle. To date, the knowledge on the functions of orexins in nonmammalian vertebrates is still limited, but the similarity of the structures of orexins and their receptors among vertebrates suggest that they have similar conserved physiological functions. This review describes our current knowledge on sleep in nonmammalian vertebrates (birds, reptiles, amphibians, and fish) and the possible role of orexins in the regulation of their energy homeostasis and arousal states. PMID:22640621

  19. Sleeping sickness

    MedlinePlus

    Human African trypanosomiasis ... Kirchoff LV. Agents of African trypanosomiasis (sleeping sickness). In: Mandell GL, Bennett JE, Dolan R, eds. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases . 8th ...

  20. Brain Basics: Understanding Sleep

    MedlinePlus

    ... Many of the body's cells also show increased production and reduced breakdown of proteins during deep sleep. ... deep sleep, REM sleep is associated with increased production of proteins. One study found that REM sleep ...

  1. American Sleep Apnea Association

    MedlinePlus

    American Sleep Apnea Association Learn About the CPAP Assistance Program About ASAA News about ASAA Who we are Leadership Team Supporting the ASAA Financials Learn Healthy sleep Sleep apnea Other sleep ...

  2. Pediatric sleep apnea

    MedlinePlus

    Sleep apnea - pediatric; Apnea - pediatric sleep apnea syndrome; Sleep-disordered breathing - pediatric ... During sleep, all of the muscles in the body become more relaxed. This includes the muscles that help keep ...

  3. Obstructive sleep apnea - adults

    MedlinePlus

    Sleep apnea - obstructive - adults; Apnea - obstructive sleep apnea syndrome - adults; Sleep-disordered breathing - adults; OSA - adults ... When you sleep, all of the muscles in your body become more relaxed. This includes the muscles that help keep your ...

  4. Snoring and Sleep Apnea

    MedlinePlus

    ... Find an ENT Doctor Near You Snoring and Sleep Apnea Snoring and Sleep Apnea Patient Health Information ... newsroom@entnet.org . Insight into sleeping disorders and sleep apnea Forty-five percent of normal adults snore ...

  5. Sleep studies in benign epilepsy of childhood with rolandic spikes. I. Sleep pathology.

    PubMed

    Clemens, B; Oláh, R

    1987-01-01

    Polygraphic all-night sleep records of 11 children with typical benign epilepsy of childhood with rolandic spikes (BERS) and those of eight nonepileptic controls were investigated with regard to sleep pathology. Basic properties of sleep organization and electromorphology were preserved in both groups. Seventeen quantitative sleep parameters were measured. Except for more waking in the BERS group, no sleep parameter showed significant differences between the BERS and the control group, but differences existed in comparison to normative values. We interpret our results as showing that in BERS epileptic neuronal malfunctioning does not affect sleep organization in a characteristic manner. The lack of detrimental interactions between epileptic neuronal behavior and pathological sleep alterations may be an additional cause of the benign course of BERS.

  6. Refreshing Sleep and Sleep Continuity Determine Perceived Sleep Quality.

    PubMed

    Libman, Eva; Fichten, Catherine; Creti, Laura; Conrod, Kerry; Tran, Dieu-Ly; Grad, Roland; Jorgensen, Mary; Amsel, Rhonda; Rizzo, Dorrie; Baltzan, Marc; Pavilanis, Alan; Bailes, Sally

    2016-01-01

    Sleep quality is a construct often measured, employed as an outcome criterion for therapeutic success, but never defined. In two studies we examined appraised good and poor sleep quality in three groups: a control group, individuals with obstructive sleep apnea, and those with insomnia disorder. In Study 1 we used qualitative methodology to examine good and poor sleep quality in 121 individuals. In Study 2 we examined sleep quality in 171 individuals who had not participated in Study 1 and evaluated correlates and predictors of sleep quality. Across all six samples and both qualitative and quantitative methodologies, the daytime experience of feeling refreshed (nonrefreshed) in the morning and the nighttime experience of good (impaired) sleep continuity characterized perceived good and poor sleep. Our results clarify sleep quality as a construct and identify refreshing sleep and sleep continuity as potential clinical and research outcome measures. PMID:27413553

  7. Cell Injury and Repair Resulting from Sleep Loss and Sleep Recovery in Laboratory Rats

    PubMed Central

    Everson, Carol A.; Henchen, Christopher J.; Szabo, Aniko; Hogg, Neil

    2014-01-01

    Study Objectives: Increased cell injury would provide the type of change in constitution that would underlie sleep disruption as a risk factor for multiple diseases. The current study was undertaken to investigate cell injury and altered cell fate as consequences of sleep deprivation, which were predicted from systemic clues. Design: Partial (35% sleep reduction) and total sleep deprivation were produced in rats for 10 days, which was tolerated and without overtly deteriorated health. Recovery rats were similarly sleep deprived for 10 days, then allowed undisturbed sleep for 2 days. The plasma, liver, lung, intestine, heart, and spleen were analyzed and compared to control values for damage to DNA, proteins, and lipids; apoptotic cell signaling and death; cell proliferation; and concentrations of glutathione peroxidase and catalase. Measurements and Results: Oxidative DNA damage in totally sleep deprived rats was 139% of control values, with organ-specific effects in the liver (247%), lung (166%), and small intestine (145%). Overall and organ-specific DNA damage was also increased in partially sleep deprived rats. In the intestinal epithelium, total sleep deprivation resulted in 5.3-fold increases in dying cells and 1.5-fold increases in proliferating cells, compared with control. Two days of recovery sleep restored the balance between DNA damage and repair, and resulted in normal or below-normal metabolic burdens and oxidative damage. Conclusions: These findings provide physical evidence that sleep loss causes cell damage, and in a manner expected to predispose to replication errors and metabolic abnormalities; thereby providing linkage between sleep loss and disease risk observed in epidemiological findings. Properties of recovery sleep include biochemical and molecular events that restore balance and decrease cell injury. Citation: Everson CA, Henchen CJ, Szabo A, Hogg N. Cell injury and repair resulting from sleep loss and sleep recovery in laboratory rats

  8. Perturbations of Amino Acid Metabolism Associated with Glyphosate-Dependent Inhibition of Shikimic Acid Metabolism Affect Cellular Redox Homeostasis and Alter the Abundance of Proteins Involved in Photosynthesis and Photorespiration1[W][OA

    PubMed Central

    Vivancos, Pedro Diaz; Driscoll, Simon P.; Bulman, Christopher A.; Ying, Liu; Emami, Kaveh; Treumann, Achim; Mauve, Caroline; Noctor, Graham; Foyer, Christine H.

    2011-01-01

    The herbicide glyphosate inhibits the shikimate pathway of the synthesis of amino acids such as phenylalanine, tyrosine, and tryptophan. However, much uncertainty remains concerning precisely how glyphosate kills plants or affects cellular redox homeostasis and related processes in glyphosate-sensitive and glyphosate-resistant crop plants. To address this issue, we performed an integrated study of photosynthesis, leaf proteomes, amino acid profiles, and redox profiles in the glyphosate-sensitive soybean (Glycine max) genotype PAN809 and glyphosate-resistant Roundup Ready Soybean (RRS). RRS leaves accumulated much more glyphosate than the sensitive line but showed relatively few changes in amino acid metabolism. Photosynthesis was unaffected by glyphosate in RRS leaves, but decreased abundance of photosynthesis/photorespiratory pathway proteins was observed together with oxidation of major redox pools. While treatment of a sensitive genotype with glyphosate rapidly inhibited photosynthesis and triggered the appearance of a nitrogen-rich amino acid profile, there was no evidence of oxidation of the redox pools. There was, however, an increase in starvation-associated and defense proteins. We conclude that glyphosate-dependent inhibition of soybean leaf metabolism leads to the induction of defense proteins without sustained oxidation. Conversely, the accumulation of high levels of glyphosate in RRS enhances cellular oxidation, possibly through mechanisms involving stimulation of the photorespiratory pathway. PMID:21757634

  9. Elevated ghrelin predicts food intake during experimental sleep restriction

    PubMed Central

    Broussard, Josiane L.; Kilkus, Jennifer M.; Delebecque, Fanny; Abraham, Varghese; Day, Andrew; Whitmore, Harry R.; Tasali, Esra

    2015-01-01

    Objective Sleep curtailment has been linked to obesity, but underlying mechanisms remain to be elucidated. We assessed whether sleep restriction alters 24-hour profiles of appetite-regulating hormones ghrelin, leptin and pancreatic polypeptide during a standardized diet, and whether these hormonal alterations predict food intake during ad libitum feeding. Methods Nineteen healthy, lean men were studied under normal sleep and sleep restriction in a randomized crossover design. Blood samples were collected for 24-hours during standardized meals. Subsequently, participants had an ad libitum feeding opportunity (buffet meals and snacks) and caloric intake was measured. Results Ghrelin levels were increased after sleep restriction as compared to normal sleep (p<0.01). Overall, sleep restriction did not alter leptin or pancreatic polypeptide profiles. Sleep restriction was associated with an increase in total calories from snacks by 328 ± 140 Kcal (p=0.03), primarily from carbohydrates (p=0.02). The increase in evening ghrelin during sleep restriction was correlated with higher consumption of calories from sweets (r=0.48, p=0.04). Conclusions Sleep restriction as compared to normal sleep significantly increases ghrelin levels. The increase in ghrelin is associated with more consumption of calories. Elevated ghrelin may be a mechanism by which sleep loss leads to increased food intake and the development of obesity. PMID:26467988

  10. Sleep in Othello

    PubMed Central

    Dimsdale, Joel E.

    2009-01-01

    Some of our best descriptions of sleep disorders come from literature. While Shakespeare is well known for his references to insomnia and sleep walking, his works also demonstrate a keen awareness of many other sleep disorders. This paper examines sleep themes in Shakespeare's play Othello. The play indicates Shakespeare's astute eye for sleep deprivation, sexual parasomnias, and effects of stress and drugs on sleep. Citation: Dimsdale JE. Sleep in Othello. J Clin Sleep Med 2009;5(3):280-281. PMID:19960651

  11. Neuronal ubiquitin homeostasis

    PubMed Central

    Hallengren, Jada; Chen, Ping-Chung; Wilson, Scott M.

    2013-01-01

    Neurons have highly specialized intracellular compartments that facilitate the development and activity of the nervous system. Ubiquitination is a post-translational modification that controls many aspects of neuronal function by regulating protein abundance. Disruption of this signaling pathway has been demonstrated in neurological disorders such as Parkinson’s disease, Amyotrophic Lateral Sclerosis and Angleman Syndrome. Since many neurological disorders exhibit ubiquitinated protein aggregates, the loss of neuronal ubiquitin homeostasis may be an important contributor of disease. This review discusses the mechanisms utilized by neurons to control the free pool of ubiquitin necessary for normal nervous system development and function as well as new roles of protein ubiquitination in regulating synaptic activity. PMID:23686613

  12. Sleep architecture in patients with fibromyalgia.

    PubMed

    Besteiro González, José Luis; Suárez Fernández, Tomás Vicente; Arboleya Rodríguez, Luis; Muñiz, José; Lemos Giráldez, Serafín; Alvarez Fernández, Angel

    2011-08-01

    The main objective of this work was to evaluate the characteristics of sleep in patients diagnosed with fibromyalgia syndrome. Sleep architecture in 32 patients with fibromyalgia and 20 healthy controls was evaluated. Following the recommendations of the International Federation of Clinical Neurophysiology, polysomnographies were conducted with fibromyalgia patients and the control subjects. The fibromyalgia patients showed alterations in cyclic organization of sleep and an increased number of periodic leg movements associated with cortical arousals. No significant differences were found in respiratory and oximetry variables or in alpha-delta sleep. The results support that fibromyalgia patients present an increase of superficial sleep at the expense of deep sleep and also an increase of periodic leg movements, which could have a pathogenic effect, facilitating the onset of the illness. Lastly, we discuss the results and propose some future lines of research. PMID:21774887

  13. Sleep architecture in patients with fibromyalgia.

    PubMed

    Besteiro González, José Luis; Suárez Fernández, Tomás Vicente; Arboleya Rodríguez, Luis; Muñiz, José; Lemos Giráldez, Serafín; Alvarez Fernández, Angel

    2011-08-01

    The main objective of this work was to evaluate the characteristics of sleep in patients diagnosed with fibromyalgia syndrome. Sleep architecture in 32 patients with fibromyalgia and 20 healthy controls was evaluated. Following the recommendations of the International Federation of Clinical Neurophysiology, polysomnographies were conducted with fibromyalgia patients and the control subjects. The fibromyalgia patients showed alterations in cyclic organization of sleep and an increased number of periodic leg movements associated with cortical arousals. No significant differences were found in respiratory and oximetry variables or in alpha-delta sleep. The results support that fibromyalgia patients present an increase of superficial sleep at the expense of deep sleep and also an increase of periodic leg movements, which could have a pathogenic effect, facilitating the onset of the illness. Lastly, we discuss the results and propose some future lines of research.

  14. An Adenosine-Mediated Glial-Neuronal Circuit for Homeostatic Sleep

    PubMed Central

    Bjorness, Theresa E.; Dale, Nicholas; Mettlach, Gabriel; Sonneborn, Alex; Sahin, Bogachan; Fienberg, Allen A.; Yanagisawa, Masashi; Bibb, James A.

    2016-01-01

    Sleep homeostasis reflects a centrally mediated drive for sleep, which increases during waking and resolves during subsequent sleep. Here we demonstrate that mice deficient for glial adenosine kinase (AdK), the primary metabolizing enzyme for adenosine (Ado), exhibit enhanced expression of this homeostatic drive by three independent measures: (1) increased rebound of slow-wave activity; (2) increased consolidation of slow-wave sleep; and (3) increased time constant of slow-wave activity decay during an average slow-wave sleep episode, proposed and validated here as a new index for homeostatic sleep drive. Conversely, mice deficient for the neuronal adenosine A1 receptor exhibit significantly decreased sleep drive as judged by these same indices. Neuronal knock-out of AdK did not influence homeostatic sleep need. Together, these findings implicate a glial-neuronal circuit mediated by intercellular Ado, controlling expression of homeostatic sleep drive. Because AdK is tightly regulated by glial metabolic state, our findings suggest a functional link between cellular metabolism and sleep homeostasis. SIGNIFICANCE STATEMENT The work presented here provides evidence for an adenosine-mediated regulation of sleep in response to waking (i.e., homeostatic sleep need), requiring activation of neuronal adenosine A1 receptors and controlled by glial adenosine kinase. Adenosine kinase acts as a highly sensitive and important metabolic sensor of the glial ATP/ADP and AMP ratio directly controlling intracellular adenosine concentration. Glial equilibrative adenosine transporters reflect the intracellular concentration to the extracellular milieu to activate neuronal adenosine receptors. Thus, adenosine mediates a glial-neuronal circuit linking glial metabolic state to neural-expressed sleep homeostasis. This indicates a metabolically related function(s) for this glial-neuronal circuit in the buildup and resolution of our need to sleep and suggests potential therapeutic targets

  15. A Physiologist's View of Homeostasis

    ERIC Educational Resources Information Center

    Modell, Harold; Cliff, William; Michael, Joel; McFarland, Jenny; Wenderoth, Mary Pat; Wright, Ann

    2015-01-01

    Homeostasis is a core concept necessary for understanding the many regulatory mechanisms in physiology. Claude Bernard originally proposed the concept of the constancy of the "milieu interieur," but his discussion was rather abstract. Walter Cannon introduced the term "homeostasis" and expanded Bernard's notion of…

  16. Daily rhythms of the sleep-wake cycle

    PubMed Central

    2012-01-01

    The amount and timing of sleep and sleep architecture (sleep stages) are determined by several factors, important among which are the environment, circadian rhythms and time awake. Separating the roles played by these factors requires specific protocols, including the constant routine and altered sleep-wake schedules. Results from such protocols have led to the discovery of the factors that determine the amounts and distribution of slow wave and rapid eye movement sleep as well as to the development of models to determine the amount and timing of sleep. One successful model postulates two processes. The first is process S, which is due to sleep pressure (and increases with time awake) and is attributed to a 'sleep homeostat'. Process S reverses during slow wave sleep (when it is called process S'). The second is process C, which shows a daily rhythm that is parallel to the rhythm of core temperature. Processes S and C combine approximately additively to determine the times of sleep onset and waking. The model has proved useful in describing normal sleep in adults. Current work aims to identify the detailed nature of processes S and C. The model can also be applied to circumstances when the sleep-wake cycle is different from the norm in some way. These circumstances include: those who are poor sleepers or short sleepers; the role an individual's chronotype (a measure of how the timing of the individual's preferred sleep-wake cycle compares with the average for a population); and changes in the sleep-wake cycle with age, particularly in adolescence and aging, since individuals tend to prefer to go to sleep later during adolescence and earlier in old age. In all circumstances, the evidence that sleep times and architecture are altered and the possible causes of these changes (including altered S, S' and C processes) are examined. PMID:22738268

  17. Bitter taste receptors influence glucose homeostasis.

    PubMed

    Dotson, Cedrick D; Zhang, Lan; Xu, Hong; Shin, Yu-Kyong; Vigues, Stephan; Ott, Sandra H; Elson, Amanda E T; Choi, Hyun Jin; Shaw, Hillary; Egan, Josephine M; Mitchell, Braxton D; Li, Xiaodong; Steinle, Nanette I; Munger, Steven D

    2008-01-01

    TAS1R- and TAS2R-type taste receptors are expressed in the gustatory system, where they detect sweet- and bitter-tasting stimuli, respectively. These receptors are also expressed in subsets of cells within the mammalian gastrointestinal tract, where they mediate nutrient assimilation and endocrine responses. For example, sweeteners stimulate taste receptors on the surface of gut enteroendocrine L cells to elicit an increase in intracellular Ca(2+) and secretion of the incretin hormone glucagon-like peptide-1 (GLP-1), an important modulator of insulin biosynthesis and secretion. Because of the importance of taste receptors in the regulation of food intake and the alimentary responses to chemostimuli, we hypothesized that differences in taste receptor efficacy may impact glucose homeostasis. To address this issue, we initiated a candidate gene study within the Amish Family Diabetes Study and assessed the association of taste receptor variants with indicators of glucose dysregulation, including a diagnosis of type 2 diabetes mellitus and high levels of blood glucose and insulin during an oral glucose tolerance test. We report that a TAS2R haplotype is associated with altered glucose and insulin homeostasis. We also found that one SNP within this haplotype disrupts normal responses of a single receptor, TAS2R9, to its cognate ligands ofloxacin, procainamide and pirenzapine. Together, these findings suggest that a functionally compromised TAS2R receptor negatively impacts glucose homeostasis, providing an important link between alimentary chemosensation and metabolic disease. PMID:19092995

  18. Do sleep abnormalities and misaligned sleep/circadian rhythm patterns represent early clinical characteristics for developing psychosis in high risk populations?

    PubMed

    Zanini, Marcio; Castro, Juliana; Coelho, Fernando Morgadinho; Bittencourt, Lia; Bressan, Rodrigo A; Tufik, Sergio; Brietzke, Elisa

    2013-12-01

    Sleep architecture changes, such as slow-wave sleep (SWS) percentage variations and reductions in latency and density of rapid eye movement (REM), are found in most patients with schizophrenia and are considered to be an important part of the pathophysiology of the disorder. In addition to these sleep parameters changes, disruptions in sleep homeostasis and the sleep/circadian rhythm also occur in these patients. Sleep/circadian rhythm abnormalities negatively affect neocortical plasticity and cognition and often precede the diagnosis of the illness. Thus, it has been suggested that the sleep/circadian rhythm might be involved in the pathophysiology of psychosis. Recent advances in the identification of individuals at a high risk for developing schizophrenia allow us to investigate several neurobiological processes involved in the development of psychosis. In this article, we review the current evidence of the effects of sleep parameter abnormalities, disruptions in sleep homeostasis and misalignments of sleep circadian rhythm on the early stages of schizophrenia. In addition, we discuss the preliminary evidence of sleep and circadian rhythm abnormalities during the prodromal stages of psychosis and propose that these abnormalities can be explored as potential predictors, as an adjunct to clinical diagnosis, of developing a psychotic disorder in at risk populations.

  19. Sleep and gastrointestinal disturbances in autism spectrum disorder in children.

    PubMed

    Klukowski, Mark; Wasilewska, Jolanta; Lebensztejn, Dariusz

    2015-01-01

    Autism spectrum disorder (ASD), a neurodevelopmental disorder with a prevalence of 1 in 68 children, commonly presents with comorbid conditions which include sleep disorders. Sleep disorders reported in ASD include, among others, increased bedtime resistance, insomnia, parasomnia, sleep disordered breathing, morning rise problems, and daytime sleepiness. Polysomnography studies show that children with ASD have altered sleep architecture including shorter total sleep time and longer sleep latency than typically developing peers. Sleep-related problems have been shown to affect overall autism scores, social skills decits, stereotypic behavior, and cognitive performance. Additionally, problematic sleep in children with ASD has been associated with higher levels of parental stress. Underlying causes specically related to sleep disorders are not fully known. Gastrointestinal (GI) disorders are commonly associated with sleep problems in these patients. Children with ASD and GI symptoms have been found to have a higher prevalence of sleep disturbances compared with typically developing peers who do not have GI symptoms. Treatment approaches to children with sleep disorders are varied and range from lifestyle modications and behavioral interventions to drug therapies and surgical interventions. Physicians should take into account GI disorders as possible underlying causes of sleep-related problems in children with ASD. Therapeutic interventions should begin with less invasive methods before progressing to more invasive options such as pharmacotherapy and should be based on medical indications in order to provide effective care while minimizing potential adverse health effects. Evidence-based studies concerning GI and sleep disorders in children with ASD are limited and further studies are warranted.

  20. Increased Sleep Depth in Developing Neural Networks: New Insights from Sleep Restriction in Children

    PubMed Central

    Kurth, Salome; Dean, Douglas C.; Achermann, Peter; O’Muircheartaigh, Jonathan; Huber, Reto; Deoni, Sean C. L.; LeBourgeois, Monique K.

    2016-01-01

    Brain networks respond to sleep deprivation or restriction with increased sleep depth, which is quantified as slow-wave activity (SWA) in the sleep electroencephalogram (EEG). When adults are sleep deprived, this homeostatic response is most pronounced over prefrontal brain regions. However, it is unknown how children’s developing brain networks respond to acute sleep restriction, and whether this response is linked to myelination, an ongoing process in childhood that is critical for brain development and cortical integration. We implemented a bedtime delay protocol in 5- to 12-year-old children to obtain partial sleep restriction (1-night; 50% of their habitual sleep). High-density sleep EEG was assessed during habitual and restricted sleep and brain myelin content was obtained using mcDESPOT magnetic resonance imaging. The effect of sleep restriction was analyzed using statistical non-parametric mapping with supra-threshold cluster analysis. We observed a localized homeostatic SWA response following sleep restriction in a specific parieto-occipital region. The restricted/habitual SWA ratio was negatively associated with myelin water fraction in the optic radiation, a developing fiber bundle. This relationship occurred bilaterally over parieto-temporal areas and was adjacent to, but did not overlap with the parieto-occipital region showing the most pronounced homeostatic SWA response. These results provide evidence for increased sleep need in posterior neural networks in children. Sleep need in parieto-temporal areas is related to myelin content, yet it remains speculative whether age-related myelin growth drives the fading of the posterior homeostatic SWA response during the transition to adulthood. Whether chronic insufficient sleep in the sensitive period of early life alters the anatomical generators of deep sleep slow-waves is an important unanswered question. PMID:27708567

  1. Obesity and upper airway control during sleep

    PubMed Central

    Patil, Susheel P.; Squier, Samuel; Schneider, Hartmut; Kirkness, Jason P.; Smith, Philip L.

    2010-01-01

    Mechanisms linking obesity with upper airway dysfunction in obstructive sleep apnea are reviewed. Obstructive sleep apnea is due to alterations in upper airway anatomy and neuromuscular control. Upper airway structural alterations in obesity are related to adipose deposition around the pharynx, which can increase its collapsibility or critical pressure (Pcrit). In addition, obesity and, particularly, central adiposity lead to reductions in resting lung volume, resulting in loss of caudal traction on upper airway structures and parallel increases in pharyngeal collapsibility. Metabolic and humoral factors that promote central adiposity may contribute to these alterations in upper airway mechanical function and increase sleep apnea susceptibility. In contrast, neural responses to upper airway obstruction can mitigate these mechanical loads and restore pharyngeal patency during sleep. Current evidence suggests that these responses can improve with weight loss. Improvements in these neural responses with weight loss may be related to a decline in systemic and local pharyngeal concentrations of specific inflammatory mediators with somnogenic effects. PMID:19875707

  2. Sleep physiology and pathology: pertinence to psychiatry.

    PubMed

    Soldatos, Constantin R; Paparrigopoulos, Thomas J

    2005-08-01

    Sleep should not be considered a behavioural state characterized by brain inertia; instead, it is a highly dynamic process involving numerous brainstem areas and all physiological systems of the body. Our understanding of the underlying mechanisms responsible for sleep regulation has considerably advanced since the discovery of rapid eye movement (REM) sleep, about half a century ago. Based on standardized electroencephalographic, electro-oculographic and electromyographic features, two distinct main states periodically alternating throughout the night have been identified: REM and non-REM sleep; the latter is further distinguished into stages 1, 2, 3 and 4. Computerized analysis of sleep recordings yielded more detailed information on sleep physiology and pathology. Although still preliminary, neuroimaging studies promise to elucidate the functional alterations of neuronal substrates during sleep. Regarding sleep disorders, which account for a substantial individual and socio-economic burden, considerable progress has been achieved in terms of their classification, assessment, clinical diagnosis and treatment. Specific sleep disorders within the three major categories, that is, 'dysomnias', 'parasomnias', and 'sleep disorders associated with mental, neurologic, or other medical conditions', exhibit characteristic clinical features; sleep laboratory recordings considerably assist to definitely diagnose several among them. Pertinence of sleep medicine for psychiatrists is obvious, taking into consideration that psychiatric disorders account for the largest diagnostic group of patients with sleep problems. In fact, the basics of this interdisciplinary field should be of special concern both to medical students and clinicians of diverse backgrounds who are interested in acquiring the necessary skills to globally and comprehensively understand and eventually effectively treat their patients.

  3. Melatonin and sleep in humans.

    PubMed

    Dawson, D; Encel, N

    1993-08-01

    Early studies on the physiological effects of melatonin typically reported hypnotic 'side-effects'. Later studies, specifically addressing this action, failed to reliably replicate hypnotic effects using standard polysomnography. This difference may be related to differences in the basic physiological action of melatonin compared with more conventional hypnotics. It is suggested that melatonin exerts a hypnotic effect through thermoregulatory mechanisms. By lowering core body temperature, melatonin reduces arousal and increases sleep-propensity. Thus, in humans, one role of melatonin is to transduce the light-dark cycle and define a window-of-opportunity in which sleep-propensity is enhanced. As such, melatonin is likely to be an effective hypnotic agent for sleep disruption associated with elevated temperature due to low circulating melatonin levels. The combined circadian and hypnotic effects of melatonin suggest a synergistic action in the treatment of sleep disorders related to the inappropriate timing of sleep and wakefulness. Adjuvant melatonin may also improve sleep disruption caused by drugs known to alter normal melatonin production (e.g., beta-blockers and benzodiazepines). If melatonin is to be developed as a successful clinical treatment, differences between the pharmacological profile following exogenous administration and the normal endogenous rhythm should be minimized. Continued development as a useful clinical tool requires control of both the amplitude and duration of the exogenous melatonin pulse. There is a need to develop novel drug delivery systems that can reliably produce a square-wave pulse of melatonin at physiological levels for 8-10 hr duration.

  4. Water Homeostasis: Evolutionary Medicine

    PubMed Central

    Zeidel, Mark L.

    2012-01-01

    As a major component of homeostasis, all organisms regulate the water composition of various compartments. Through the selective use of barrier membranes and surface glycoproteins, as well as aquaporin water channels, organisms ranging from Archaebacteria to humans can vary water permeabilities across their cell membranes by 4 to 5 orders of magnitude. In barrier epithelia the outer, or exofacial, leaflet acts as the main resistor to water flow; this leaflet restricts water flow by minimizing the surface area of lipid molecules which is not covered by phosphate headgroups and by packing hydrocarbon chains at maximal density. Cells may enhance the barrier by expressing glycoproteins that augment the “thickness” of unstirred layers at their surfaces, reducing osmotic gradients at the lipid bilayer surface. Aquaporins markedly and highly selectively accelerate water flux and are “switched on” either by deployment into membranes or gating. This review summarizes these mechanisms in many species, and indicates potential roles for manipulating water permeabilities in treating disease. PMID:23303973

  5. Sleep dysfunction and role of dysautonomia in Parkinson's disease.

    PubMed

    Mitra, Tanya; Chaudhuri, K Ray

    2009-12-01

    Altered sleep is a common non motor symptom in Parkinson's disease. Sleep dysfunction has been reported to occur in 60-90% of all PD patients, having a detrimental impact on quality of life and increasing disability. alpha-Synuclein deposits in the lower brainstem affecting autonomic and sleep regions have been identified in the pathophysiology. The resultant non motor symptoms such as REM sleep behaviour disorder (RBD) can precede the motor symptoms by years. RBD is violent, enacted dreams that expose the patient or their sleeping partner to night-time injuries. Excessive daytime sleepiness, sometimes with a narcolepsy-like phenotype, is a common occurrence in PD, owing to lesions in the arousal systems of the brain. Restless legs syndrome and sleep disordered breathing can all affect daytime alertness of PD patients. Autonomic deregulation can also negatively affect sleep patterns, by adding to night-time wakening and disrupting sleep.

  6. REM sleep dysregulation in depression: state of the art.

    PubMed

    Palagini, Laura; Baglioni, Chiara; Ciapparelli, Antonio; Gemignani, Angelo; Riemann, Dieter

    2013-10-01

    Disturbances of sleep are typical for most depressed patients and belong to the core symptoms of the disorder. Since the 1960s polysomnographic sleep research has demonstrated that besides disturbances of sleep continuity, depression is associated with altered sleep architecture, i.e., a decrease in slow wave sleep (SWS) production and disturbed rapid eye movement (REM) sleep regulation. Shortened REM latency (i.e., the interval between sleep onset and the occurrence of the first REM period), increased REM sleep duration and increased REM density (i.e., the frequency of rapid eye movements per REM period) have been considered as biological markers of depression which might predict relapse and recurrence. High risk studies including healthy relatives of patients with depression demonstrate that REM sleep alterations may precede the clinical expression of depression and may thus be useful in identifying subjects at high risk for the illness. Several models have been developed to explain REM sleep abnormalities in depression, like the cholinergic-aminergic imbalance model or chronobiologically inspired theories, which are reviewed in this overview. Moreover, REM sleep alterations have been recently considered not only as biological "scars" but as true endophenotypes of depression. This review discusses the genetic, neurochemical and neurobiological factors that have been implicated to play a role in the complex relationships between REM sleep and depression. We hypothesize on the one hand that REM sleep dysregulation in depression may be linked to a genetic predisposition/vulnerability to develop the illness; on the other hand it is conceivable that REM sleep disinhibition in itself is a part of a maladaptive stress reaction with increased allostatic load. We also discuss whether the REM sleep changes in depression may contribute themselves to the development of central symptoms of depression such as cognitive distortions including negative self-esteem and the

  7. Sleep and vigilance linked to melanism in wild barn owls.

    PubMed

    Scriba, M F; Rattenborg, N C; Dreiss, A N; Vyssotski, A L; Roulin, A

    2014-10-01

    Understanding the function of variation in sleep requires studies in the natural ecological conditions in which sleep evolved. Sleep has an impact on individual performance and hence may integrate the costs and benefits of investing in processes that are sensitive to sleep, such as immunity or coping with stress. Because dark and pale melanic animals differentially regulate energy homeostasis, immunity and stress hormone levels, the amount and/or organization of sleep may covary with melanin-based colour. We show here that wild, cross-fostered nestling barn owls (Tyto alba) born from mothers displaying more black spots had shorter non-REM (rapid eye movement) sleep bouts, a shorter latency until the occurrence of REM sleep after a bout of wakefulness and more wakefulness bouts. In male nestlings, the same sleep traits also correlated with their own level of spotting. Because heavily spotted male nestlings and the offspring of heavily spotted biological mothers switched sleep-wakefulness states more frequently, we propose the hypothesis that they could be also behaviourally more vigilant. Accordingly, nestlings from mothers displaying many black spots looked more often towards the nest entrance where their parents bring food and towards their sibling against whom they compete. Owlets from heavily spotted mothers might invest more in vigilance, thereby possibly increasing associated costs due to sleep fragmentation. We conclude that different strategies of the regulation of brain activity have evolved and are correlated with melanin-based coloration.

  8. Sleep and vigilance linked to melanism in wild barn owls.

    PubMed

    Scriba, M F; Rattenborg, N C; Dreiss, A N; Vyssotski, A L; Roulin, A

    2014-10-01

    Understanding the function of variation in sleep requires studies in the natural ecological conditions in which sleep evolved. Sleep has an impact on individual performance and hence may integrate the costs and benefits of investing in processes that are sensitive to sleep, such as immunity or coping with stress. Because dark and pale melanic animals differentially regulate energy homeostasis, immunity and stress hormone levels, the amount and/or organization of sleep may covary with melanin-based colour. We show here that wild, cross-fostered nestling barn owls (Tyto alba) born from mothers displaying more black spots had shorter non-REM (rapid eye movement) sleep bouts, a shorter latency until the occurrence of REM sleep after a bout of wakefulness and more wakefulness bouts. In male nestlings, the same sleep traits also correlated with their own level of spotting. Because heavily spotted male nestlings and the offspring of heavily spotted biological mothers switched sleep-wakefulness states more frequently, we propose the hypothesis that they could be also behaviourally more vigilant. Accordingly, nestlings from mothers displaying many black spots looked more often towards the nest entrance where their parents bring food and towards their sibling against whom they compete. Owlets from heavily spotted mothers might invest more in vigilance, thereby possibly increasing associated costs due to sleep fragmentation. We conclude that different strategies of the regulation of brain activity have evolved and are correlated with melanin-based coloration. PMID:25056556

  9. Circadian rhythm sleep disorders.

    PubMed

    Zhu, Lirong; Zee, Phyllis C

    2012-11-01

    There have been remarkable advances in our understanding of the molecular, cellular, and physiologic mechanisms underlying the regulation of circadian rhythms, and of the impact of circadian dysfunction on health and disease. This information has transformed our understanding of the effect of circadian rhythm sleep disorders (CRSD) on health, performance, and safety. CRSDs are caused by alterations of the central circadian timekeeping system, or a misalignment of the endogenous circadian rhythm and the external environment. This article reviews circadian biology and discusses the pathophysiology, clinical features, diagnosis, and treatment of the most commonly encountered CRSDs in clinical practice.

  10. Circadian Rhythm Sleep Disorders

    PubMed Central

    Zhu, Lirong; Zee, Phyllis C.

    2012-01-01

    There have been remarkable advances in our understanding of the molecular, cellular and physiological mechanisms underlying the regulation of circadian rhythms, as well as the impact of circadian dysfunction on health and disease. This information has transformed our understanding of the effect of circadian rhythm sleep disorders (CRSD) on health, performance and safety. CRSDs are caused by alterations of the central circadian time-keeping system, or a misalignment of the endogenous circadian rhythm and the external environment. In this section, we provide a review of circadian biology and discuss the pathophysiology, clinical features, diagnosis, and treatment of the most commonly encountered CRSDs in clinical practice. PMID:23099133

  11. Hypothalamic prepro-orexin mRNA level is inversely correlated to the non-rapid eye movement sleep level in high-fat diet-induced obese mice.

    PubMed

    Tanno, Shogo; Terao, Akira; Okamatsu-Ogura, Yuko; Kimura, Kazuhiro

    2013-01-01

    Orexins are hypothalamic neuropeptides, which play important roles in the regulation and maintenance of sleep/wakefulness states and energy homeostasis. To evaluate whether alterations in orexin system is associated with the sleep/wakefulness abnormalities observed in obesity, we examined the mRNA expression of prepro-orexin, orexin receptor type 1 (orexin 1r), and orexin receptor type 2 (oxexin 2r) in the hypothalamus in mice fed with a normal diet (ND) and high-fat diet (HFD)-induced obese mice. We also compared their relationships with sleep/wakefulness. Twenty-four, 4-week-old, male C57BL/6J mice were divided randomly into three groups, which received the following: (1) ND for 17 weeks; (2) HFD for 17 weeks; and (3) ND for 7 weeks and HFD for a further 10 weeks. The body weights of mice fed the HFD for 10-17 weeks were 112-150% of the average body weight of the ND group. The daily amount of non-rapid eye movement (NREM) sleep increased significantly in HFD-fed mice. These changes were accompanied by increases in the number but decreases in the duration of each NREM sleep episode. In addition, brief awakenings (<20 s epoch) during NREM sleep was nearly 2-fold more frequent. The mRNA level of prepro-orexin in the hypothalamus was significantly reduced in HFD-induced obese mice, whereas the levels of orexin 1r and orexin 2r were unaffected. The daily amount of NREM sleep was negatively correlated with the hypothalamic prepro-orexin mRNA level, so these results suggest that the increased NREM sleep levels in HFD-induced obese mice are attributable to impaired orexin activity.

  12. Sleep-wake cycle abnormalities in fatal familial insomnia. Evidence of the role of the thalamus in sleep regulation.

    PubMed

    Sforza, E; Montagna, P; Tinuper, P; Cortelli, P; Avoni, P; Ferrillo, F; Petersen, R; Gambetti, P; Lugaresi, E

    1995-06-01

    Alterations in sleep organization were longitudinally studied in 6 new cases of fatal familial insomnia (FFI) by 24 h polygraphic recording. All patients showed an early reduction in sleep spindles and K complexes, and a drastic reduction in total sleep time and disruption of the cyclic sleep organization. Complete abolition of NREM sleep and persistence of only brief residual periods of REM sleep without atonia were features characteristic of the 3 patients with a short (less than 1 year) clinical course, and lacking in the 3 cases with a longer (more than 2 years) disease course. In the latter, sudden transitions from waking to NREM or REM sleep occurred, sometimes recurring periodically. Our findings confirm that impairment of sleep-wake regulation is a consistent distinctive feature of FFI.

  13. Sleep in the intensive care unit.

    PubMed

    Pisani, Margaret A; Friese, Randall S; Gehlbach, Brian K; Schwab, Richard J; Weinhouse, Gerald L; Jones, Shirley F

    2015-04-01

    Sleep is an important physiologic process, and lack of sleep is associated with a host of adverse outcomes. Basic and clinical research has documented the important role circadian rhythm plays in biologic function. Critical illness is a time of extreme vulnerability for patients, and the important role sleep may play in recovery for intensive care unit (ICU) patients is just beginning to be explored. This concise clinical review focuses on the current state of research examining sleep in critical illness. We discuss sleep and circadian rhythm abnormalities that occur in ICU patients and the challenges to measuring alterations in circadian rhythm in critical illness and review methods to measure sleep in the ICU, including polysomnography, actigraphy, and questionnaires. We discuss data on the impact of potentially modifiable disruptors to patient sleep, such as noise, light, and patient care activities, and report on potential methods to improve sleep in the setting of critical illness. Finally, we review the latest literature on sleep disturbances that persist or develop after critical illness.

  14. Sleep and its regulation in zebrafish.

    PubMed

    Zhdanova, Irina V

    2011-01-01

    The function of sleep remains a central enigma of modern biology, in spite of the obvious importance of sleep for normal physiology and cognition. The zebrafish has emerged as a promising new model for studying sleep, its changes with age, and the impact of sleep alterations on cognitive function. Recent studies of this diurnal vertebrate have provided new insights into the dual role of the pineal hormone melatonin and its receptors, regulating sleep in diurnal vertebrates through both homeostatic and circadian mechanisms. Research in zebrafish has also revealed interactions between melatonin and the hypocretin/orexin system, another important sleep-wake modulator. Future investigations should benefit from the conservation in zebrafish of mechanisms that regulate normal sleep, our extensive knowledge of their molecular biology, the availability of multiple transgenic and mutant phenotypes, and the feasibility of applying sensitive in vivo imaging techniques to record sleep-related neuronal activity in these optically transparent subjects. The established sensitivity of zebrafish to many pharmacological hypnotics should also contribute to the development of new, safe and effective sleep medications.

  15. Sleep Deprivation and Recovery Sleep Prior to a Noxious Inflammatory Insult Influence Characteristics and Duration of Pain

    PubMed Central

    Vanini, Giancarlo

    2016-01-01

    Study Objectives: Insufficient sleep and chronic pain are public health epidemics. Sleep loss worsens pain and predicts the development of chronic pain. Whether previous, acute sleep loss and recovery sleep determine pain levels and duration remains poorly understood. This study tested whether acute sleep deprivation and recovery sleep prior to formalin injection alter post-injection pain levels and duration. Methods: Male Sprague-Dawley rats (n = 48) underwent sleep deprivation or ad libitum sleep for 9 hours. Thereafter, rats received a subcutaneous injection of formalin or saline into a hind paw. In the recovery sleep group, rats were allowed 24 h between sleep deprivation and the injection of formalin. Mechanical and thermal nociception were assessed using the von Frey test and Hargreaves' method. Nociceptive measures were performed at 1, 3, 7, 10, 14, 17 and 21 days post-injection. Results: Formalin caused bilateral mechanical hypersensitivity (allodynia) that persisted for up to 21 days post-injection. Sleep deprivation significantly enhanced bilateral allodynia. There was a synergistic interaction when sleep deprivation preceded a formalin injection. Rats allowed a recovery sleep period prior to formalin injection developed allodynia only in the injected limb, with higher mechanical thresholds (less allodynia) and a shorter recovery period. There were no persistent changes in thermal nociception. Conclusion: The data suggest that acute sleep loss preceding an inflammatory insult enhances pain and can contribute to chronic pain. The results encourage studies in a model of surgical pain to test whether enhancing sleep reduces pain levels and duration. Citation: Vanini G. Sleep deprivation and recovery sleep prior to a noxious inflammatory insult influence characteristics and duration of pain. SLEEP 2016;39(1):133–142. PMID:26237772

  16. Sleep in Neurodegenerative Diseases.

    PubMed

    Iranzo, Alex

    2016-03-01

    Disorders of sleep are an integral part of neurodegenerative diseases and include insomnia, sleep-wake cycle disruption, excessive daytime sleepiness that may be manifested as persistent somnolence or sudden onset of sleep episodes, obstructive and central sleep apnea, rapid eye movement sleep behavior disorder, and restless legs syndrome. The origin of these sleep disorders is multifactorial including degeneration of the brain areas that modulate sleep, the symptoms of the disease, and the effect of medications. Treatment of sleep disorders in patients with neurodegenerative diseases should be individualized and includes behavioral therapy, sleep hygiene, bright light therapy, melatonin, hypnotics, waking-promoting agents, and continuous positive airway pressure. PMID:26972029

  17. Sleep disruption and the sequelae associated with traumatic brain injury

    PubMed Central

    Lucke-Wold, Brandon P.; Smith, Kelly E.; Nguyen, Linda; Turner, Ryan C.; Logsdon, Aric F.; Jackson, Garrett J.; Huber, Jason D.; Rosen, Charles L.; Miller, Diane B.

    2016-01-01

    Sleep disruption, which includes a loss of sleep as well as poor quality fragmented sleep, frequently follows traumatic brain injury (TBI) impacting a large number of patients each year in the United States. Fragmented and/or disrupted sleep can worsen neuropsychiatric, behavioral, and physical symptoms of TBI. Additionally, sleep disruption impairs recovery and can lead to cognitive decline. The most common sleep disruption following TBI is insomnia, which is difficulty staying asleep. The consequences of disrupted sleep following injury range from deranged metabolomics and blood brain barrier compromise to altered neuroplasticity and degeneration. There are several theories for why sleep is necessary (e.g., glymphatic clearance and metabolic regulation) and these may help explain how sleep disruption contributes to degeneration within the brain. Experimental data indicate disrupted sleep allows hyperphosphorylated tau and amyloid β plaques to accumulate. As sleep disruption may act as a cellular stressor, target areas warranting further scientific investigation include the increase in endoplasmic reticulum and oxidative stress following acute periods of sleep deprivation. Potential treatment options for restoring the normal sleep cycle include melatonin derivatives and cognitive behavioral therapy. PMID:25956251

  18. Redox homeostasis: The Golden Mean of healthy living

    PubMed Central

    Ursini, Fulvio; Maiorino, Matilde; Forman, Henry Jay

    2016-01-01

    The notion that electrophiles serve as messengers in cell signaling is now widely accepted. Nonetheless, major issues restrain acceptance of redox homeostasis and redox signaling as components of maintenance of a normal physiological steady state. The first is that redox signaling requires sudden switching on of oxidant production and bypassing of antioxidant mechanisms rather than a continuous process that, like other signaling mechanisms, can be smoothly turned up or down. The second is the misperception that reactions in redox signaling involve “reactive oxygen species” rather than reaction of specific electrophiles with specific protein thiolates. The third is that hormesis provides protection against oxidants by increasing cellular defense or repair mechanisms rather than by specifically addressing the offset of redox homeostasis. Instead, we propose that both oxidant and antioxidant signaling are main features of redox homeostasis. As the redox shift is rapidly reversed by feedback reactions, homeostasis is maintained by continuous signaling for production and elimination of electrophiles and nucleophiles. Redox homeostasis, which is the maintenance of nucleophilic tone, accounts for a healthy physiological steady state. Electrophiles and nucleophiles are not intrinsically harmful or protective, and redox homeostasis is an essential feature of both the response to challenges and subsequent feedback. While the balance between oxidants and nucleophiles is preserved in redox homeostasis, oxidative stress provokes the establishment of a new radically altered redox steady state. The popular belief that scavenging free radicals by antioxidants has a beneficial effect is wishful thinking. We propose, instead, that continuous feedback preserves nucleophilic tone and that this is supported by redox active nutritional phytochemicals. These nonessential compounds, by activating Nrf2, mimic the effect of endogenously produced electrophiles (parahormesis). In summary

  19. Lentiviral infection, immune response peptides and sleep.

    PubMed

    Darko, D F; Mitler, M M; Henriksen, S J

    1995-01-01

    The aberrant sleep documented in subjects with human immunodeficiency virus (HIV) infection is uniquely important because of the contribution this poor quality sleep makes to the fatigue, disability, and eventual unemployment that befalls these patients. Especially given this importance in clinical care, the research on the prominent sleep changes described in HIV infection remains modest in quantity. The chronic asymptomatic stage of HIV infection is associated with the most intriguing and singular sleep structure changes. Especially robust is the increase in slow wave sleep, particularly in latter portions of the sleep period. This finding is rare in other primary or secondary sleep disorders. The sleep structure alterations are among the most replicable of several pathophysiological sequelae in the brain associated with early HIV infection. It is unlikely that these sleep architecture changes are psychosocial in etiology, and they occur before medical pathology is evident. They are not associated with stress, anxiety, or depression. Evidence is accumulating to support a role for the somnogenic immune peptides tumor necrosis factor (TNF)alpha and interleukin (IL-1 beta) in the sleep changes and fatigue commonly seen in HIV infection. These peptides are elevated in the blood of HIV-infected individuals, and are somnogenic in clinical use and animal models. The peripheral production of these peptides may also have a role in the regulation of normal sleep physiology. The lentivirus family contains both HIV and the feline immunodeficiency virus (FIV). The use of the FIV model of HIV infection may provide a way to further investigate the mechanism of a neurotropic, neurotoxic virus initiating the immune acute phase response and affecting sleep. Neurotropic lentivirus infection is a microbiological probe facilitating neuroimmune investigation. PMID:7795894

  20. Consideration of sleep dysfunction in rehabilitation.

    PubMed

    Valenza, Marie Carmen; Rodenstein, Daniel O; Fernández-de-las-Peñas, César

    2011-07-01

    The physiology of sleep is not completely understood but it is widely accepted that sleep is important to the human body in the recovery of metabolic and neurological processes. This paper summarizes the effects of sleep dysfunction on different systems and considers implications in the context of rehabilitation. When sleep is experimentally completely or partially curtailed important brain functions are impacted leading to psychological and neurological disturbances. Increased cortisol levels, reduction of glucose tolerance, and increased sympathetic nervous system activity have also been identified in healthy subjects under such conditions. Several studies show that 50-80% of patients with chronic pain suffer from sleep dysfunction. It has been suggested that on the one hand pain can cause sleep dysfunction and on the other hand that sleep dysfunction can aggravate pain. The physiologic mechanism behind this interaction is not completely clear; although most authors describe the relationship between pain and sleep dysfunction as aberrant processing of tactile-cutaneous sensory inputs at the meso-encephalic level and in the trigeminal nucleus both when asleep and awake. Decreased duration of sleep also increases heart rate, blood pressure and sympathetic activity magnifying the individual's response to stressful stimuli. Possible causal mechanisms for the established connection between short sleep cycles and coronary pathology include sympathetic nervous system hyperactivity, increased blood pressure increase or reduced glucose tolerance. Finally, sleep and fatigue have traditionally been linked. Fatigue can have a physical etiology but is also associated with depression. Sleep alterations are also considered an important risk factor for psychological dysfunction and also mental illness. However, despite the noted repercussions of sleep dysfunction, studies investigating interventions to improve sleep have been limited in number. Benefits of exercise programs on

  1. Effects of sleeping position and time after feeding on the organization of sleep/wake states in prematurely born infants.

    PubMed

    Myers, M M; Fifer, W P; Schaeffer, L; Sahni, R; Ohira-Kist, K; Stark, R I; Schulze, K F

    1998-06-15

    Epidemiologic studies provide strong evidence for the conclusion that sleeping in the prone position places infants at greater risk for sudden infant death syndrome (SIDS). Prior studies in newborn infants found that in the prone sleeping position there is less time awake and more quiet sleep, but little change in the amount of active sleep. To determine whether the effects of sleeping position on state distribution vary with time after feeding, we studied prematurely born infants in both the prone and supine sleeping positions. Sleep states were recorded each minute during interfeed intervals. Results demonstrate expected effects of sleep position on state distribution: prone sleeping is associated with a 79% increase in quiet sleep and a 71% decrease in time awake. While the decreases in time awake are seen throughout the interfeed interval, increases in quiet sleep in the prone position are found only within the first hour and again near the end of the interfeed interval. These results are consistent with the hypothesis that prone sleeping could increase risk for SIDS by altering the organization of sleep, and that time after feeding may play an important role in the expression of these effects. PMID:9646378

  2. Origin, Development, and Homeostasis of Tissue-resident Macrophages

    PubMed Central

    Haldar, Malay; Murphy, Kenneth M.

    2014-01-01

    Summary Macrophages are versatile cells of the hematopoietic system that display remarkable functional diversity encompassing innate immune responses, tissue development, and tissue homeostasis. Macrophages are present in almost all tissues of the body and display distinct location-specific phenotypes and gene expression profiles. Recent studies also demonstrate distinct origins of tissue-resident macrophages. This emerging picture of ontological, functional, and phenotypic heterogeneity within tissue macrophages has altered our understanding of these cells, which play important roles in many human diseases. In this review, we discuss the different origins of tissue macrophages, the transcription factors regulating their development, and the mechanisms underlying their homeostasis at steady state. PMID:25319325

  3. Is sleep-related verbal memory consolidation impaired in sleepwalkers?

    PubMed

    Uguccioni, Ginevra; Pallanca, Olivier; Golmard, Jean-Louis; Leu-Semenescu, Smaranda; Arnulf, Isabelle

    2015-04-01

    In order to evaluate verbal memory consolidation during sleep in subjects experiencing sleepwalking or sleep terror, 19 patients experiencing sleepwalking/sleep terror and 19 controls performed two verbal memory tasks (16-word list from the Free and Cued Selective Reminding Test, and a 220- and 263-word modified story recall test) in the evening, followed by nocturnal video polysomnography (n = 29) and morning recall (night-time consolidation after 14 h, n = 38). The following morning, they were given a daytime learning task using the modified story recall test in reverse order, followed by an evening recall test after 9 h of wakefulness (daytime consolidation, n = 38). The patients experiencing sleepwalking/sleep terror exhibited more frequent awakenings during slow-wave sleep and longer wakefulness after sleep onset than the controls. Despite this reduction in sleep quality among sleepwalking/sleep terror patients, they improved their scores on the verbal tests the morning after sleep compared with the previous evening (+16 ± 33%) equally well as the controls (+2 ± 13%). The performance of both groups worsened during the daytime in the absence of sleep (-16 ± 15% for the sleepwalking/sleep terror group and -14 ± 11% for the control group). There was no significant correlation between the rate of memory consolidation and any of the sleep measures. Seven patients experiencing sleepwalking also sleep-talked during slow-wave sleep, but their sentences were unrelated to the tests or the list of words learned during the evening. In conclusion, the alteration of slow-wave sleep during sleepwalking/sleep terror does not noticeably impact on sleep-related verbal memory consolidation. PMID:25212397

  4. Is sleep-related verbal memory consolidation impaired in sleepwalkers?

    PubMed

    Uguccioni, Ginevra; Pallanca, Olivier; Golmard, Jean-Louis; Leu-Semenescu, Smaranda; Arnulf, Isabelle

    2015-04-01

    In order to evaluate verbal memory consolidation during sleep in subjects experiencing sleepwalking or sleep terror, 19 patients experiencing sleepwalking/sleep terror and 19 controls performed two verbal memory tasks (16-word list from the Free and Cued Selective Reminding Test, and a 220- and 263-word modified story recall test) in the evening, followed by nocturnal video polysomnography (n = 29) and morning recall (night-time consolidation after 14 h, n = 38). The following morning, they were given a daytime learning task using the modified story recall test in reverse order, followed by an evening recall test after 9 h of wakefulness (daytime consolidation, n = 38). The patients experiencing sleepwalking/sleep terror exhibited more frequent awakenings during slow-wave sleep and longer wakefulness after sleep onset than the controls. Despite this reduction in sleep quality among sleepwalking/sleep terror patients, they improved their scores on the verbal tests the morning after sleep compared with the previous evening (+16 ± 33%) equally well as the controls (+2 ± 13%). The performance of both groups worsened during the daytime in the absence of sleep (-16 ± 15% for the sleepwalking/sleep terror group and -14 ± 11% for the control group). There was no significant correlation between the rate of memory consolidation and any of the sleep measures. Seven patients experiencing sleepwalking also sleep-talked during slow-wave sleep, but their sentences were unrelated to the tests or the list of words learned during the evening. In conclusion, the alteration of slow-wave sleep during sleepwalking/sleep terror does not noticeably impact on sleep-related verbal memory consolidation.

  5. Markers of Oxidative Stress in Pregnant Women with Sleep Disturbances

    PubMed Central

    Rajendiran, Soundravally; Nimesh, Archana; Ananthanarayanan, P. H.; Dhiman, Pooja

    2015-01-01

    Objective The quality and duration of sleep is impaired during pregnancy. Our study aimed to determine whether maternal sleep deprivation occurring during the second and third trimester of pregnancy could alter fetal well-being with respect to birth weight and APGAR score by altering the inflammatory status and oxidative stress in the mothers.  Methods Sleep adequacy was assessed using the Pittsburgh Sleep Quality Index (PSQI). We investigated the inflammatory status and oxidative stress at term in the blood of pregnant subjects with and without sleep deprivation by measuring the levels of protein-bound sialic acid (PBSA), high-sensitivity C-reactive protein (hsCRP), malondialdehyde (MDA) and protein carbonyl (PCO). Homocysteine (Hcy) and its vitamin determinants were also measured. Fetal outcome with respect to birth weight and APGAR score were compared between study subjects.  Results A significant increase was observed in the levels of hsCRP, PBSA, Hcy, MDA, and PCO, in the sleep-deprived group when compared to the control group. Fetal outcome at birth showed a significant difference between the cases with high sleep deprivation and those with low sleep deprivation.  Conclusion Sleep deprivation in pregnancy leads to an increase in the inflammatory parameters, oxidative stress, and Hcy levels. Fetal outcome at birth was affected more in mothers with high sleep deprivation than those with low sleep deprivation. Follow-up in these babies are needed to reveal any differences in their growth and development. PMID:26366260

  6. American Academy of Sleep Medicine

    MedlinePlus

    ... need to excel in the profession of sleep technology. Sleep Education SleepEducation.org provides patients and the general public with comprehensive, accurate information about healthy sleep and sleep disorders, along with ...

  7. Sleep studies (image)

    MedlinePlus

    ... person during sleep may also be used. The test is performed for people who suffer from insomnia, excessive daytime sleepiness, obstructive sleep apnea, breathing difficulties during sleep, or behavior disturbances ...

  8. Aging changes in sleep

    MedlinePlus

    ... a health care provider to find out whether depression or another health condition is affecting your sleep. COMMON PROBLEMS Insomnia is one of the more common sleep problems in the elderly. Other sleep disorders , such as restless legs syndrome, ...

  9. Isolated sleep paralysis

    MedlinePlus

    Sleep paralysis - isolated; Parasomnia - isolated sleep paralysis ... Episodes of isolated sleep paralysis last from a few seconds to 1 or 2 minutes. During these episodes the person is unable to move ...

  10. Sleep Troubles, Heart Troubles?

    MedlinePlus

    ... page: https://medlineplus.gov/news/fullstory_161037.html Sleep Troubles, Heart Troubles? American Heart Association says it's ... 19, 2016 MONDAY, Sept. 19, 2016 (HealthDay News) -- Sleep disorders -- including too little or too much sleep -- ...

  11. Treatments for Sleep Changes

    MedlinePlus

    ... Contributing medical factors Non-drug strategies Medications Common sleep changes Many people with Alzheimer’s experience changes in ... at night. Subscribe now Non-drug treatments for sleep changes Non-drug treatments aim to improve sleep ...

  12. Sleep and your health

    MedlinePlus

    ... back pain, heart disease, and conditions such as asthma that make it hard to breathe. Depression , anxiety, and substance abuse also make sleep hard to come by. Some medicines disrupt sleep. Stress about sleeping . After several nights of tossing and ...

  13. Magnesium homeostasis and aging.

    PubMed

    Barbagallo, Mario; Belvedere, Mario; Dominguez, Ligia J

    2009-12-01

    Aging is very often associated with magnesium (Mg) deficit. Total plasma magnesium concentrations are remarkably constant in healthy subjects throughout life, while total body Mg and Mg in the intracellular compartment tend to decrease with age. Dietary Mg deficiencies are common in the elderly population. Other frequent causes of Mg deficits in the elde