Biomedical subjects

J M Krueger

Publications and source records attributed to J M Krueger.

At least 19 recordsLinked to original sources

PubMed1999

Nerve growth factor enhances sleep in rabbits.

Nerve growth factor (NGF) elicits rapid-eye-movement sleep (REMS) in cats. Removal of NGF receptor-positive cholinergic basal forebrain neurons inhibits REMS in rats. The aim of the present study was to determine the effects of NGF on sleep and brain temperature (Tbr) in rabbits. Male rabbits were implanted with electroencephalograph (EEG) electrodes, a brain thermistor and an intraventricular (i.c.v.) guide cannula. Rabbits received human beta-NGF i.c.v. (0.01, 0.1, 1.0 or 10 microg] and on a separate day, 25 microl pyrogen-free saline i.c.v. as control. EEG and Tbr were recorded for 23 h after injections. The highest two doses of NGF increased both non-REMS and REMS across the 23-h recording period. REMS was enhanced dose-dependently. Tbr was not affected by any dose of NGF. These results suggest that NGF is involved in both REMS and non-REMS regulation.

Animals↗

PubMed1999

Intrapreoptic microinjection of GHRH or its antagonist alters sleep in rats.

Previous reports indicate that growth hormone-releasing hormone (GHRH) is involved in sleep regulation. The site of action mediating the nonrapid eye movement sleep (NREMS)-promoting effects of GHRH is not known, but it is independent from the pituitary. GHRH (0.001, 0. 01, and 0.1 nmol/kg) or a competitive antagonist of GHRH (0.003, 0.3, and 14 nmol/kg) was microinjected into the preoptic area, and the sleep-wake activity was recorded for 23 hr after injection in rats. GHRH elicited dose-dependent increases in the duration and in the intensity of NREMS compared with that in control records after intrapreoptic injection of physiological saline. The antagonist decreased the duration and intensity of NREMS and prolonged sleep latency. Consistent alterations in rapid eye movement sleep (REMS) and in brain temperature were not found. The GHRH antagonist also attenuated the enhancements in NREMS elicited by 3 hr of sleep deprivation. Histological verification of the injection sites showed that the majority of the effective injections were in the preoptic area and the diagonal band of Broca. The results indicate that the preoptic area mediates the sleep-promoting activity of GHRH.

Animals↗

PubMed1999

Insulin-like growth factor-1 (IGF-1)-induced inhibition of growth hormone secretion is associated with sleep suppression.

The hypothalamic growth hormone (GH)-releasing hormone (GHRH) promotes non-rapid eye movement sleep (NREMS). Insulin-like growth factor-1 (IGF-1) acts as a negative feedback in the somatotropic axis inhibiting GHRH and stimulating somatostatin. To determine whether this feedback alters sleep, rats and rabbits were injected intracerebroventricularly (i.c.v.) with IGF-1 (5.0 and 0.25 microgram, respectively) and the sleep-wake activity was studied. Compared to baseline (i.c.v. injection of physiological saline), IGF-1 elicited prompt suppressions in both NREMS and rapid eye movement sleep (REMS) in postinjection hour 1 in rats and rabbits. The intensity of NREMS (characterized by the slow wave activity of the EEG by means of fast-Fourier analysis) was significantly enhanced 7 to 11 h postinjection in rats. Plasma GH concentrations were measured in 30-min samples after i.c.v. IGF-1 injection in rats and a significant suppression of GH secretion was observed 30 min postinjection. The simultaneous inhibition of the somatotropic axis and sleep raises the possibility that the sleep alterations also result from an IGF-1-induced suppression of GHRH. The late increases in NREMS intensity are attributed to metabolic actions of IGF-1 or to a release of GHRH from the IGF-1-induced inhibition.

Analysis of Variance↗

PubMed1999

Somnogenic relationships between tumor necrosis factor and interleukin-1.

Both tumor necrosis factor (TNF) and interleukin (IL)-1 are somnogenic cytokines. They also induce each other's production and both induce nuclear factor kappa B activation, which in turn enhances IL-1 and TNF transcription. We hypothesized that TNF and IL-1 could influence each other's somnogenic actions. To test this hypothesis, we determined the effects of blocking both endogenous TNF and IL-1 on spontaneous sleep and on sleep rebound after sleep deprivation in rabbits. Furthermore, the effects of inhibition of TNF on IL-1-induced sleep and the effects of blocking IL-1 on TNF-induced sleep were determined. A TNF receptor fragment (TNFRF), as a TNF inhibitor, and an IL-1 receptor fragment (IL-1RF), as an IL-1 inhibitor, were used. Intracerebroventricular injection of a combination of the TNFRF plus the IL-1RF significantly reduced spontaneous non-rapid eye movement sleep by 87 min over a 22-h recording period. Pretreatment of rabbits with the combination of TNFRF and IL-1RF also significantly attenuated sleep rebound after sleep deprivation. Furthermore, the TNFRF significantly attenuated IL-1-induced sleep but not fever. Finally, the IL-1RF blocked TNF-induced sleep responses but not fever. Results indicate that TNF and IL-1 cooperate to regulate physiological sleep.

Animals↗

PubMed1999

Brain-derived neurotrophic factor enhances spontaneous sleep in rats and rabbits.

Various growth factors are involved in sleep regulation. Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family; it and its receptors are found in normal brain. Furthermore, cerebral cortical levels of BDNF mRNA have a diurnal variation and increase after sleep deprivation. Therefore, we investigated whether BDNF would promote sleep. Twenty-four male Sprague-Dawley rats (320-380 g) and 25 male New Zealand White rabbits (4.5-5.5 kg) were surgically implanted with electroencephalographic (EEG) electrodes, a brain thermistor, and a lateral intracerebroventricular cannula. The animals were injected intracerebroventricularly with pyrogen-free saline and, on a separate day, one of the following doses of BDNF: 25 or 250 ng in rabbits; 10, 50, or 250 ng in rats. The EEG, brain temperature, and motor activity were recorded for 23 h after the intracerebroventricular injections. BDNF increased time spent in non-rapid eye movement sleep (NREMS) in rats and rabbits and REMS in rabbits. Current results provide further evidence that various growth factors are involved in sleep regulation.

Animals↗

PubMed1999

Nuclear factor-kappaB-like activity increases in murine cerebral cortex after sleep deprivation.

Several well-defined sleep regulatory substances, e.g., interleukin-1beta, activate the heterodimeric transcription factor nuclear factor-kappaB (NF-kappaB). Several substances that inhibit sleep, e.g., interleukin-4, inhibit NF-kappaB activation. NF-kappaB activation promotes production of several additional substances thought to be involved in sleep regulation, e.g., nitric oxide. We investigated, therefore, whether there are diurnal rhythms of NF-kappaB activation in brain and changes in the activation after sleep deprivation. Mice were kept on a 12:12-h light-dark cycle. In one experiment, groups of mice were killed every 3 h across the 24-h cycle. In another experiment, mice were killed at 1500 after 6 h of sleep deprivation, and a group of control mice were killed at the same time. Nuclear proteins were extracted from each brain tissue sample, and NF-kappaB-like activity was determined with an electrophoretic mobility shift assay. In cerebral cortex, but not other areas of brain, there was a diurnal rhythm in NF-kappaB-like activation; highest levels were found during the light period. NF-kappaB-like activation was higher in cerebral cortex after sleep deprivation compared with values obtained from control mice. The results are consistent with the hypothesis that sleep regulation involves multiple gene events, some of which include enhanced production of sleep regulatory substances, the actions of which involve NF-kappaB activation.

Animals↗

PubMed1999

Synthetic influenza viral double-stranded RNA induces an acute-phase response in rabbits.

Numerous studies have characterized the physiological effects of synthetic, high-molecular-weight, homopolymeric, double-stranded RNA (dsRNA), particularly polyriboinosinic.polyribocytidylic acid [Carter and De Clercq (1974): Science 186:1172-1178], but limited information exists regarding the physiological effects of dsRNA of viral composition and size. In this report, we determined sleep and fever responses of rabbits to intracerebroventricular injection of different doses of synthetic viral dsRNA (either 108 base pairs or 661 base pairs) derived from the N-terminal sequence of gene segment 3 of the A/PR/8/34-H1N1 (PR8) influenza virus. Both the108-mer and the 661-mer dsRNAs increased nonrapid eye movement sleep, suppressed rapid eye movement sleep, and induced fever. The 661-mer dsRNA had more potent somnogenic and pyrogenic effects than the 108-mer dsRNA on the basis of weight. Neither single-stranded RNA from the corresponding sequences had significant effects on sleep or brain temperature. These results demonstrate for the first time that low-molecular-weight, viral dsRNA has the stability in vivo that is required to induce the fever and sleep changes found in natural viral infections, and the hypothesis is supported that virus-associated dsRNA may be responsible for initiating the acute-phase response during viral infections.

Acute-Phase Reaction↗

PubMed1998

Albumin enhances sleep in the young rat.

Rats 4 to 7 days after weaning received intraperitoneal (i.p.) injections of vehicle (baseline day), and either serum (2 mL of lyophilized rabbit serum), 140 mg of rat albumin, or hyperosmotic NaCl (experimental day). Injections were given 1 h before light onset. Sleep-wake activity and cortical brain temperature were recorded during the subsequent 12-h light period. The intensity of non-rapid eye movement sleep (NREMS) was characterized by the power density values of the electroencephalogram slow-wave activity. The sera and albumin preparations enhanced both NREMS and slow-wave activity for 5 to 6 h starting during Hour 2 after light onset. Rapid eye movement sleep (REMS) tended to decrease. Modest (0.6 degrees C maximum deviation) biphasic changes were observed in cortical brain temperature with initial decreases for 3 h followed by rises between Hours 3 and 9 of the light period. There were no differences in the sleep responses to albumin between male and female rats. Albumin also enhanced NREMS in young rats on a protein-rich diet. A significant negative correlation was found between the NREMS promoting activity of albumin injections and the body weight of the rats. NaCl solution with the same osmolarity as that of the albumin solution failed to alter sleep. I.p. albumin injection elicited significant increases in the concentrations of cholecystokinin-like immunoreactivity in the plasma. Sleep-promoting materials (hormones) in the albumin fraction, the calorigenic or nutritional value of proteins, the release of somnogenic cytokines by albumin, or endogenous humoral mechanisms stimulated by proteins (e.g., cholecystokinin or the somatotropic axis) might mediate the enhanced sleep after albumin.

Albumins↗

PubMed1998

Subdiaphragmatic vagotomy does not block sleep deprivation-induced sleep in rats.

Cytokines, such as interleukin-1beta (IL-1beta), are involved in physiological sleep regulation and in the sleep responses to sleep deprivation. Sleep deprivation increases systemic cytokine levels and recent evidence suggests that cytokine-to-brain communication occurs via the vagus nerve. Furthermore, the vagus nerve plays a role in sleep responses elicited by feeding and vagal activity affects electroencephalographic (EEG) activity. Thus, this study examined sleep-wake activity and brain temperature (Tbr) responses to sleep deprivation in subdiaphragmatically vagotomized and sham-operated rats. In control rats, 6 h of total sleep deprivation significantly increased nonrapid eye movement sleep (NREMS), rapid eye movement sleep (REMS), and electroencephalographic slow-wave activity during nonrapid eye movement sleep. Brain temperature was significantly increased during the 6 h of sleep deprivation and decreased following sleep deprivation. Vagotomy had no significant effects on any of these variables. These results indicate that the subdiaphragmatic vagus nerve is not critical in the sleep and thermoregulatory responses after 6 h of sleep deprivation. Together with other data, the current results suggest that central pools of interleukin-1 are important in moderate sleep deprivation-induced sleep responses and that vagotomy does not disrupt the ability to increase sleep using a well-known sleep-inducing stimulus likely mediated by brain cytokines.

Animals↗

PubMed1998

Effects of short-term sleep deprivation on murine immunity to influenza virus in young adult and senescent mice.

Sleep has been proposed as an innate host defense, exerting effects on both specific and nonspecific immunity. In one of the more striking papers dealing with the effects of sleep on specific immunity, Brown et al (Reg. Immunol. 1989; 2: 321-325) reported that depriving influenza virus-immune mice of sleep for 7 hours following total respiratory tract viral challenge abrogated anti-viral immunity within the lungs and lowered the level of anti-influenza antibody in lung homogenates. In the solidly-immune convalescent mouse, nasobronchial immunity to influenza virus has been shown to be due to secretory IgA (S-IgA) within the mucosal mucocilliary blanket, while serum IgG has been shown to mediate protection within the lung parenchyma. In this study we attempted to duplicate the work of Brown et al in solidly immune mice. We were unable to abrogate mucosal anti-influenza viral immunity with a single post-viral-challenge sleep-deprivation episode, nor were we able to depress this immunity with one pre- and two post-challenge sleep-deprivation episodes in young adult or old mice, or with two pre-challenge sleep-deprivation episodes in old mice. Sleep deprivation did not depress the level of serum influenza-specific IgG antibodies, and resulted in increased influenza-specific serum IgG compared with normally sleeping mice in aged immune mice boosted 3 weeks before challenge and sleep deprived once before and twice after challenge (p = 0.005). No differences in anti-viral respiratory immunity were apparent between young and old mice. We conclude that short-term sleep deprivation has minimal effects on pre-existing mucosal and humoral immunity in either the young adult or the senescent mouse.

Aging↗

PubMed1998

An interleukin-1 receptor fragment blocks ambient temperature-induced increases in brain temperature but not sleep in rabbits.

The effects of intracerebroventricular injection (i.c.v.) of an interleukin-1 (IL-1) inhibitor, a soluble IL-1 receptor fragment (IL-1RF), on sleep and brain temperature (Tbr) responses of rabbits induced by mild increases in ambient temperature (Tamb) were determined. Each rabbit was recorded under three conditions: (1) 21 degrees C Tamb plus pyrogen-free saline (PFS); (2) 27 degrees C Tamb plus PFS; (3) 27 degrees C Tamb plus the IL-1RF. The higher Tamb significantly increased Tbr during the warming period; this effect was attenuated by pretreatment with the IL-1RF. The higher Tamb alone (6 h exposure) significantly increased non-rapid eye movement sleep (NREMS) across the 23-h recording period. However, during the 6-h warming period NREMS values, obtained after IL-1 RF treatment, were not significantly different from those obtained from PFS-treated animals at 27 degrees C Tamb. The ability of the IL-1 RF to block Tamb-induced changes in Tbr and the failure of the IL-1RF to block Tamb-induced NREMS responses is different from previous results which indicated that a tumor necrosis factor receptor fragment (TNF-RF) inhibits warm Tamb-induced sleep but not Tbr responses. Thus, brain IL-1 and TNF sleep and thermo mechanisms are, in part, different.

Animals↗

PubMed1998

Vagotomy blocks the induction of interleukin-1beta (IL-1beta) mRNA in the brain of rats in response to systemic IL-1beta.

There is considerable interest in the mechanisms by which systemic cytokines signal the CNS to elicit centrally controlled biological actions. This study determined the effects of intraperitoneal injections of interleukin-1beta (IL-1beta) on IL-1beta mRNA and IL-1 receptor accessory protein (IL-1RAP) mRNA production in rat liver and brain using the reverse transcription-PCR. Saline or IL-1beta (0.5 microg/kg) was injected intraperitoneally in subdiaphragmatically vagotomized and sham-operated (SHAM) rats. All injections were performed at dark onset, and rats were killed 2 hr after the injection. In SHAM rats, IL-1beta increased IL-1beta mRNA levels in the liver, hypothalamus, hippocampus, and brainstem. Subdiaphragmatic vagotomy blocked the IL-1beta-induced increase in IL-1beta mRNA in the brainstem and hippocampus and significantly attenuated the increase in the hypothalamus. Vagotomy did not affect IL-1beta-induced IL-1beta mRNA production in the liver. IL-1RAP mRNA was highly expressed in each region examined; however, no significant differences in IL-1RAP mRNA production were found in any region after IL-1beta injection. The current results indicate that the vagus nerve is involved in transmitting cytokine signals to the brain and suggest that the induction of brain cytokines is a critical step in the pathway by which vagal-mediated signals result in centrally controlled symptoms of the acute phase response.

Animals↗

PubMed1998

Spontaneous release of stable viral double-stranded RNA into the extracellular medium by influenza virus-infected MDCK epithelial cells: implications for the viral acute phase response.

The viral factor responsible for triggering the acute phase response, or 'flu' syndrome, associated with many acute viral infections is not defined. One candidate viral factor is double-stranded RNA (dsRNA) generated during viral replication. In this report we demonstrate by reverse-transcriptase polymerase-chain reaction that nuclease-stable viral RNA was released from influenza-infected MDCK epithelial cells at the time of cell lysis. Removal of virion-associated RNA by ultracentrifugation left equal amounts of positive- and negative-strand viral RNA in the medium that resisted degradation by endogenous RNase in the medium and by exogenous RNase added prior to phenol extraction. These data are the first demonstration that viral RNA with characteristics of dsRNA is spontaneously released from dying influenza virus-infected cells, and thus is available to amplify cytokine induction and contribute to systemic disease.

Acute-Phase Reaction↗

PubMed1998

Oxidized glutathione promotes sleep in rabbits.

Glutatione is implicated in sleep regulation. There are circadian changes in brain glutathione levels, and nocturnal intracerebroventricular (i.c.v.) slow infusion of oxidized glutathione (GSSG) or reduced glutathione (GSH) promotes rapid-eye-movement sleep (REMS) and non-REMS (NREMS) in rats. In the present experiments, we tested the effects of GSSG on duration of sleep, NREMS intensity, and brain temperature in another species, rabbits. Male New Zealand rabbits were injected with isotonic NaCl on a baseline day and one dose of GSSG on the test day [0.15, 1.5, 15, and 150 microg/rabbit, i.c.v., or 1.5 or 15 mg/kg intravenously (i.v.)]. Electroencephalogram (EEG), motor activity, and brain temperature were recorded for 6 h. Injection of 15 microg GSSG i.c.v. significantly increased the time spent in NREMS in the first 3 h after the injection. Injection of 0.15, 1.5, and 150 microg i.s.v. GSSG, as well as systemic injections of GSSG did not affect NREMS. Intensity of NREMS as measured by EEG slow-wave activity during NREMS, and brain temperature were not affected by any of the treatments. These results are consistent with the hypothesis that glutathione may be a sleep-inducing factor in the brain.

Animals↗

PubMed1998

Sleep-associated changes in interleukin-1beta mRNA in the brain.

Much evidence implicates interleukin-1beta (IL-1beta) in sleep regulation. Two previous studies indicated that levels of IL-1beta in mRNA were affected by sleep. In the current study, levels of IL-1beta mRNA and IL-1 receptor assessory protein (IL-1RAP) mRNA were determined 1 h after the beginning of light and dark periods and after sleep deprivation, using the reverse transcriptase-polymerase chain reaction (RT-PCR) and mutated internal standards. Daytime samples contained relatively more IL-1beta mRNA than nighttime samples, and levels of IL-1beta mRNA were higher after sleep deprivation. These changes occurred in the hypothalamus, hippocampus, cerebral cortex, and mesencephalon/pons. In contrast, the IL-1 RAP mRNA level did not seem to be affected by sleep.

Animals↗

PubMed1998

Cafeteria diet-induced sleep is blocked by subdiaphragmatic vagotomy in rats.

Feeding rats a cafeteria diet results in increased food intake and excess sleep. Furthermore, vagal afferent activity is altered by a variety of gastrointestinal factors, and vagal stimulation can induce sleep. We investigated, therefore, the hypothesis that the vagal nerve plays a critical role in mediating the sleep-inducing effects of cafeteria feeding. We examined the effects of a cafeteria diet on sleep, electroencephalographic (EEG) slow-wave activity (SWA), and brain temperature (Tbr) in control and vagotomized rats. EEG, electromyogram, and Tbr were recorded for 7 consecutive days. Day 1 was considered a baseline day; normal rat chow was available ad libitum. On days 2-4, the animals were fed, in addition to normal chow, a mixed, energy-rich diet (cafeteria diet). On days 5-7, the rats were again fed only normal rat chow. In control rats, the cafeteria diet resulted in an increase in non-rapid eye movement sleep (NREMS), which was the result of a significant lengthening of the NREMS episodes. In contrast, feeding vagotomized rats the cafeteria diet resulted in a decrease in NREMS. Cafeteria feeding decreased REMS and EEG SWA and increased Tbr in both control and vagotomized rats. These results suggest that an intact vagus plays a key role in the NREMS-inducing effects of the cafeteria diet.

Afferent Pathways↗

PubMed1998

Vagotomy attenuates but does not prevent the somnogenic and febrile effects of lipopolysaccharide in rats.

The role of the vagus nerve in the somnogenic and pyrogenic effects of lipopolysaccharide (LPS) was studied in rats. Control rats (n = 8) and rats subjected to bilateral subdiaphragmal vagotomy (VX; n = 9) were injected with 100 micrograms/kg i.p. LPS at the beginning of the dark period. Sleep and brain temperature (Tbr) were recorded for 23 h after the injections. LPS caused increases in non-rapid eye movement sleep (NREMS) for 12 h after the injection in control rats. Sleep intensity, as indicated by the slow-wave activity (SWA) of the electroencephalogram during NREMS, was suppressed. LPS elicited biphasic Tbr responses: an initial hypothermia was followed by increases in Tbr that lasted for approximately 20 h. In vagotomized rats, the NREMS responses to LPS were blunted. The magnitude of the LPS-induced NREMS increases was about one-half of that seen in control rats, and these sleep responses lasted only for 6 h. LPS did not affect SWA in VX animals. VX completely abolished the hypothermic responses to LPS and shortened the duration of the hyperthermia. The results suggest that the subdiaphragmal vagi play an important, but not exclusive, role in the somnogenic and pyrogenic actions of intraperitoneally injected LPS.

Animals↗

PubMed1998

Effects of interleukin-1 beta on sleep are mediated by the type I receptor.

Interleukin-1 beta (IL-1 beta) is a well characterized sleep regulatory substance. To study receptor mechanisms for the sleep-promoting effects of IL-1 beta, sleep patterns were determined in control and IL-1 type I receptor knockout (IL-1RI KO) mice with a B6x129 background after intraperitoneal injections of saline or murine recombinant IL-1 beta. The IL-1RI KO mice had slightly but significantly less sleep during the dark period compared with the controls. IL-1 beta dose dependently increased non-rapid eye movement sleep (NREMS) and suppressed rapid eye movement sleep (REMS) in the controls. The IL-1RI KO mice did not respond to IL-1 beta. In contrast, the IL-1RI KO mice increased NREMS and decreased REMS after administration of tumor necrosis factor-alpha (TNF-alpha), another well characterized sleep-promoting substance. These results 1) provide further evidence that IL-1 beta is involved in sleep regulation, 2) indicate that the effects of IL-1 beta on sleep are mediated by the type I receptor, and 3) suggest that TNF-alpha is capable of inducing sleep without the involvement of IL-1.

Animals↗