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Department of Physiology and Biophysics, The University of Tennessee, Memphis, Tennessee 38163
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ABSTRACT |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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The
mechanism by which peripheral cytokines signal the central nervous
system to elicit central manifestations of the acute phase response
remains unknown. Recent evidence suggests that cytokines
may signal the brain via the vagus nerve. To test this possibility, we
examined sleep-wake activity and brain temperature (Tbr) after the intraperitoneal
administration of saline or three doses (0.1, 0.5, and 2.5 µg/kg) of
interleukin-1
(IL-1) in subdiaphragmatically vagotomized (Vx) and
sham-operated (Sham) rats. The lowest dose of IL-1 (0.1 µg/kg)
increased non-rapid eye movement sleep (NREMS) and slightly elevated
Tbr in Sham rats; both responses
were blocked in Vx animals. The middle dose tested (0.5 µg/kg)
increased NREMS and Tbr in Sham
animals; however, in Vx rats, the increase in NREMS was attenuated and
the increase in Tbr was blocked.
The highest dose of IL-1 used (2.5 µg/kg) induced increases in
NREMS, decreases in rapid eye movement sleep, and a hypothermic
response followed by a biphasic fever; these responses were similar in both Sham and Vx rats. These data provide strong evidence that the
subdiaphragmatic vagus plays an important role in communicating both
sleep and fever signals to the brain. However, there is clearly an
alternative pathway by which IL-1 can signal the brain; whether it
occurs through activation of other vagal afferents or through direct or
indirect actions on the brain remains unknown.
cytokine; vagus nerve; non-rapid eye movement sleep; rapid eye movement sleep; brain temperature; electroencephalogram slow-wave activity
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INTRODUCTION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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THERE IS CONSIDERABLE evidence linking interleukin-1
(IL-1) to physiological sleep regulation.
Administration of exogenous IL-1 via intraperitoneal, intravenous,
or intracerebroventricular routes results in relatively large increases
in non-rapid eye movement sleep (NREMS) in rats, rabbits, mice, cats,
and monkeys (reviewed in Ref. 19). Inhibition of
endogenous IL-1, using the IL-1 receptor antagonist, anti-IL-1
antibodies, or the soluble IL-1 receptor, reduces spontaneous sleep
(19) and inhibits sleep rebound after sleep deprivation (35). IL-1
and other members of the IL-1 family of molecules are constitutively
expressed in the brain (19). Cat cerebrospinal fluid levels of IL-1 are
reported to vary in phase with the sleep-wake cycle (24). Furthermore, there is a diurnal rhythm of IL-1 mRNA in the hypothalamus,
hippocampus, and cortex of rats with the highest levels corresponding
to peak sleep periods (34). Finally, after sleep deprivation, brain stem and hypothalamic levels of IL-1 mRNA increase (25).
In addition to its role in physiological sleep regulation, IL-1 also
appears to play a key role in mediating the various facets of the acute
phase response, such as loss of appetite, social withdrawal, fever, and
excess sleep, which occur during infectious disease. Indeed,
administration of exogenous IL-1 elicits all of these illness
responses (17). In contrast, the administration of antibodies or
antagonists to IL-1 blocks illness responses induced by agents such
as lipopolysaccharide (LPS) (17, 18) or muramyl dipeptide (36).
Although it is clear that IL-1 and other products of the immune
system, such as tumor necrosis factor-
, have far-ranging effects on
central nervous system functions, it is still unclear how such
molecules, whether systemically released or experimentally injected,
gain access to the brain because most are relatively large and
hydrophilic peptides that are not expected to readily cross the
blood-brain barrier.
Various hypotheses have been proposed to address this issue, including
entry into the brain at sites where the blood-brain barrier is
deficient, e.g., through circumventricular organs, and active transport
into the brain (1, 3). Although each hypothesis has its supporting
data, it is uncertain whether the amounts shown to enter the brain are
sufficient to induce sleep and/or fever. Furthermore,
peripherally released cytokines induce the synthesis and release of
cytokines in the brain, and these locally produced cytokines are likely
critical for brain-cytokine actions. For example, an intravenous
injection of muramyl dipeptide increases sleep in rabbits; this sleep
response is blocked with an intracerebroventricular injection of the
IL-1 receptor fragment, an inhibitor of IL-1 (36). Hence, an
alternative pathway by which peripheral cytokines can affect central
nervous system functions has recently been suggested (reviewed in Refs.
3 and 39): that is, that neural afferents, such as the vagus nerve, are
posited to transmit peripheral immune messages to the brain. Indeed,
IL-1-induced fever (28, 38), taste aversion (11), and behavioral
changes (5, 6), as well as LPS-induced fever (13, 32), gene expression
(23, 37), and depression of food-motivated behavior (6) are blocked or
attenuated by vagotomy.
In addition to this putative role of the vagal nerve in communicating
immune signals to the brain, the vagus nerve is known to play a role in
the regulation of vigilance. Vagal nerve stimulation induces
electroencephalographic (EEG) synchronization (7) and excess sleep
(30). The NREMS-promoting effects of increased food intake are
inhibited by vagotomy (M. K. Hansen, L. Kapás, J. Fang, and J. M. Krueger, unpublished data). In addition, viscerosensory activity
influences the sleep-wakefulness rhythm. For example, low-frequency
stimulation of the small intestine and splanchnic nerve induces EEG
activity characteristic of sleep that outlasts the period of
stimulation (22), and repetitive intestinal stimulation increases sleep
duration in both starved and satiated cats (21). We hypothesized that
the NREMS-promoting effects of intraperitoneal IL-1 are dependent on
an intact vagal nerve and that the role of the vagal nerve may vary
with differing doses of IL-1. To test this hypothesis,
subdiaphragmatically vagotomized (Vx) and sham-operated (Sham) rats
were injected with three doses of IL-1, and the resultant effects on
sleep-wake activity and brain temperature
(Tbr) were evaluated.
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MATERIALS AND METHODS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Animals
Male Sprague-Dawley rats (250-275 g at purchase; Harlan Sprague Dawley, Indianapolis, IN) were used in this study. The animals were housed individually and maintained on a light-dark cycle of 12:12 h (lights on at 0600) and at an ambient temperature of 25 ± 1°C. Food and water were continuously available.Surgical Techniques
Vagotomy and pyloroplasty. Subdiaphragmatic vagotomy and pyloroplasty were performed on rats as previously described (M. K. Hansen, L. Kapás, J. Fang, and J. M. Krueger, unpublished data). Briefly, after an overnight fast, rats were anesthetized using ketamine-xylazine (87 and 13 mg/kg ip, respectively). The stomach and lower esophagus were visualized from an upper midline laparotomy. The stomach was gently retracted down beneath the diaphragm to clearly expose both vagal trunks. Each vagal trunk was ligated, and at least 1 cm of the visible vagal nerve was dissected. In addition, all neural and connective tissue surrounding the esophagus immediately below the diaphragm was removed to transect all small vagal branches. The vagotomy was supplemented with pyloroplasty to prevent gastric stasis. An incision was made parallel to the axis of the pylorus, through the pyloric sphincter, and then the pylorus wall was reconstructed by sutures perpendicular to the pylorus axis. The stomach was returned to its normal position, and the incisions were closed. Sham animals were also prepared, subjected only to pyloroplasty.
It has been suggested that the lack of responsiveness in Vx rats may be due to their poor health and malnutrition (31). Thus, in an attempt to monitor the health of the animals, body weight was measured daily in both Vx and Sham animals for 2 wk after surgery. Vx rats initially lost more weight than their Sham controls; however, they began to gain weight at a similar rate as Sham rats (Fig. 1). Furthermore, the body weight did not differ significantly when experimental testing was begun (Sham 377 ± 5 g; Vx 370 ± 7 g).
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Sleep surgery. Three weeks after either Vx or Sham surgery, the animals were implanted with cortical EEG and nuchal electromyographic (EMG) electrodes and a brain thermistor to measure Tbr as previously described (20). Briefly, EEG electrodes were placed over the frontal and parietal cortices, and a thermistor (model 44008; Omega Engineering, Stamford, CT) was placed on the dura over the parietal cortex. Insulated leads from the EEG and EMG electrodes and thermistor were routed to a Teflon pedestal (Plastics One, Roanoke, VA) and cemented to the skull with dental adhesive (3M, St. Paul, MN). After a 1-wk recovery period, the animals were placed into individual, sound-attenuated, sleep-recording cages for adaptation to the experimental conditions.
Recordings
EEG, EMG, and Tbr were recorded by computer. EMG activity served as an aid for determining the vigilance states and was not further quantified. EEG was filtered below 0.1 and above 40 Hz. The amplified signals were digitized at a frequency of 128 Hz for EEG and EMG and 2 Hz for Tbr. Single Tbr samples were saved on hard disk in 10-s intervals. Average Tbr values were calculated in 1-h time blocks. The vigilance states were determined off-line in 10-s epochs. EEG, EMG, and Tbr were displayed on the computer monitor in 10-s epochs and also simultaneously in a more condensed form in 12-min epochs. Wakefulness, NREMS, and rapid eye movement sleep (REMS) were distinguished as described before in detail (20). Briefly, the criteria for vigilance states are as follows (NREMS: high-amplitude EEG slow waves, low-level EMG activity, and declining Tbr on entry; REMS: highly regular theta activity in the EEG, general lack of body movements with occasional twitches, and a rapid rise in Tbr at onset; wakefulness: low-amplitude, fast EEG activity, high EMG activity, and a gradual increase in Tbr after arousal). Time spent in each vigilance state was calculated for 2-h intervals. On-line fast Fourier analysis of the EEG was performed in 10-s intervals on 2-s segments of the EEG in 0.5-Hz bands of the 0.5-4.0 Hz frequency range. The EEG power density values in the delta frequency range were summed for each 10-s epoch of NREMS, and average activities in 2-h intervals were calculated for the NREMS periods. The delta activity during NREMS (also called slow-wave activity, SWA) is often regarded as a measure of sleep intensity.Experimental Protocol
Pyrogen-free saline (0.9% NaCl) was obtained from Abbott Laboratories (North Chicago, IL), and recombinant human IL-1 was obtained from
R&D Systems (Minneapolis, MN). IL-1 was dissolved in pyrogen-free
saline and delivered in an injection volume of 2 ml/kg. All injections
were given intraperitoneally.
One week after EEG-implant surgery, thus approximately 4 wk after
either Vx or Sham surgery, the rats (n = 8 for each group) were attached to recording cables for habituation.
During this 7- to 10-day period the animals received daily
intraperitoneal injections of saline at the time when the experimental
treatments were to be done. Three doses of IL-1 were tested (0.1, 0.5, and 2.5 µg/kg). These doses were chosen on the basis of a
dose-response curve determined in a pilot study of IL-1 on
sleep-wake activity in rats (M. K. Hansen, L. Kapás, and J. M. Krueger, unpublished data). A within-subject
experimental design was used; thus the animals were injected with
saline on one day (control day) and with one dose of IL-1 on the
following day (test day). At least a 1-wk period was allowed between
test days. Furthermore, for each rat, recordings were taken on three
separate control days. When rats received IL-1, it was in the order
of the lowest dose to highest dose. There were no signs of tolerance to
IL-1 in either the pilot study or in this experimental study. All
injections were given promptly at dark onset (1800). EEG, EMG, and
Tbr were recorded for 23 h
beginning at dark onset for each control day (n = 3 for each rat) and each test
day.
Verification Procedures
On completion of the experiments the completeness of vagotomy was assessed using two independent approaches. The first test is based on the satiety effect of cholecystokinin (CCK, Ref. 33). Saline or CCK (4 µg/kg; Peninsula Laboratories) was injected intraperitoneally after 20 h of food deprivation, and food intake was measured after 1 h. The second test is based on the stimulation of gastric acid secretion via the vagus nerve by 2-deoxy-D-glucose (2-DG, Ref. 8) and was performed as previously described (M. K. Hansen, L. Kapás, J. Fang, and J. M. Krueger, unpublished data). Briefly, gastrotomy was performed along the greater curvature in anesthetized rats, the mucosa was exposed, and the bleeding points were ligated. A moistened gauze sponge was placed over the gastric mucosa, and 2 ml of 5% 2-DG were injected intravenously via the femoral vein. This was followed, after a period of 10 min, by 1 ml of a 1% solution of neutral red. The moistened sponge was periodically examined for the presence of a purple color. The neutral red, which is secreted in conjunction with gastric acid, appears purple on the sponge in those rats with an intact vagus; all Vx rats failed this test.Statistical Analysis
The effects of IL-1 on sleep, SWA, and
Tbr were determined by two-way
analysis of variance (ANOVA) for repeated measures across the 23-h
recording period. The first independent variable was the treatment
(saline vs. IL-1) and the second independent variable was time. When
ANOVA indicated significant effects, the Student-Newman-Keuls (SNK)
test was used to reveal where the significant effect had occurred. In
all tests an -level of P < 0.05 was taken as an indication of statistical significance.
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RESULTS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Vagotomy Blocks Satiety Effect of CCK
CCK significantly inhibited food intake in Sham [F(1,14) = 32.748, P < 0.0001; SNK q(4,14) = 14.35, P < 0.01], but not Vx rats, thereby confirming the role of the vagus nerve in CCK-induced satiety (33). Food intake was decreased by about 50% in CCK-injected Sham rats compared with saline-injected Sham rats (3.25 ± 0.40 vs. 6.46 ± 0.4 g, respectively). In contrast, CCK did not significantly decrease food intake in Vx rats compared with saline injection (4.90 ± 0.7 vs. 5.55 ± 0.78 g, respectively).Vagotomy Blocks Effects of 0.1 µg/kg
IL-1
increased NREMS (Fig.
2, Table 1).
On the control day Sham rats spent 61 ± 3 min in NREMS during the
first 4 h compared with 90 ± 6 min on the test day [SNK
q(6,35) = 9.307, P < 0.01]. In addition, this
dose of IL-1 significantly increased
Tbr in hour
2 [SNK q(4,154) = 4.40, P < 0.01]. In
contrast, this dose of IL-1 failed to induce significant changes in
NREMS or Tbr in Vx rats. REMS and
EEG SWA were not altered in either group.
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Vagotomy Attenuates NREMS-Inducing Effects of 0.5 µg/kg IL-1
increased NREMS
and Tbr in Sham rats (Fig.
3, Table 1). NREMS was increased in the
first 6 h [SNK q(4,21) = 9.596, P < 0.01], and
Tbr was increased in
hours 1 and
2 [SNK (hour
1) q(3,154) = 3.75, P < 0.05; (hour
2) q(10,154) = 5.56, P < 0.01]. In Vx rats NREMS
was also significantly increased [SNK
q(3,21) = 4.829, P < 0.01]; however, this
response was significantly attenuated in Vx rats compared with Sham
rats (t14 = 4.09, P < 0.002). NREMS was increased by
about 58 min in Sham rats compared with about 22 min in Vx rats during
this time period. The increase in
Tbr was completely blocked in Vx
animals. REMS was not affected in either group, and there was a slight,
but not significant, decrease in EEG SWA in both Sham and Vx rats.
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Vagotomy Does Not Block Effects of 2.5 µg/kg
IL-1
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Vagotomy Does Not Affect Normal Sleep-Wake Activity or Tbr
To compare sleep-wake activity and Tbr in Sham and Vx rats, the data on the 3 control days for each group were averaged. Confirming a previous report (M. K. Hansen, L. Kapás, J. Fang, and J. M. Krueger, unpublished data), vagotomy does not significantly alter sleep-wake activity or Tbr (Fig. 5). In both Sham and Vx rats the distribution of the states of vigilance followed a normal diurnal pattern with high percentages of sleep during the day. Maximum durations of NREMS and REMS occurred during the first and second portions of the light period, respectively. Furthermore, Tbr varied with the diurnal cycle, being higher during the dark period (the behaviorally active period of rats).
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DISCUSSION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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The present results demonstrate that the vagus is indeed a crucial
component in the pathway by which peripheral IL-1 signals the
central nervous system to elicit various components of the acute phase
response. However, the importance of the subdiaphragmatic vagus varies
greatly depending on the dose of IL-1 used. Thus at low doses both
IL-1-induced NREMS and fever were completely abolished by
subdiaphragmatic vagotomy. These results are consistent with the
findings that IL-1 increases the afferent activity of the vagal
nerve (26), and IL-1 receptors are found on paraganglia in the hepatic
vagus (12). Furthermore, they are consistent with a previous study that
found that the somnogenic and pyrogenic effects of LPS (100 µg/kg ip)
are attenuated in Vx rats (15). Finally, they are consistent with the
finding that vagotomy blocked the increase in sleep, which accompanies
increased feeding (M. K. Hansen, L. Kapás, J. Fang, and J. M. Krueger, unpublished data).
The finding that vagotomy did not block the sleep and fever responses
to a high dose of IL-1 indicates that IL-1 also triggers sleep
and thermoregulatory mechanisms that are not dependent on intact
subdiaphragmal vagi. It is expected that after the intraperitoneal administration of high doses, significant quantities of IL-1 may
enter the systemic circulation. When plasma levels of IL-1 are
relatively high, they may then be able to reach intact vagal afferents
in other peripheral sites, such as in the lung. In support of this,
mice inoculated with influenza virus exhibit symptoms of the acute
phase response, yet there is no increase in the circulating levels of
cytokines (9). Significant elevations of cytokine activity were,
however, found in the lung lavage fluid; hence, it is likely, and even
suggested, that cytokine signals may be conveyed to the brain by a
neural pathway. In addition, it is possible that cytokines in the
plasma may enter the brain in amounts sufficient to activate central
somnogenic and pyrogenic structures; if plasma levels of cytokines were
high, this mechanism could supplement vagal-mediated events. Cytokine
entry into the brain may take place at sites where the blood-brain
barrier is missing, e.g., the organum vasculosum laminae terminalis or
area postrema, or via blood-to-brain transport mechanisms.
Alternatively, it is possible that IL-1 or LPS stimulates the
production of one or more low-molecular-weight messengers outside the
blood-brain barrier. These messengers may then enter the brain and act
on neurons within the brain. One possible candidate for such a
diffusable molecule is nitric oxide (NO). NO is induced by microbial
products and also induces sleep (16).
Although these "other" vagal and nonvagal arguments remain
speculative, recent data in the literature provide some support for
these ideas. Thus vagotomy suppresses fever in guinea pigs in response
to LPS or muramyl dipeptide when administered intraperitoneally but not
when given by the intramuscular route (13). Furthermore, vagotomy
attenuated the depression in social behavior in mice only when IL-1
was given by the intraperitoneal route and not when administered
intravenously or subcutaneously (5). In both studies, it was concluded
that the vagus only conveys immune signals to the brain when injected
into the abdominal cavity. However, in this study, when higher doses
were injected into the abdominal cavity, sleep and fever were not
blocked by vagotomy, thereby suggesting that in addition to the
subdiaphragmatic vagus alternate pathways exist that contribute to the
centrally controlled symptoms of the acute phase response.
EEG delta-wave amplitudes are thought to reflect the intensity of
NREMS. For example, EEG SWA increases after sleep deprivation (29). In
the present study, the highest dose of IL-1 induced increases in EEG
SWA during maximum sleep responses. This finding is consistent with
studies showing that central or systemic injections of IL-1 or
microbial products, such as LPS, increase EEG SWA (19, 27). Similar
increases in EEG SWA occur during the initial phase of the NREMS
responses to infection (19). These changes in EEG SWA, like those
occurring after sleep deprivation, are likely mediated in part by
IL-1 because inhibition of IL-1 attenuates sleep
deprivation-induced (35) and microbial product-induced (36) increases
in EEG SWA. However, the highest dose of IL-1 also caused a large
initial suppression of EEG SWA and a long-lasting suppression in
hours 7-23. Similar results were
found in mice injected intraperitoneally with a high dose of IL-1
(10) and suggest that the effects of IL-1 on EEG SWA and duration of
NREMS can be dissociated. Indeed, it is known that circadian factors modulate the effects of IL-1-induced duration of NREMS and EEG SWA
independently (27). Furthermore, there are many interactions between
IL-1 and classic neurotransmitters and humoral factors that could
independently affect duration of NREMS and EEG SWA. For example,
IL-1 induces the release of growth hormone-releasing hormone,
another well characterized sleep-promoting substance that also enhances
EEG SWA (19). In contrast, intraperitoneal administration of IL-1
increases brain norepinephrine (NE) turnover rate; activation of brain
NE systems is known to suppress EEG SWA (2). Therefore, it is likely
that the enhancing and suppressing effects of IL-1 on EEG SWA are
mediated by different molecular pathways and that these mechanisms are
independent of those responsible for duration of NREMS.
It has been suggested that the lack of effects in Vx animals may be due
to poor health (31). In the present study, it is very unlikely that the
unresponsiveness of Vx rats to low and intermediate doses of IL-1
was due to malnutrition because the body weights of each group of rats
were similar, and high doses of IL-1 were capable of inducing both
sleep and fever in the same rats. Secondly, the fact that Vx rats had
normal sleep patterns at the time of experimental testing indicates
that the rats were not seriously distressed; it is well known that any
distress seriously affects sleep. Finally, the finding that Vx rats
respond to central injections of IL-1 (4) suggests that vagotomy
itself does not impair the direct sensitivity of the brain to immune
signals. The current data clearly demonstrate that the vagal nerve is
an important element in the pathway by which peripheral cytokines signal the central nervous system to elicit various facets of the
sickness syndrome.
Perspectives
Much evidence supports the hypothesis that brain IL-1 is critical for immune-cytokine interactions. The central administration of anti-IL-1 antibodies, the IL-1 receptor antagonist, or the IL-1 receptor fragment inhibits sleep (36) and behavioral responses (17), as well as fever (18), in response to peripherally injected immune stimuli. Furthermore, peripheral immune stimuli induce cytokine expression in the brain. Subdiaphragmatic vagotomy blocks the induction of IL-1 mRNA in the
hippocampus and hypothalamus of LPS-treated mice (23). This evidence
therefore suggests that the induction and subsequent release of IL-1
in the brain may be a final and critical step in the pathway by which
vagally mediated immune signals result in centrally controlled symptoms
of the acute phase response.
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ACKNOWLEDGEMENTS |
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We thank Dr. Levente Kapás for contributions in the experimental design and Dr. Jidong Fang for help with the statistical analysis. We thank Maria Swayze-Nations for secretarial assistance and Jin Emerson-Cobb for editorial assistance.
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FOOTNOTES |
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This work was supported in part by the National Institute of Neurological Disorders and Stroke Grants NS-25378, NS-27250, and NS-31453, the Office of Naval Research (N00014-90-J-1069), and by a National Research Service Award (MH-11688) from the National Institute of Mental Health.
Address for reprint requests: J. M. Krueger, Dept. of VCAPP, College of Veterinary Medicine, Washington State Univ., Pullman, WA 99164-6520.
Received 4 April 1997; accepted in final form 20 June 1997.
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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and 
), rapid
eye movement sleep (REMS, 
and 
), electroencephalographic (EEG)
slow-wave activity (SWA, 
and 
) during NREMS, and brain
temperature (Tbr, 
and 
) in
Sham (A) and vagotomized
(B) rats. Data points for NREMS,
REMS, and SWA represent values averaged in 2-h intervals ± SE (the
last data point is a 1-h time block).
Tbr values represent 1-h averages ± SE. Open symbols, saline treatment; solid symbols, IL-1
treatment; horizontal dark bar, dark period of day.
