Sleep deprivation and host defense.
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Animals↗
Biomedical subjects
A Rechtschaffen
Publications and source records attributed to A Rechtschaffen.
Vascular resistance in the rat during baseline, chronic total sleep deprivation, and recovery from total sleep deprivation.
Rats subjected to total sleep deprivation (TSD) by the disk-over-water method exhibit an elevated temperature set point, increased energy expenditure (EE), and increased circulating norepinephrine--all of which should militate for an increase in body temperature. Instead, after a small rise early in TSD, intraperitoneal temperature (T(ip)) fell progressively, indicating a reduced ability to retain body heat. To evaluate whether vasoconstrictor defenses against heat loss in the regions of major heat dissipation in the rat (hindpaws and tail) were impaired, peripheral vascular resistance (PVR) was calculated from aortic blood pressure (BP) and blood flow (BF) (BP and BF were continuously recorded at the aortic-iliac junction). TSD rats and their yoked control (TSC) rats were subjected to TSD for 10 to 22 days. As in earlier studies, TSD rats showed excessive heat loss indicated by a falling T(ip) (after an initial rise) while EE was elevated. Temperature set point was presumably raised throughout deprivation as shown previously. Although a small decline in PVR early in deprivation could have increased heat loss, there was no evidence of a massive vasodilation in the region examined which could, in itself, account for the progressive inability to retain heat over the course of TSD. In fact, PVR was near baseline levels during the latter half of TSD. Nevertheless, there was evidence of impaired vasoconstrictive defenses in TSD rats inasmuch as they showed significantly lower PVR than TSC rats during most of the deprivation period in spite of indications that they were farther below set point. It is not yet clear whether this impairment was a major determinant of the heat loss in TSD rats. A rapid PVR rebound during recovery suggested a release from a TSD-linked blockage of vasomotor compensation for excessive heat loss.
Animals↗
No evidence of brain cell degeneration after long-term sleep deprivation in rats.
Sleep deprivation leads to cognitive impairments in humans and, if sustained for 2-3 weeks in rats, it is invariably fatal. It has been suggested that neural activity associated with waking, if it is not interrupted by periods of sleep, may damage brain cells through excitotoxic or oxidative mechanisms and eventually lead to cell death. To determine whether sustained waking causes brain cell degeneration, three parallel strategies were used. The presence and extent of DNA fragmentation was analyzed with the TUNEL technique on brain sections from rats sleep deprived for various periods of time (from 8 h to 14 days) and from their respective controls. Adjacent sections from the same animals were stained with a newly developed fluorochrome (Fluoro-Jade) specific for degenerating neurons. Finally, total RNA from the cerebral cortex of the same animals was used to determine whether the expression of several stress response genes and apoptosis-related genes is modified after sustained waking. In most long-term sleep deprived rats only a few scattered TUNEL positive nuclei (1-3) were found in any given brain section. The overall number, distribution, and morphology of TUNEL positive cells in long-term sleep deprived rats did not differ significantly from yoked controls, short-term sleep deprived rats, and sleep controls. No evidence of degenerating neurons as detected by Fluoro-Jade was found in any experimental group. mRNA levels of all the stress response genes and apoptosis-related genes tested did not differ between long-term sleep deprived rats and their yoked controls. These results argue against the hypothesis that sustained waking can significantly damage brain cells through excitotoxic or oxidative mechanisms and that massive cell death may explain the fatal consequences of sleep deprivation.
Animals↗
Effects of method, duration, and sleep stage on rebounds from sleep deprivation in the rat.
Total sleep deprivation (TSD) of rats for 24 hours or less by continually enforced locomotion has consistently produced subsequent rebounds of slow-wave or high-amplitude EEG activity in NREM sleep, which has contributed to the widely held view that this EEG activity reflects particularly "intense" or restorative sleep. These rebounds usually have been accompanied by substantial rebounds of REM sleep. In contrast, chronic TSD (2 weeks or longer) by the disk-over-water (DOW) method has produced only huge, long-lasting rebounds of REM sleep with no rebound of high-amplitude NREM sleep. To evaluate whether the different rebounds result from different methods or from different lengths of deprivation, rats were subjected to 24-hour TSD by the DOW method. Rebounds included increases in high-amplitude and slow-wave activity; i.e., the methods produced similar rebound patterns following short-term TSD. (Chronic TSD by continually enforced locomotion would be strategically difficult and severely confounded with motor fatigue.) Rats subjected to DOW-TSD for 4 days, well before the development of severe TSD symptoms, showed primarily REM sleep rebounds. Rats subjected to 1 day of selective REM sleep deprivation, but not their closely yoked control rats, showed large, significant REM sleep rebounds, which evidently were not induced by the stress of the deprivation method per se. The combined findings prompted reexamination of published evidence relevant to "sleep intensity," including "negative rebounds," rebounds in other species, the effects of stress and fatigue, depth of sleep indicators, and extended sleep. The review points out pitfalls in the designation of any specific pattern as intense sleep.
Animals↗
Effects of paradoxical sleep deprivation on thermoregulation in the rat.
Rats were subjected to chronic paradoxical sleep deprivation (PSD) by the disk-over-water method to determine if they would develop the sustained increase in core (hypothalamic) temperature (T(hy)); elevated temperature setpoint (Tset); and the attenuation of the normal decline in core temperature during the transition from wake to sleep observed in rats subjected to total sleep deprivation (TSD). PSD rats did not show a significant elevation in T(hy). PSD rats and their yoked controls (PSC) were provided with a continuously available operant by which they could increase ambient temperature (Tamb). Change in Tset was assessed by evaluating operant behavior as a function of hypothalamic and intraperitoneal temperature (T(ip)). Unlike TSD rats, PSD and PSC rats maintained near-baseline Tamb at all T(hy) and T(ip) values throughout the deprivation, indicating no change in Tset. As deprivation progressed, PSD rats displayed an attenuation of the normal fall of T(hy) and T(ip) during the transition from wake to sleep. PSC rats did not. During the final quarter of survival time, T(ip) in PSD rats actually rose above waking values during the transition to NREM. These results indicate that PS loss may alter thermoregulation during sleep. It would appear that selective PSD is sufficient to attenuate the normal decline in T(hy) and T(ip) during NREM sleep, whereas NREM loss is required for elevations in T(hy) and Tset.
Animals↗
Current perspectives on the function of sleep.
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Operant control of ambient temperature during sleep deprivation.
Rats subjected to total sleep deprivation (TSD) by the disk-over-water method were provided with a continuously available operant by which they could increase ambient temperature (T(amb)). TSD rats progressively increased operant responses for heat to 700% of baseline levels. During the last quarter of sleep deprivation, they maintained mean T(amb) at 9 degrees C above baseline and held T(amb) over 40 degrees C for 35% of the day. In contrast, yoked control rats (TSC) did not change mean T(amb). Although both TSD and TSC rats showed a progressive decline in intraperitoneal temperature (T(ip)), TSD rats maintained an elevated T(amb) even during periods when T(ip) and brain temperatures (T(br)) were above baseline levels. Thus these results confirm and extend earlier findings that rats subjected to TSD show an increase in temperature set point (T(set)). The earlier studies, which utilized short daily trials in a thermal gradient, demonstrated an increase in T(set) early in the deprivation period. The present study, which obtained more extensive data on thermal preference at a range of body temperatures demonstrated an increasing T(amb) for almost all T(ip) and T(br) values, suggesting a progressive increase in T(set) over the course of sleep deprivation. Surprisingly, survival time was shorter than in previous TSD studies. Reduced survival could not be attributed to differences in T(br), T(ip), energy expenditure, or sleep loss from previous studies.
Animals↗
Are physiological effects of sleep deprivation in the rat mediated by bacterial invasion?
Recent reports have indicated that rats subjected to total sleep deprivation (TSD) by the disk-over-water method and sacrificed when death appeared imminent showed aerobic bacteria in their blood. Yoked control rats did not. Extrapolating from these results, it has been suggested that the late body temperature declines and eventual deaths of TSD rats are caused by septicemia, and that other, earlier-appearing effects of TSD-including weight loss, increased energy expenditure, and regulation of temperature at a higher level-might be mediated by impaired host defenses against bacterial invasion. Three measures of aerobic bacterial invasion were used to evaluate these hypotheses: bacteremia, bacterial colonization in major organs of filtration (liver, kidney, and mesenteric lymph nodes), and adherence of bacteria to the cecal wall. Experiment 1 showed nonsignificant trends toward more bacterial invasion in 4-day TSD rats compared to yoked control rats and no relationship between the bacterial indicators and the early TSD effects. Experiment 2 showed that the elimination of aerobic bacterial infection by antibiotic treatment did not prevent the early TSD effects in 4-day TSD rats. Experiment 3 showed that the elimination of aerobic bacterial invasion in TSD rats did not eliminate the late temperature decline or the progression towards death. The results showed no significant evidence of aerobic bacterial invasion early in TSD and no indication that the major effects of TSD were dependent upon aerobic bacterial invasion.
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Effect of extended sleep deprivation on tumor growth in rats.
To assess the effect of chronic sleep deprivation on host defense, we observed growth and regression of a subdermal allogenic carcinoma (Walker 256 rat tumor) in rats undergoing 10 days of total sleep deprivation (TSD rats), yoked stimulus control (TSC) rats that were partially sleep deprived, and home cage control (HCC) rats. Tumor size was measured daily. Integrated tumor size was smaller in TSD rats than in both TSC (P = 0.04) and HCC rats (P = 0.0003). Thus host defense against these tumors (as defined by reduction in tumor size) was improved by sleep deprivation. This improvement could be a nonspecific effect, e.g., tumor growth can be inhibited by a catabolic state (dietary restriction). TSD and TSC rats lost body weight, indicating a catabolic state. However, tumor size was not predicted by body weight change, but was predicted by change in sleep time (P = 0.02). Host defense enhancement could alternatively result from enhanced immune response. Early tumor size (5 days) was similar in the three groups, but peaked sooner in TSD rats than in both TSC (P = 0.05) and HCC rats (P = 0.01), leading to large differences in size later. Immune-suppressed rats also showed little difference from HCC rats in early growth but large differences later. Thus host defense in an in vivo model that manifests a systemic immune response can be enhanced by sleep deprivation with timing, which is consistent with an enhancement of the immune response.
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Sleep deprivation in rats with preoptic/anterior hypothalamic lesions.
Chronic total sleep deprivation (TSD) of rats by the disk-over-water method reliably produces initial increases and subsequent decreases in waking intraperitoneal (Tip) and hypothalamic (Thy) temperatures, progressive increases in energy expenditure, skin lesions on the tail and plantar surfaces, debilitated appearance, and eventual death. We investigated the possible role of the preoptic/anterior hypothalamus (POAH) in the mediation of the TSD effects by comparing these effects in POAH-lesioned and unlesioned rats. Bilateral POAH lesions sufficient in size to impair homeothermic responses to changes in ambient temperature did not produce TSD-like temperature changes under baseline ambient temperatures of 28-29 degrees C, implying that the thermoregulatory changes produced by TSD do not result from impairment of the lesioned area. However, the possibility remains that the TSD effects are mediated by damage to POAH areas that were not lesioned. During TSD, lesioned and unlesioned rats showed similar progressive increases in energy expenditure, but the lesioned rats showed earlier, steeper, and eventually greater declines in Tip and Thy. This result suggests that in unlesioned rats the POAH may counter-regulate against, and thereby attenuate, the reduction in heat retention caused by TSD. This failure of regulation in lesioned rats is consistent with their impaired response to ambient temperature change and implies that, in unlesioned rats, some POAH thermoregulatory mechanisms continue to function normally during TSD. Lesioned rats did not show the characteristic TSD-induced early increases in Tip and Thy. This result could imply either that heat retention was so compromised that body temperatures did not rise in spite of a TSD-induced increases in thermoregulatory setpoint, or that the setpoint increase in unlesioned rats is POAH-mediated. Notwithstanding the greater Tip and Thy declines in lesioned rats, they survived the TSD procedure longer than the unlesioned rats, thus supporting previous indications that death did not result from hypothermia.
Analysis of Variance↗
Sleep deprivation in the rat: XIX. Effects of thyroxine administration.
Chronic total sleep deprivation (TSD) in the rat produces an initial elevation and then declining body temperatures, increasing metabolic rate and eventual death. Because TSD rats will engage in warming behavior, one hypothesis is that the metabolic increase is an unsuccessful attempt at warming to combat a lethal hypothermia. However, TSD rats also undergo weight loss and progressive deterioration of skin and fur, suggesting TSD-induced pathological catabolic activity, possibly secondary to increased metabolic rate, that could be lethal. To evaluate these alternatives, the metabolic rate of rats was increased by thyroxine (T4) treatment while subjecting them to TSD. Compared to TSD rats not given T4, they had higher metabolic rates, higher body temperatures and reduced warming behavior, but their survival period was 37% shorter. Thus, it is unlikely that hypothermia is the cause of death in TSD rats. Weight and appearance declined more rapidly in T4-treated rats, but at the same proportions of survival time, skin pathology and decline in appearance were less evident in T4-treated rats than in TSD rats not given T4. Thus, there is some doubt whether a general pathological catabolic process is the cause of death. It is also possible that a specific morbid process normally reversed by sleep was accelerated by T4 administration.
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Sleep deprivation in the rat: XX. Differences in wake and sleep temperatures during recovery.
We examined the relationship between wake and sleep peritoneal temperature (T(ip)) during recovery from short-term (five rats, 5 days of deprivation) and long-term (nine rats, 14-21 days) total sleep deprivation (TSD). Mammalian body temperature normally declines in the passage from wakefulness to sleep. Recovery from TSD featured reductions of the typical wake-sleep T(ip) differences. Previous studies from our laboratory have shown that chronic TSD in the rat produces a progressive rise in energy production and an initial rise in wake T(ip), followed by a later fall in T(ip) to below baseline that becomes more acute as death becomes imminent. During recovery from both short-term TSD (wherein pre-recovery wake T(ip) was still above baseline) and long-term TSD (wherein pre-recovery wake T(ip) had fallen to below baseline), wake T(ip) and energy production quickly returned towards baseline. On the first recovery day, both short- and long-term TSD rats showed mean non-rapid eye movement (NREM) and paradoxical sleep (PS) T(ip) values that were slightly, although not significantly, above mean wake T(ip). In short-term TSD rats, wake-NREM and wake-PS T(ip) differences were reduced from baseline significantly (p < 0.0025) on the first recovery day and nonsignificantly on the remaining three recovery days. In long-term TSD rats, wake-NREM and wake-PS T(ip) differences were significantly (p < 0.001) reduced from baseline on the first four recovery day block. On the last four recovery day block, wake-sleep T(ip) differences tended to return toward baseline. Hypothalamic wake-sleep temperature differences in long-term TSD rats showed similar reductions during recovery. The reduction of wake-sleep temperature differences in recovery does not support either energy reduction or cooling functions for sleep.
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Effects of chronic sleep deprivation on central cholinergic receptors in rat brain.
Rats subjected to chronic total sleep deprivation (TSD) by the disk-over-water method have shown very large, sustained rebounds in paradoxical sleep (PS) (also known as REM sleep). Other studies have indicated that cholinergic mechanisms are involved in the instigation and maintenance of PS. Hypothetically, the large PS rebounds could be mediated by an upregulation of cholinergic receptors during TSD. To evaluate this hypothesis, regional brain cholinergic receptors were compared in rats subjected to 10-day TSD by the disk-over-water method (TSD rats), yoked control (TSC) rats which received the same physical stimulation but with much smaller reductions in sleep, and home cage control (HCC) rats. L-[3H]nicotine and [3H]quinuclidinyl benzilate were used as specific cholinergic radioligands for nicotinic and muscarinic receptor binding assays, respectively. Nicotinic receptor binding was not significantly different among groups for any of the brain regions assayed, including frontal cortex, parietal cortex, thalamus, amygdala, hippocampus, anterior hypothalamus, posterior hypothalamus, caudate, limbic system (including septal area, olfactory tubercle, and nucleus accumbens), midbrain, pons, and medulla. Thus, there was no evidence that changes in nicotinic receptors mediate the PS rebounds. For muscarinic receptor binding, TSD rats differed significantly from control rats only in showing a higher binding affinity than TSC rats in the limbic system and a lower binding density than HCC rats in the hippocampus. On the other hand, significant differences in muscarinic receptor binding sites between rats selectively deprived of PS and their yoked controls were found only for the septal area.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Sleep deprivation in the rat: XVIII. Regional brain levels of monoamines and their metabolites.
Several theories have linked sleep with change in monoamine activity. However, the use of sleep deprivation to show that changes in sleep generate changes in monoamines (directly or through feedback) has produced inconsistent results. To explore whether longer sleep deprivation, better documented sleep loss, more complete controls or regional brain analyses would produce clear sleep loss-induced change, eight rats were subjected to total sleep deprivation (TSD) by the disk-over-water method for 11-20 days and were guillotined along with yoked control (TSC) and home-cage control (HCC) rats. Brains were removed and dissected to obtain the caudate, frontal cortex, hippocampus, hypothalamus, midbrain and hindbrain (pons-medulla). Tissue sections were analyzed for concentrations of serotonin (5HT), its metabolite 5-hydroxyindoleacetic acid (5HIAA), dopamine (DA), its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), and either norepinephrine or, in the caudate section, the DA metabolite homovanillic acid. The ratios DOPAC/DA and 5HIAA/5HT, which under some conditions are indicators of turnover, were also calculated. Because sleep deprivation time varied across sets of TSD, TSC and HCC rats and not all eight sets were analyzed simultaneously, a repeated-measures ANOVA was performed within sets with HCC, TSC and TSD considered as successive levels of sleep deprivation treatment. In no case did TSD rats have significantly higher or lower values of amines, metabolites or ratios than both HCC and TSC rats. The most common outlying values were for TSC rats. Thus, these results failed to demonstrate sleep loss-induced regional changes in levels of major brain monoamines or their metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)
3,4-Dihydroxyphenylacetic Acid↗
Effects of chronic total sleep deprivation on central noradrenergic receptors in rat brain.
The effect of chronic total sleep deprivation (TSD) on the regulation of central noradrenergic receptors was evaluated. Rats were subjected to 10 days of TSD by the disk-over-water method. As in previous TSD studies, these rats showed greater increases in food intake and energy expenditure and greater eventual declines in waking body temperature than their yoked-control (TSC) rats. After sacrifice, alpha 1-, alpha 2-, and beta-adrenoceptors were determined in 11 brain regions using radioligand binding assays with [3H]prazosin, [3H]rauwolscine, and 125I-iodocyanopindolol, respectively. Adrenoceptor density and affinity values were significantly different among TSD, TSC, and normally caged control rat groups only for the cerebellum, which showed higher alpha 2-binding density concomitant with lower affinity and lower beta-binding density than cage control rats. Such changes are attributable to apparatus or stimulus effects common to TSD and TSC rats. Given the absence of firm evidence for a TSD-induced downregulation of central noradrenergic receptors, the present results offer no support for the hypothesis of Siegel and Rogawski that a major function of paradoxical sleep is to upregulate these receptors.
Animals↗
Expression of Egr-1 in the brain of sleep deprived rats.
In previous research, rats subjected to prolonged sleep deprivation have shown disturbances of thermoregulation, hormonal and metabolic changes in apparent response to the thermoregulatory problems, lesions on the tail and paws, and eventual death. To search for alterations of functional activity in brain, the expression of the immediate early gene Egr-1 was examined by immunocytochemistry and Northern blotting in rats subjected to total sleep deprivation (TSD) for 10 days. Controls included yoked stimulus-control (TSC) rats, surgically implanted but otherwise undisturbed control rats, and unoperated control rats. Photographs of immunoreacted coronal sections from four sets of rats were ranked blindly for 25 brain regions. TSD rats showed tendencies for regionally specific increases in Egr-1-like immunoreactivity in dorsal raphe, lateral habenula, superior colliculus, and ventral periaqueductal grey. However, most regions showed no differences in Egr-1-like immunoreactivity between TSD and control rats. Neither was there a difference in whole brain Egr-1 mRNA by Northern blot in two additional sets of rats. Thus, this study, like previous studies of brain histology, amines, adrenoceptors, and glucose utilization, does not provide positive support for the hypothesis that sleep protects the central nervous system against massive global damage, fatigue, or dysfunction.
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Sleep deprivation in the rat: XVII. Effect of aspirin on elevated body temperature.
Previous studies of total sleep deprivation (TSD) in the rat have shown an elevation of waking body temperature (Tb) early in the deprivation period. TSD rats defend this rise behaviorally by selecting warm ambient temperatures and autonomically by increasing heat production, thus indicating an elevation of thermoregulatory setpoint. Prostaglandins (PGs) can elevate setpoint and Tb. To investigate whether the TSD-induced rise in setpoint and Tb was mediated by PGs, aspirin, which blocks the synthesis of PGs, was administered 100 mg/kg s.q. to 11 TSD and 13 control (TSC) rats in baseline and deprivation. During baseline, aspirin produced a nonsignificant (0.16 degrees C) rise across all rats in waking Tb. For the sampled time period, waking Tb during deprivation day 3 was significantly elevated in TSD rats (0.64 degrees C, p < 0.01) but not in TSC rats (0.27 degrees C). Aspirin was administered on deprivation day 4. It produced a fall in waking Tb in TSD rats from its deprivation-induced elevation. The difference between the response to aspirin during baseline and during deprivation was significant (-0.25 degrees C, p < 0.05) for TSD rats but not TSC rats (-0.17 degrees C). Time awake after aspirin increased significantly (16.2%, p < 0.05) during baseline and declined nonsignificantly (1.1%) during deprivation. These data imply that at least part of the rise in Tb that is characteristic of TSD is mediated by PGs. To the extent that PGD2 promotes lower Tb and sleep in rats but PGE2 has opposite effects, the results are consistent with a shift from PGD2 predominance in baseline toward PGE2 predominance during TSD.(ABSTRACT TRUNCATED AT 250 WORDS)
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Heritability of dark pulse triggering of paradoxical sleep in rats.
A previous study showed that albino Lewis (L) rats could be triggered into paradoxical sleep (PS) by dark pulse stimulation, i.e., turning off cage lights, whereas brown Norway (BN) rats showed no evidence of PS triggering by dark pulses (2). The transmission of the PS triggering behavior was studied in L x [L x BN]F1 hybrid backcross (BC) animals. Albino BC rats increased PS% during 5-minute dark pulses to three times the average PS% for the preceding 5 minutes of lights-on. In contrast, no significant PS triggering was observed in pigmented BC rats. These data support the hypothesis that PS triggering by dark pulse stimulation is related to albinism in these rat strains. The absence of a connection between PS triggering and total daily amounts of PS suggests independent genetic transmission of these two parameters.
Albinism↗