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-induced sleep
and EEG 
-activity in rats
Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, Washington 99164-6520
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Much evidence suggests that tumor necrosis
factor-
(TNF-) is involved in the regulation of physiological
sleep. However, it remains unclear whether peripheral administration of
TNF- induces sleep in rats. Furthermore, the role of the vagus nerve in the somnogenic actions of TNF- had not heretofore been studied. Four doses of TNF- were administered intraperitoneally just before the onset of the dark period. The three higher doses of TNF- (50, 100, and 200 µg/kg) dose dependently increased nonrapid eye movement
sleep (NREMS), accompanied by increases in electroencephalogram (EEG)
slow-wave activity. TNF- increased EEG 
-power and decreased EEG
- and 
-power during the initial 3 h after injection. In vagotomized rats, the NREMS responses to 50 or 100 µg/kg of TNF- were attenuated, while significant TNF--induced increases in NREMS
were observed in a sham-operated group. Moreover, the vagotomized rats
failed to exhibit the increase in EEG -power induced by TNF-
intraperitoneally. These results suggest that peripheral TNF- can
induce NREMS and vagal afferents play an important role in the effects
of peripheral TNF- and EEG synchronization on sleep. Intraperitoneal
TNF- failed to affect brain temperature at the doses tested, thereby
demonstrating that TNF--induced sleep effects are, in part,
independent from its effects on brain temperature. Results are
consistent with the hypothesis that a cytokine network is involved in
sleep regulation.
electroencephalogram; brain; vagus nerve
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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TUMOR NECROSIS FACTOR
(TNF)- is involved in physiological sleep regulation (reviewed in
Ref. 20). Administration of exogenous TNF- induces
physiological nonrapid eye movement sleep (NREMS) in various species
(8, 18, 27, 35). TNF-enhanced sleep appears to be similar
to physiological sleep; for instance, it is readily reversible, and
sleep-coupled autonomic changes [e.g., brain temperature
(Tbr)] remain intact (reviewed in Ref. 19). Inhibition of endogenous TNF- activity during the light period using
an anti-TNF- antibody (30), the soluble TNF receptor (34), or fragments of soluble TNF receptors
(31-33) reduces spontaneous sleep. TNF- is
constitutively expressed in the normal brain (2). Brain
TNF- and its mRNA levels correlate with sleep propensity; they are
highest at light onset, which is the period of maximal sleep in rats
(3, 9). TNF receptor mRNA is also expressed in the normal
brain (16). There are two cell surface receptors for TNF
(55 and 75 kDa), and the TNF 55-kDa receptor is thought to be involved
in sleep regulation (8). Mice lacking the 55-kDa TNF
receptor do not exhibit enhanced NREMS responses if given exogenous
TNF; these mice also have less spontaneous sleep than do control
strains of mice (8). TNF- activates nuclear factor-
B (NF-B), a transcriptional factor that can promote transcription of
several substances also implicated in sleep regulation, e.g., nitric
oxide synthase, cyclooxygenase-2 (Cox-2), the adenosine A1
receptor, interleukin (IL)-1, nerve growth factor, and TNF- (reviewed in Ref. 20).
Many TNF- actions on the central nervous system (CNS), including
anorexia and changes in body temperature and sleep, occur after
peripheral administration of TNF- (8, 23, 27, 29). In
humans, blood levels of TNF- are related to electroencephalogram (EEG) -activity during sleep (5). Also, higher plasma
levels of TNF- are thought to contribute to daytime somnolence in
patients with obstructive sleep apnea (7). Sleep loss is
also associated with increases in TNF plasma levels (15),
and the ability of circulating white blood cells to produce TNF- is
enhanced after sleep deprivation (36, 38). Although these
findings suggest that peripheral TNF- is associated with, and may
affect, the sleep/wake cycle, the effects of peripheral administration
of TNF- on sleep have not been elucidated in rats. Moreover, how peripheral TNF- affects the CNS remains obscure. TNF- could penetrate the blood-brain barrier and thereby affect the CNS
(11). Another possible mechanism is that cytokines may act
on brain capillary endothelium and circumventricular organs
(22). TNF might also act on vagal afferents to transmit
information to the brain in a manner similar to that demonstrated for
IL-1 (13, 14). For instance, Hansen and Krueger
(13) reported that subdiaphragmatic vagotomy attenuated
IL-1-induced sleep and fever responses. They also showed that
vagotomy blocked IL-1 mRNA expression in the brain that was induced
by intraperitoneal administration of IL-1 (14).
Furthermore, considerable evidence suggests that the activity of vagal
afferents can affect sleep. For instance, EEG synchronization is
affected by stimulation of vagal afferents (reviewed in Ref. 25). Repetitive intestinal stimulation or carotid sinus
stimulation can induce sleep (reviewed in Ref. 25). Thus
we hypothesized that the sleep-promoting effects of systemic TNF-
may be mediated in part by intact vagal afferents. We report here that
vagotomy attenuated intraperitoneal TNF--induced sleep responses.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Agents
Rat recombinant TNF- was purchased from Peprotech (Rocky
Hill, NJ). In a preliminary study, rats were given recombinant rat TNF- (50 µg/kg) purchased from R&D Systems (Minneapolis, MN); results were indistinguishable from those reported here (data not
shown). TNF- was dissolved in pyrogen-free saline (PFS; Abbott Laboratories, North Chicago, IL) and stored at 
20°C until the experiment.
Animals and Surgery
Male Sprague-Dawley rats (270-350 g for experiment I and 320-400 g for experiment II) were purchased from Taconic Farms (Germantown, NY). The rats were kept on a 12:12-h light-dark cycle (lights on at 0900) at 23 ± 2°C ambient temperature. They had free access to water and food during the experiment. The implantation surgery for EEG and electromyogram (EMG) electrodes and thermistors was performed under ketamine and xylazine (87 and 13 mg/kg, respectively) anesthesia. Stainless steel jewelry screws for EEG recording were placed over the frontal and parietal cortices. An EMG electrode was implanted in the dorsal neck muscles. To measure Tbr, a calibrated 30-k
thermistor (model 44008;
Omega Engineering, Stanford, CT) was placed on the dura mater over the
parietal cortex. The leads from the EEG and EMG electrodes and the
thermistor were routed to a Teflon pedestal. They were attached to the
skull with dental acrylic (Duz-All; Coralite Dental Products, Skokie, IL).
Recording and Analysis
After the recovery period (at least 1 wk), rats were moved to a sleep-recording chamber (model 352600; Hot Pack, Philadelphia, PA), and they were acclimated to the experimental chamber for at least 7 days. The rats were allowed relatively unrestricted movement inside the recording cages. A flexible tether connected the electrodes and thermistor leads to an electronic swivel (SL6C; Plastics One, Roanoke, VA). The leads from the swivel were routed to Grass model 7D polygraphs in an adjacent room. The EEG was filtered below 0.1 Hz and above 35 Hz. The amplified EEG and EMG signals were digitized at a frequency of 128 Hz, and on-line Fourier analysis of the EEG was performed. Tbr signals were digitized at 2 Hz. The EEG, EMG, and Tbr data were saved on the computer in 10-s intervals. The vigilance states of wakefulness, NREMS, and rapid eye movement sleep (REMS) were determined off-line in 10-s epochs according to criteria previously reported (21). Briefly, wakefulness was characterized by fast low-amplitude EEG waves, gradually increasing Tbr, and a high incidence of gross body movements. NREMS was associated with slow high-amplitude EEG waves, slowly decreasing Tbr, and lack of body movement. In contrast, REMS was characterized by fast low-amplitude EEG waves, appearance of rhythmic
-EEG, rapidly increasing Tbr at REMS onset, and lack of
body movement. The amount of time spent in each vigilance state was
calculated hourly. In addition, the number and duration of NREMS and
REMS episodes were determined using a computer program. EEG -wave
activity during NREMS, also called EEG slow-wave activity (SWA), was
determined by using 2-h time blocks because within 1-h time blocks
there were some missing data. EEG power spectrum analysis during the
initial 3-h post-TNF treatment during NREMS was also performed for the
0.5- to 25-Hz frequency range.
Experimental Protocols
Experiment I: Effects of intraperitoneal administration of
TNF- on spontaneous sleep in rats.
Twenty-eight rats were used for this experiment. All rats received PFS
intraperitoneally on the control day. The next day, rats were injected
with one of the following four doses of TNF-: 10 µg/kg
(n = 8), 50 µg/kg (n = 7), 100 µg/kg (n = 7), and 200 µg/kg (n = 6). The injection volume for each rat was 1 ml/kg, and a corresponding
volume of PFS was given as control. All injections took place between
2030 and 2100. After the injection, EEG, EMG, and Tbr were
recorded for the next 12 h.
Experiment II: Effects of subdiaphragmatic vagotomy on
TNF--induced sleep.
Fourteen rats were randomly assigned to one of two groups. The rats in
the first group (sham group; n = 7) received only
pyloroplasty surgery. The rats of the second group (vagotomy group;
n = 7) received bilateral subdiaphragmatic vagotomy and
pyloroplasty under ketamine and xylazine (87 and 13 mg/kg,
respectively) anesthesia according to the method of Hansen et al.
(12-14). Four weeks later, to verify the
effectiveness of the vagotomy, rats received intraperitoneal injections
of saline and 4 µg/kg CCK (Sigma, St. Louis, MO) after 22 h of
food deprivation, as previously described (12-14).
CCK inhibits food intake in normal or sham-operated animals but not in
vagotomized rats; this test was originally described by Smith et al.
(28) and is now widely used to verify the effectiveness of
subdiaphragmatic vagotomies (reviewed in Ref. 26). Three days were allowed between the saline and CCK injections. Food intake
(in g) was measured during the first hour after injection. Rats with
verified vagotomies and sham rats then received EEG and EMG electrodes
and thermistor implantation surgery as described above in
experiment I. After the second surgery, an additional 2 wk
were allowed for recovery and adaptation before the sleep experiment
was started. After the first surgery, rats went through an initial 1- to 2-day period of weight loss, then after that they gained weight at
the same rate as sham-operated controls (13). These rats
received two doses of TNF- 10 days apart. All rats received an
intraperitoneal injection of PFS on the control day. On the next day,
they received intraperitoneal TNF- [50 µg/kg (n = 6 in both groups) or 100 µg/kg (n = 7 in both
groups)]. The injection volume was 1 ml/kg. After the injection, EEG,
EMG, and Tbr were recorded for 12 h. All injections
took place between 2030 and 2100.
Statistical Analysis
Two-way ANOVA for repeated measures across the 12-h recording period was used. The first independent variable was the treatment (saline vs. TNF-), and the second independent variable was time. When ANOVA indicated significant effects, it was followed by the Student-Newman-Keuls (SNK) test to reveal where the significant effect
occurred. Four 3-h time blocks were used for the analyses of the time
spent in each vigilance state, EEG SWA, and Tbr. For the
sleep episode data, one-way ANOVA for repeated measures was used for
the entire 12-h time period. Paired or unpaired t-tests were
used for the comparison of the body weight and CCK test data. For power
spectrum analysis data, the EEG power density values were summed in
four frequency bands as follows: (0.5-4.0 Hz)-, (4.5-8.0 Hz)-, (8.5-12.0 Hz)-, and (12.5-25.0
Hz)-wave activities; separate ANOVAs for each bandwidth were performed
for the initial 3-h time block. A significance level of
P < 0.05 was accepted.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Experiment I: Effects of Intraperitoneal Administration of TNF-
on Spontaneous Sleep in Rats
intraperitoneal
injections [ANOVA for the 12-h period, 50 µg/kg: treatment effect, F(1,6) = 6.00, P < 0.05;
100 µg/kg: treatment effect, F(1,6) = 30.38, P < 0.005 with time-treatment interaction,
F(3,18) = 3.38, P < 0.05; 200 µg/kg: treatment effect,
F(1,5) = 8.00, P < 0.05 with time-treatment interaction, F(3,15) = 9.38, P < 0.005; Table 1]. These effects were most evident
during the initial 6 h after the injections (Fig.
1). The increase in time spent in NREMS
resulted from an increase in the number and duration of NREMS episodes, although neither of these parameters was significantly increased after
intraperitoneal TNF- (Table 1). The lower three doses of TNF- did
not affect REMS. The highest dose of TNF- (200 µg/kg) significantly decreased REMS [ANOVA, treatment effect;
F(1,5) = 11.60, P < 0.05], and this effect was due to a decrease in the number of REMS
episodes [ANOVA, F(1,5) = 7.97, P < 0.05].
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Although SNK tests in each of the time blocks did not reach
significance, EEG SWA during NREMS increased after the two higher doses
of TNF- during the initial 4 to 6 h postinjection [ANOVA, 100 µg/kg: time-treatment interaction,
F(3,18) = 7.66, P < 0.005; 200 µg/kg, time-treatment interaction,
F(3,15) = 3.48, P < 0.05; Fig. 1]. EEG power spectrum analysis during the initial 3 h
also showed that TNF- dose dependently increased EEG -power and
decreased EEG - and -activities [ANOVA for -band; 200 µg/kg: F(1,5) = 10.80, P < 0.05; -band; 100 µg/kg: F(1,6) = 9.54, P < 0.05; 200 µg/kg:
F(1,6) = 16.70, P < 0.01;
-band; 100 µg/kg: F(1,5) = 11.30, P < 0.05; 200 µg/kg:
F(1,5) = 17.40, P < 0.01;
Table 2 and Fig. 2A]. TNF- failed to
affect Tbr after any dose.
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Experiment II: Effects of Subdiaphragmatic Vagotomy on
TNF--Induced Sleep
NREMS was significantly increased after 50 or 100 µg/kg of TNF-
intraperitoneally in the sham group; these effects were similar in
magnitude to those described in experiment I [ANOVA,
treatment effect; 50 µg/kg: F(1,5) = 6.76, P < 0.05; 100 µg/kg:
F(1,6) = 115.86, P < 0.0001; Table 3 and Fig.
3]. The enhanced NREMS in the sham
group was due to an increase in the mean duration of NREMS episodes
[ANOVA, 100 µg/kg: F(1,6) = 11.00, P < 0.05]. In the vagotomy group, TNF- given
intraperitoneally failed to significantly enhance NREMS, although small
nonsignificant increases in NREMS were observed [ANOVA, treatment
effect; 50 µg/kg: F(1,5) = 1.42 (NS);
100 µg/kg: F(1,6) = 3.39 (NS)]. In the
vagotomy group, the mean duration of NREMS episodes was suppressed
after intraperitoneal TNF- [ANOVA, 100 µg/kg:
F(1,6) = 7.30, P < 0.05]. Although numbers of NREMS episodes tended to increase after
intraperitoneal TNF- in both groups, these changes did not reach
significance. In the sham group, REMS significantly decreased after 100 µg/kg of intraperitoneal TNF- [ANOVA, treatment effect;
F(1,6) = 13.49, P < 0.05], and this was due to a decrease in the number of REMS episodes
[ANOVA, 100 µg/kg: F(1,6) = 16.70, P < 0.01]. The REMS inhibitory effect was not
observed in the vagotomy group (Table 3 and Fig. 3).
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Although the changes in EEG SWA after 50 and 100 µg/kg of TNF-
injections did not reach significance in either group, EEG power
spectrum analysis during the initial 3 h showed that EEG -power
tended to be enhanced after 50 or 100 µg/kg of intraperitoneal TNF- in the sham group but not in the vagotomy group. The increase in EEG -power after 100 µg/kg of intraperitoneal TNF- in the sham group was significantly higher than that in the vagotomy group
[F(1,12) = 4.85, P < 0.05; Table 2 and Fig. 2B]. EEG power spectrum analysis
also showed that 100 µg/kg of TNF- significantly decreased -,
-, and -power in the sham group [ANOVA for -band; F(1,6) = 10.50, P < 0.05;
-band: F(1,6) = 14.50, P < 0.01; -band: F(1,6) = 7.92, P < 0.05]
and -power in the vagotomy group [ANOVA; F(1,6) = 8.50, P < 0.05;
Table 2 and Fig. 2B]. As in experiment I,
TNF- did not affect the Tbr.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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One of the major findings of this study is that
intraperitoneal administration of TNF- increased NREMS in rats.
Previously, we showed that intravenous injections of TNF- enhanced
NREMS in rabbits (18) and that intraperitoneal injections
of TNF- increased NREMS in mice (8). The current
results extend those findings to rats and expand on them by providing
EEG spectral analysis after TNF- treatment.
An important finding in the current study is that vagotomy
attenuates TNF--induced NREMS responses. This finding is
similar to that reported by Hansen and Krueger (13) after
intraperitoneal IL-1 injection in vagotomized animals. In that
study, the NREMS-promoting actions of intraperitoneal IL-1 in
vagotomized rats were blocked after a low dose of IL-1, attenuated
after a midlevel dose, and not affected after a high IL-1 dose. As a
consequence, those authors concluded that it was likely that systemic
IL-1 affects the CNS via multiple mechanisms, including vagal
afferents. It is likely that similar mechanisms exist for the systemic
actions of TNF- on the brain. Thus there is an active transport
system for TNF- from blood to brain (11). TNF- also
can enter the brain via circumventricular organs; lesion of the area
postrema attenuates TNF-induced anorexia (1). TNF could
also act directly on brain capillary endothelium; NF-B in brain
capillaries and parenchymal microglia is activated by systemic TNF-
(22). Regardless, the current results suggest that the
vagus is an important route for conveying systemic TNF- signals to
the brain to affect sleep. This conclusion is consistent with previous
work. Thus subdiaphragmatic vagotomy of rats blocks conditioned taste
aversion (10) and hyperalgesia (37) induced
by systemic TNF-.
In this study, we also showed that systemic TNF- administration
increases EEG -wave activity. This response was not observed in the
vagotomized rats. EEG -wave amplitudes are thought to reflect the
intensity of NREMS. For example, EEG SWA increases to supranormal
levels during the deep sleep after sleep deprivation in rabbits
(24). The effects of TNF- on EEG SWA were different from those of IL-1. In rats, intraperitoneal injection of IL-1 induces biphasic EEG SWA responses. Thus EEG SWA is significantly inhibited in the first 2-h post-IL-1 treatment and is then followed by an increase in EEG SWA for 4 h (13). Furthermore,
that report showed that those changes in EEG SWA induced by IL-1
were not affected by subdiaphragmatic vagotomy. Our previous study
showed that systemic TNF- decreased EEG SWA in mice
(8). The reason for this discrepancy is unknown; probably,
species differences are involved. The current study is consistent with
the previous finding that blood levels of TNF- are related to the
EEG -activity during sleep in humans (5). Furthermore,
Chase et al. (4) showed that electrical stimulation of
vagal afferents induced EEG synchronization in cats. Thus it is likely
that systemic TNF- stimulates vagal afferents and thereby increases
EEG SWA.
In the current study, we did not show any changes in Tbr in
response to TNF-. In contrast, several reports suggest that TNF- is involved in fever responses. In rabbits, intracerebroventricular injection or intravenous injection of TNF- induces fevers (18, 23). Furthermore, inhibition of TNF- using a TNF receptor
fragment inhibits muramyl dipeptide-induced fever (32).
TNF- induces Cox-2 via the activation of NF-B and thereby
promotes the production of prostaglandins (17). Terao and
co-workers (35) reported that continuous infusion of
TNF- into the subarachnoid space of the rostral basal forebrain
induces fever, and these reactions are blocked by a Cox-2 inhibitor in
rats. Although TNF- is a pyrogenic substance when it is directly
administered in the CNS, the effects of peripheral TNF- on body
temperature are complicated. Derijk and Berkenbosch (6)
reported that intravenous administration of lipopolysaccharide induced
hypothermia, and this effect was due to the release of TNF from
peripheral macrophages. It was hypothesized that peripheral TNF
activates the arginine vasopressin system, which is thought to act as
an antipyretic in the ventral septal area. Thus TNF- can
simultaneously activate central pyretic and antipyretic mechanism in
rats, and this might explain why we did not observe TNF-induced effects
on body temperature in this study. Regardless of such possibilities,
the current results clearly indicate that TNF--induced fevers are
not responsible for TNF--induced NREMS responses.
In summary, we reported herein that intraperitoneal administration of
TNF- induces NREMS and EEG synchronization in rats without a
concomitant increase in Tbr. The sleep responses were attenuated by subdiaphragmatic vagotomy. These results suggest that
TNF- stimulates vagal afferents, and this action is involved in the
modulation of sleep by systemic TNF-.
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ACKNOWLEDGEMENTS |
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We thank M. K. Hansen (University of Colorado) for kind advice about vagotomy.
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FOOTNOTES |
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This work was supported, in part, by National Institutes of Health Grants NS-25378, NS-31453, and HD-36520.
Address for reprint requests and other correspondence: J. M. Krueger, Washington State Univ., College of Veterinary Medicine, Dept. of VCAPP, P.O. Box 646520, Pullman, WA 99164-6520 (E-mail: krueger{at}vetmed.wsu.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 4 August 2000; accepted in final form 17 November 2000.
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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and 
, Vehicle
control and TNF-
), and 200 µg/kg (
) of TNF-
), and 100 µg/kg of TNF-
). In
the vagotomy group, there was no significant increase in EEG 