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.
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.
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. Recovery sleep restored the balance between DNA damage and repair, and resulted in normal or below-normal metabolic burdens and oxidative damage.
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.
Chronic sleep disruption in laboratory rats leads to increased energy expenditure, connective tissue abnormalities, and increased weights of major organs relative to body weight. Here we report on ...expanded findings and the extent to which abnormalities become long-lasting, potentially permanent changes to health status after apparent recuperation from chronic sleep disruption. Rats were exposed 6 times to long periods of disrupted sleep or control conditions during 10 weeks to produce adaptations and then were permitted nearly 4 months of undisturbed sleep. Measurements were made in tissues from these groups and in preserved tissue from the experimental and control groups of an antecedent study that lacked a lengthy recuperation period. Cycles of sleep restriction resulted in energy deficiency marked by a progressive course of hyperphagia and major (15%) weight loss. Analyses of tissue composition in chronically sleep-restricted rats indicated that protein and lipid amounts in internal organs were largely spared, while adipose tissue depots appeared depleted. This suggests high metabolic demands may have preserved the size of the vital organs relative to expectations of severe energy deficiency alone. Low plasma corticosterone and leptin concentrations appear to reflect low substrate availability and diminished adiposity. After nearly 4 months of recuperation, sleep-restricted rats were consuming 20% more food and 35% more water than did comparison control rats, despite normalized weight, normalized adipocytes, and elevated plasma leptin concentrations. Plasma cholesterol levels in recuperated sleep-restricted rats were diminished relative to those of controls. The chronically increased intake of nutriments and water, along with altered negative feedback regulation and substrate use, indicate that internal processes are modified long after a severe period of prolonged and insufficient sleep has ended.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Adequate sleep timed appropriately during the circadian night is important for numerous biological processes and systems. New evidence suggests that both sleep timing and duration may be important ...for optimal bone health as well. This review examines the diurnal variation of bone turnover markers (BTMs) and the importance of circadian clock genes in regulating bone mass. In addition, this review explores the evidence for a link between shift work (and its associated disturbances in sleep duration/quality and circadian alignment) and alterations in bone metabolism and bone health. Finally, we review how commonly used medications and over-the-counter substances (e.g. caffeine, melatonin) complicate the relationship between sleep and circadian disorders and bone health.
Hypothalamic-pituitary-adrenal (HPA) axis dynamics are disrupted by opioids and may be involved in substance abuse; this persists during withdrawal and abstinence and is associated with co-morbid ...sleep disruption leading to vulnerability to relapse. We hypothesized that chronic sleep restriction (SR) alters the HPA axis diurnal rhythm and the sexually dimorphic response to acute stressor during opioid abstinence. We developed a rat model to evaluate the effect of persistent sleep loss during opioid abstinence on HPA axis dynamics in male and female rats. Plasma ACTH and corticosterone were measured diurnally and in response to acute restraint stress in rats Before (control) compared to During subsequent opioid abstinence without or with SR. Abstinence, regardless of sleep state, led to an increase in plasma ACTH and corticosterone in the morning in males. There was a tendency for higher PM plasma ACTH during abstinence in SR males (p = 0.076). ACTH and corticosterone responses to restraint were reduced in male SR rats whereas there was a failure to achieve the post-restraint nadir in female SR rats. There was no effect of the treatments or interventions on adrenal weight normalized to body weight. SR resulted in a dramatic increase in hypothalamic PVN AVP mRNA and plasma copeptin in male but not female rats. This corresponded to the attenuation of the HPA axis stress response in SR males during opioid abstinence. We have identified a potentially unique, sexually dimorphic role for magnocellular vasopressin in the control of the HPA axis during opioid abstinence and sleep restriction.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Little evidence exists about how mild traumatic brain injury (mTBI) is affected by commonly encountered exposures of sleep loss, sleep aids, and caffeine that might be potential therapeutic ...opportunities. In addition, while propofol sedation is administered in severe TBI, its potential utility in mild TBI is unclear. Each of these exposures is known to have pronounced effects on cerebral metabolism and blood flow and neurochemistry. We hypothesized that they each interact with cerebral metabolic dynamics post-injury and change the subclinical characteristics of mTBI. MTBI in rats was produced by head rotational acceleration injury that mimics the biomechanics of human mTBI. Three mTBIs spaced 48 h apart were used to increase the likelihood that vulnerabilities induced by repeated mTBI would be manifested without clinically relevant structural damage. After the third mTBI, rats were immediately sleep deprived or administered caffeine or suvorexant (an orexin antagonist and sleep aid) for the next 24 h or administered propofol for 5 h. Resting state functional magnetic resonance imaging (rs-fMRI) and diffusion tensor imaging (DTI) were performed 24 h after the third mTBI and again after 30 days to determine changes to the brain mTBI phenotype. Multi-modal analyses on brain regions of interest included measures of functional connectivity and regional homogeneity from rs-fMRI, and mean diffusivity (MD) and fractional anisotropy (FA) from DTI. Each intervention changed the mTBI profile of subclinical effects that presumably underlie healing, compensation, damage, and plasticity. Sleep loss during the acute post-injury period resulted in dramatic changes to functional connectivity. Caffeine, propofol sedation and suvorexant were especially noteworthy for differential effects on microstructure in gray and white matter regions after mTBI. The present results indicate that commonplace exposures and short-term sedation alter the subclinical manifestations of repeated mTBI and therefore likely play roles in symptomatology and vulnerability to damage by repeated mTBI.
Department of Neurology, Medical College of Wisconsin, Milwaukee, Wisconsin
Submitted 11 January 2005
; accepted in final form 30 May 2005
The specific systems and mechanisms affected by sleep ...deprivation that may perpetuate disease processes in humans still are speculative. In laboratory rats, prolonged sleep deprivation induces a state marked by abnormal control over indigenous bacteria that results in transient infections of internal tissues and eventual lethal septicemia. The present studies investigated changes in blood, serum, and bone marrow parameters that may provide diagnostic clues to immunopathology. Prolonged sleep deprivation was produced in rats by the disk-over-water method, a well-established and selective means that does not interfere with normal waking behaviors. Measurements included bone and blood differential white blood cell counts, multiple serum cytokines and chemokines, several major Ig classes and subclasses, and serum endotoxin concentrations. The results indicated mild, regenerative neutrophilia in sleep-deprived rats, initially accompanied by immature neutrophils and later by monocytosis. The corresponding serum cytokine profile revealed an evolving proinflammatory state, particularly by high incidence of interleukin-1 , implicating mononuclear phagocytes and resident tissue cells as main intermediary sources. In addition, multiple serum Ig classes were increased by sleep deprivation without experimental administration of an exogenous antigen. Despite this immune activation, there was failure to eradicate invading bacteria and toxins, suggesting competing anti-inflammatory processes or interference with immune effector functions during sleep deprivation. Nearly all of the immune-related events that emerged as responses to sleep deprivation have been implicated as etiological or provocative factors in other disease processes and may provide means by which sleep deprivation as a risk factor in disease may become understood.
interleukin-1 ; inflammation; endotoxin
Address for reprint requests and other correspondence: C. A. Everson, Medical College of Wisconsin, Veterans Affairs Medical Center, Neurology Research 151, 5000 West National Ave., Milwaukee WI 53295 (e-mail: ceverson{at}mcw.edu )
•Rats self-administered oxycodone, then underwent sleep restriction or control procedures, then were tested for drug seeking.•Sleep restriction did not affect oxycodone seeking in male or female ...rats.•In female rats, pain-related phenotypes were related to high levels of drug seeking during the initial extinction session.•In male rats, lower anxiety-like behavior in the open field was associated with greater drug seeking.
During opioid use and abstinence, sleep disturbances are common and are thought to exacerbate drug craving. In this study, we tested the hypothesis that sleep restriction during abstinence from oxycodone self-administration would increase drug seeking during extinction and footshock reinstatement tests. We also performed behavioral phenotyping to determine if individual variation in responses to stressors and/or pain are associated with oxycodone seeking during abstinence, as stress, pain and sleep disturbance are often co-occurring phenomena. Sleep restriction during abstinence did not have selective effects on oxycodone seeking for either sex in extinction and footshock reinstatement tests. Some phenotypes were associated with drug seeking; these associations differed by sex and type of drug seeking assessment. In female rats, pain-related phenotypes were related to high levels of drug seeking during the initial extinction session. In male rats, lower anxiety-like behavior in the open field was associated with greater drug seeking, although this effect was lost when correcting for oxycodone intake. Adrenal sensitivity prior to oxycodone exposure was positively associated with footshock reinstatement in females. This work identifies sex-dependent relationships between HPA axis function and opioid seeking, indicating that HPA axis function could be a therapeutic target for the treatment of opioid use disorder, with tailored approaches based on sex. Sleep disturbance during abstinence did not appear to be a major contributing factor to opioid seeking.
Insufficient sleep over long durations of the lifespan is believed to adversely affect proper development and healthful aging, although how this might become manifested is unknown. In the present ...study, rats were repeatedly sleep-restricted during 72 days to permit maladaptations to evolve, thereby permitting study. Densitometric and histomorphometric analyses were performed on harvested bone. In sleep-restricted rats, bone lined by osteoid was reduced 45-fold and osteoid thickness was decreased, compared with controls. This corresponded to a decrease in osteoblast number and activity. The percentage of bone lined by osteoclasts did not differ from that of controls. Plasma concentrations of an osteoclast marker (TRACP 5b) were increased in sleep-restricted rats, indicating increased bone resorption. The low amount of new bone formation without a reduction in bone resorption is diagnostic of osteopenia. Bone mineral density was decreased in femurs from sleep-restricted rats compared with controls, indicating osteoporosis. Red marrow in sleep-restricted rats contained only 37% of the fat and more than twice the number of megakaryocytes compared with that of the control rats. These findings in marrow suggest changed plasticity and increased hematopoiesis. Plasma concentrations of insulin-like growth factor-1, a known, major mediator of osteoblast differentiation and the proliferation of progenitor cells, was decreased by 30% in sleep-restricted rats. Taken together, these findings suggest that chronically inadequate sleep affects bone metabolism and bone marrow composition in ways that have implications for development, aging, bone healing and repair, and blood cell differentiation.
Departments of 1 Neurology and
2 Population Health, The Medical College of Wisconsin, Milwaukee, Wisconsin
Submitted April 29, 2009
; accepted in final form August 14, 2009
Chronic restriction of a ...basic biological need induces adaptations to help meet requisites for survival. The adaptations to chronic restriction of sleep are unknown. A single episode of 10 days of partial sleep loss in rats previously was shown to be tolerated and to result in increased food intake and loss of body weight as principal signs. The purpose of the present experiment was to investigate the extent to which adaptation to chronic sleep restriction would ameliorate short-term effects and result in a changed internal phenotype. Rats were studied during 10 wk of multiple periods of restricted and unrestricted sleep to allow adaptive changes to develop. Control rats received the same ambulatory requirements only consolidated into periods that lessened interruptions of their sleep. The results indicate a latent period of relatively stable food and water intake without weight gain, followed by a dynamic phase marked by enormous increases in food and water intake and progressive loss of body weight, without malabsorption of calories. Severe consequences ensued, marked especially by changes to the connective tissues, and became fatal for two individuals. The most striking changes to internal organs in sleep-restricted rats included lengthening of the small intestine, decreased size of adipocytes, and increased incidence of multilocular adipocytes. Major organs accounted for an increased proportion of total body mass. These changes to internal tissues appear adaptive in response to high energy production, decomposition of lipids, and increased need to absorb nutrients, but ultimately insufficient to compensate for inadequate sleep.
sleep rebound; adaptation; metabolism; adiposity; connective tissues; visceral organs
Address for reprint requests and other correspondence: C. A. Everson, The Medical College of Wisconsin, Neurology Research 151, Veterans Affairs Medical Center, 5000 W. National Ave., Milwaukee, WI 53295 (e-mail: ceverson{at}mcw.edu ).
1 Department of Neurology, The Medical College of Wisconsin, Milwaukee, Wisconsin 53226; and 2 Department of Pharmacology and Toxicology, University of Utah Health Sciences Center, Salt Lake City, ...Utah 84112
Submitted 5 December 2003
; accepted in final form 2 February 2004
The main systemic disorders resulting from prolonged sleep deprivation in laboratory animals are a negative energy balance, low circulating thyroid hormones, and host defense impairments. Low thyroid hormones previously have been found caused by altered regulation at the level of the hypothalamus with possible pituitary involvement. The present studies investigated the effects of sleep deprivation on other major anabolic hormonal systems. Plasma growth hormone (GH) concentrations and major secretory bursts were characterized. Insulin-like growth factor I (IGF-I) was evaluated as an integrative marker of peripheral GH effector activity. Prolactin (PRL) was assessed by basal concentrations and by stimulating the pituitary with exogenous thyrotropin-releasing hormone. Leptin was studied for its linkage to metabolic signs of sleep loss and its correspondence to altered neuroendocrine regulation in other disease states. Last, plasma corticosterone was measured to investigate the degree of hypothalamic-pituitary-adrenal activation. Sleep deprivation was produced by the disk-over-water method, a well-established means of selective deprivation of sleep and noninterference with normal waking behaviors. Hormone concentrations were determined in sham comparisons and at intervals during baseline and experimental periods lasting at least 15 days in partially and totally sleep-deprived rats. The results indicate that high-amplitude pulses of GH were nearly abolished and that concentrations of GH, IGF-I, PRL, and leptin all were suppressed by sleep deprivation. Corticosterone concentration was relatively unaffected. Features of these results, such as low GH and low IGF-I, indicate failed negative feedback and point to hypothalamic mechanisms as containing the foci responsible for peripheral signs.
growth hormone; thyroxine; prolactin; insulin-like growth factor I; leptin; corticosterone
Address for reprint requests and other correspondence: C. A. Everson, Medical College of Wisconsin, Neurology Research 151, VA Medical Center, Bldg. 70, D-117, 5000 West National Ave., Milwaukee, WI 53295 (E-mail: ceverson{at}mcw.edu ).
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