Vol. 280, Issue 2, R398-R403, February 2001
Sleep changes induced by lipopolysaccharide in the rat are
influenced by age
Thomas
Schiffelholz1 and
Marike
Lancel2
1 Department of Psychiatry, University of Kiel, 24115 Kiel;
and 2 Max-Planck Institute of Psychiatry, 80804 Munich,
Germany
 |
ABSTRACT |
In mammals, aging is associated with immune senescense.
To examine whether the sleep changes occurring during immune challenge are affected by age, we assessed sleep alterations induced by the
administration of lipopolysaccharide (LPS) in young and middle-aged rats. During vehicle, the middle-aged rats exhibited less pre-rapid eye
movement sleep (pre-REMS) as well as REMS, due to a smaller number and
shorter duration of REMS episodes, than young rats. LPS elevated body
temperature, increased non-REMS, and suppressed both pre-REMS and REMS
in the young as well as in the middle-aged rats. However, in the young
animals, LPS significantly enhanced slow-wave activity in the
electroencephalogram (EEG) within non-REMS, reflecting an increase in
sleep intensity. In contrast, LPS attenuated EEG power in most
frequency bands in the older animals. This finding indicates
age-related changes in the modulation of sleep by LPS.
EEG spectral analysis; aging
| |
INTRODUCTION |
SENESCENSE SEEMS TO BE
ASSOCIATED with a dysregulation of the immune system. Studies in
humans indicate that aging causes a decrease in T cell proliferation
and function, a reduced secretion of interleukin-2 (IL-2), and an
increased production of IL-4, IL-5, and IL-6 (reviewed in Ref.
19). Furthermore, the release of tumor necrosis factor-
(TNF-) from monocytes in elderly subjects exceeds that in young
subjects during basal conditions, but it is lower during immune
challenge (8). In rodents, comparable age-related changes
in immune functioning have been observed, including a progressive
dysfunction of T cells and alterations in the release of cytokines,
such as TNF-, IL-1
, IL-2, IL-4, IL-5, and IL-6 (5,
31). The hypothalamus-pituitary-adrenal (HPA) axis, which plays
an important role in immune system regulation, also undergoes
alterations during aging in humans and rodents, such as basal
hypersecretion of corticosteroids as well as an increased release of
ACTH in response to stress (14).
The acute phase response, as evoked by microorganisms or by specific
microbial components, including lipopolysaccharide (LPS), is
characterized by fever, sickness behavior, and consistent changes in
sleep-wake behavior, consisting of a promotion of non-rapid eye
movement sleep (non-REMS), an enhancement of slow-wave activity (SWA)
in the electroencephalogram (EEG) within non-REMS, and an inhibition of
REMS. Animal studies indicate that these effects are mediated by
cytokines, particularly IL-1 and TNF- (reviewed in Ref.
16). IL-1 and TNF- also evoke fever, increase
non-REMS, enhance SWA, and decrease REMS, whereas antagonists of their
activity block these effects (4, 17, 23, 28, 36). It is
generally assumed that the promotion of non-REMS and enhancement of SWA in the EEG within non-REMS support host defense (reviewed in Ref. 16), e.g., rabbits reacting with a robust increase in
non-REMS time and SWA within non-REMS during immune challenge have a
higher chance of survival than those responding with a decrease in both sleep parameters (40). Additionally, prolonged sleep
deprivation in rats has been shown to prominently attenuate host
defense against indigenous and pathogenic microorganisms, resulting in
increased mortality (3). The objective of the present
experiment is to investigate whether the sleep response to LPS in the
rat is affected by age.
| |
MATERIALS AND METHODS |
Seven young male Wistar rats (Charles River Laboratories,
Sulzfeld, Germany), ~3 mo old and weighing 250-350 g, and seven middle-aged male Wistar rats, ~14 mo old and weighing 750-900 g,
were prepared for EEG and electromyogram (EMG) recordings. Under deep
halothane (Hoechst, Frankfurt am Main, Germany) anesthesia, they were
implanted with four stainless steel screws to record EEG (frontal
cortex: 3.9 mm anterior and ±2 mm lateral to bregma; occipital cortex:
6.4 mm posterior and ±4 mm lateral to bregma) and with two stainless
steel screws to record neck-muscle EMG. The EEG signal was derived from
a frontal electrode and the contralateral occipital electrode. Animals
were housed individually in a sound-attenuated Faraday room under a
12:12-h light-dark schedule (lights on at 7:30 AM; 50-120 lx) at
an ambient temperature of 20 ± 1°C with food and water
available ad libitum. After 2 wk of recovery, the rats were connected
to recording cables for adaptation. During the following 5 days, body
temperature (Tc) was measured 6, 9, and 24 h after
light onset every day. On day 6, the animals were injected
intraperitoneally with vehicle (pyrogen-free saline), and on day
7 they were injected with 100 µg/kg LPS (Salmonella abortus equi, Sigma, Deisenhofen, Germany) immediately after light onset. Tc was measured 6, 9, and 24 h after light
onset, and EEG and EMG were continuously recorded during the first 12-h
postinjection. EEG and EMG signals were amplified and filtered (EEG:
high pass 0.3 Hz and low pass 29 Hz, 48 dB/octave; EMG: high pass 16 Hz and low pass 3,000 Hz, 6 dB/octave). Both the EEG and the rectifed and
integrated EMG were digitized with a sampling rate of 64 Hz. The EEG
signal was subjected to an online fast Fourier transform routine, and
for each 2-s epoch, an EEG power spectrum was computed for the
frequencies between 0.5 and 25 Hz (0.5-Hz bins in the 0.5- to 4.5-Hz
frequency range and 1-Hz bins for the higher frequencies). Power
spectra were averaged over 10-s epochs. Recordings were analyzed
offline by visual scoring of the raw EEG and the rectified and
integrated EMG displayed on-screen in 10-s epochs, distinguishing wakefulness, non-REMS, REMS, and pre-REMS (for scoring criteria, see
Ref. 21). Pre-REMS, also called the intermediate stage
(7), preceeds REMS and is characterized by high-amplitude
spindles on a background of theta (6-9 Hz) activity. For each
recording period, the latency to non-REMS and REMS (arbitrarily defined as the 20th epoch of non-REMS and the 3rd epoch of REMS) and the number
and average duration of the non-REMS (including pre-REMS) and REMS
episodes were computed. Time in each vigilance state and average EEG
power densities within non-REMS (excluding pre-REMS) were determined
per 2-h interval. For standardization, the EEG values were expressed as
percentage of the average power density within non-REMS in the same
frequency band during the corresponding 12-h vehicle period and were
then log transformed.
To analyze the effects of LPS within each and between the two age
groups, a two- or three-factor repeated-measures ANOVA (Greenhouse Geisser correction) was performed with age (young vs. middle-aged rats)
as between-subjects factor and treatment (vehicle vs. LPS) and time
(6 × 2-h intervals for sleep variables and 3 time points for
Tc) as within-subjects factor. Where appropriate, the
ANOVAs were followed by two-sided, paired or unpaired
t-tests.
| |
RESULTS |
Tc.
Analysis of Tc yielded a significant effect of treatment
(F1,12 = 20.1, P = 0.0007).
Irrespective of age, LPS increased Tc. Pairwise comparisons
over both age groups revealed significant increases at 9 and 24 h
after LPS administration (Fig. 1).
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Fig. 1.
Time course of body temperature and percentage of time
spent in wakefulness, non-rapid eye movement sleep (non-REMS),
pre-REMS, and REMS in young and middle-aged rats after intraperitoneal
injection of vehicle ( ) and 100 µg/kg
lipopolysaccharide (LPS) ( ). Curves connect means ± SE (n = 7). ANOVA yielded a significant treatment
effect for wakefulness (F1,12 = 5.0, P = 0.05), non-REMS (F1,12 = 6.2, P = 0.03), pre-REMS
(F1,12 = 42.4, P < 0.0001), and REMS (F1,12 = 39.4, P < 0.0001); a significant effect of age for pre-REMS
(F1,12 = 6.4, P = 0.03) and
REMS (F1,12 = 53.4, P < 0.0001) as well as an effect of age × treatment × time for
REMS (F1,12 = 3.2, P = 0.03). Shaded areas refer to time points for which post hoc analysis
yielded significant differences between vehicle and LPS over both age
groups and * for each age group (P < 0.05, 2-sided,
paired t-test).
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Vigilance states.
For wakefulness and non-REMS, ANOVA found a significant treatment
effect (see Fig. 1 legend for results of ANOVA). Independent of age,
LPS increased both wakefulness and non-REMS. Pairwise comparisons
showed that during the first 2-h interval, wakefulness was
significantly increased and non-REMS decreased (Fig. 1). The increase
in total non-REMS was mainly due to changes during the second half of
the recording period. Pre-REMS was significantly affected by age and by
treatment. The middle-aged rats exhibited less pre-REMS than the young
rats during both the vehicle and the LPS condition. Yet, LPS powerfully
suppressed this state throughout the recording period to a similar
extent in young and middle-aged rats. For REMS, a significant effect of
age was found. Compared with the young rats, the middle-aged rats had
less REMS during both conditions. Furthermore, a significant effect of
treatment and of age × treatment × time emerged, reflecting
that LPS-evoked changes evolved differently between the groups. In the
young rats, LPS significantly decreased REMS during the first four 2-h
intervals, whereas in the middle-aged rats, LPS almost completely
abolished REMS throughout the recording period.
Sleep architecture.
ANOVA did not yield significant effects of LPS on the latency to
non-REMS nor on the duration of non-REMS episodes (Table 1), but it revealed a significant
treatment effect (F1,12 = 7.1, P = 0.02) for the number of non-REMS episodes. LPS
increased the number of non-REMS episodes to a similar degree in the
young and middle-aged rats. Although the latency to REMS was not
affected by age or treatment, significant age and treatment effects
were observed for the number of REMS episodes
(F1,12 = 17.7, P < 0.001 and F1,12 = 37.6, P < 0.0001). Irrespective of treatment, middle-aged rats had less REMS
episodes than young rats. LPS reduced the number of REMS episodes in
both age groups. Analysis of the duration of REMS episodes revealed a
significant effect of age (F1,12 = 15.3, P = 0.002), which was due to the fact that the
middle-aged rats exhibited shorter REMS episodes than the young rats
during both vehicle and LPS.
EEG power densities within non-REMS.
ANOVA run on the normalized and log-transformed EEG power densities
within non-REMS yielded a significant effect of age × treatment
for all frequencies 
8 Hz. During the 12-h recording period, LPS
significantly enhanced low-frequency activity in the young
rats, whereas it tended to attenuate the same activity in the
middle-aged rats (Fig. 2). ANOVA
revealed a significant effect of treatment for the frequencies between
8 and 15 Hz, which was due to the fact that LPS depressed EEG activity
in the respective frequency bands in both groups of rats. For the same
frequency bands, a significant age × treatment × time
effect was found, reflecting age-related differences in the time course
of the LPS-evoked alterations. In the young rats, a dramatic
attenuation of power in the frequencies between 8 and 15 Hz occurred
mainly during the last 2-h interval, whereas it was evident throughout
the entire recording period in the middle-aged rats (Fig. 2). A
significant age × treatment × time effect also emerged for
most frequencies 
19 Hz. LPS slightly augmented high-frequency EEG
activity during the third and fourth 2-h interval in the young rats and
markedly depressed it during the last 2-h interval in both the young
and middle-aged rats.
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Fig. 2.
Changes in electroencephalogram (EEG) power density
within non-REMS during 2-h intervals after administration of LPS in
young ( ) and middle-aged () rats.
Curves connect means ± SE (n = 7). For plotting
purposes, the data are expressed as a percentage of the corresponding
vehicle values. Bars below the graph refer to frequency bands for which
post hoc analysis yielded significant differences between vehicle and
LPS in each age group (P < 0.05, 2-sided, paired
t-test).
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| |
DISCUSSION |
The present study demonstrates for the first time that specific
aspects of the acute phase sleep response change as a function of age
in the rat. In the young rats, LPS induced fever, increased the total
amount of non-REMS that was related to an increase in the number of
non-REMS episodes, enhanced SWA in the EEG within non-REMS,
persistently inhibited pre-REMS, and transiently decreased REMS. In
middle-aged rats, LPS elicited comparable alterations in Tc
and, except for a longer-lasting suppression of REMS, in sleep
architecture, but generally it attenuated power densities in the
non-REMS-specific EEG signals, including the delta frequency bands.
In accordance with most earlier reports (9, 10, 34, 38),
middle-aged rats displayed practically identical amounts of wakefulness
and non-REMS during the vehicle light period as young rats, but they
spent less time in REMS. The latter was due to fewer as well as
shorter-lasting REMS episodes, which implicate an age-related
disruption of REMS initiation and maintenance. Furthermore, the present
study shows a concomitant reduction in pre-REMS. As this state
constitutes the transition from non-REMS to REMS, this finding
indicates that the age-related decrease in the number of REMS episodes
may be a direct consequence of the decreased occurrence of pre-REMS.
The administration of microbial constituents that evoke an acute phase
response, such as LPS, is a common strategy to examine the influence of
an immune challenge on central nervous system function. The effects of
LPS on sleep in the young rats are in accordance with previous findings
in rodents (13, 15, 17, 29). LPS initially promoted
wakefulness. This was followed by an increase in non-REMS, which was
typically associated with many but relatively short-lasting non-REMS
episodes, and an enhancement of SWA in the EEG within this state.
Furthermore, LPS decreased REMS during the first 8 h, which was
mainly caused by a reduction in the number of REMS episodes. Moreover,
the present study reveals that LPS also robustly decreases pre-REMS.
This observation implies that the decreased occurrence of REMS episodes
during immune challenge may be partially due to the fragmentation of
non-REMS, resulting in fewer entries in pre-REMS and, consequently, in REMS.
In agreement with an earlier investigation (5), LPS
elicited similar increases in Tc in young and middle-aged
rats. Furthermore, most LPS-induced changes in sleep architecture in
the middle-aged and young rats were indistinguishable. As in the young
animals, LPS increased non-REMS initiation and decreased both pre-REMS and REMS, the latter due to a reduction in the number of REMS episodes.
However, in contrast to the young rats, REMS in the older rats was
decreased over the entire recording period. The alterations in the EEG
power density within non-REMS differed prominently between the age
groups in that LPS did not elevate but rather attenuated SWA in the
middle-aged rats. The usually observed increase in the amount and
intensity of non-REMS during immune challenge reflects an increase in
sleep need (32, 40). On the basis of the finding that
rabbits in which immune challenge stimulates non-REMS and augments SWA
have a higher survival chance than animals that fail to respond in such
a fashion (40), it is assumed that these sleep changes
contribute considerably to host defense. If so, the depression of SWA
elicited by LPS in the middle-aged rats may reflect a diminished
ability of the immune system to respond optimally to immune challenge.
Although the precise mechanism(s) underlying the presently observed
age-related differences in the acute phase sleep response are unclear,
various cytokines and hormones may be involved. IL-1 and TNF- are
known to mediate sleep regulation under physiological conditions and
during immune challenge in a cooperative manner (26, 27,
39). In rats and rabbits, central or peripheral injection of
IL-1 or TNF- increases non-REMS and SWA within non-REMS and
reduces REMS (4, 18, 23, 28, 36). Intracerebroventricular injection of an IL-1 antibody in rats has been shown to attenuate the
non-REMS rebound after sleep deprivation (27). In humans, the production of both IL-1 and TNF- is increased as a function of age (1). Compared with young control animals, aged rats show higher TNF- levels after LPS injection (5). Such
age-related changes in the production and release of IL-1 and TNF-
may play a role in the differences in spontaneously occurring REMS and in LPS-induced suppression of REMS in young and middle-aged rats.
In mammals, aging is accompanied by changes in HPA axis function. In
rodents, the production and release of corticotropin-releasing hormone
(CRH) increase as a function of age (14, 30).
Additionally, the effectiveness of the glucocorticoid-mediated negative
feedback is reduced, which induces hyperactivity of the HPA axis in
response to stress in rodents and humans (14, 35, 41).
Consequently, ACTH release from the pituitary during stress is higher
in aged rats than in young rats (14).
Intracerebroventricular injection of CRH has been shown to increase
wakefulness at the expense of non-REMS and REMS in different rat
strains and to reduce EEG power density in the delta range (2,
25). Accordingly, studies on humans have demonstrated that
exogenous CRH and ACTH evoke a decrease of non-REMS and SWA within
non-REMS, a disruption of sleep continuity, and a reduction of REMS
(reviewed in Refs. 6, 14, 37).
Thus age-related alterations in the HPA axis may be, at least
partially, responsible for the differences in the amount of pre-REMS
and REMS during vehicle, the differences in the duration of REMS
suppression, and the EEG responses to LPS between young and middle-aged rats.
Furthermore, changes in growth hormone-releasing hormone (GHRH) may be
involved. The activity and efficacy of the GHRH system, including the
hypothalamus and pituitary, decrease with advancing age (11, 20;
reviewed in Refs. 16, 37). Exogenous GHRH is known to increase non-REMS and SWA in rats and humans (2, 11, 33,
42). Conversely, experimental reduction of GHRH reduces the
amount of non-REMS as well as SWA within non-REMS, and it attenuates
the increase of both parameters normally following LPS or IL-1
injection (12, 22-24). Thus the age-related decrease of the efficacy of the GHRH system may contribute to the absence of an
enhancement of SWA within non-REMS in the middle-aged rats.
Perspectives
The present paper demonstrates that the changes in sleep
architecture evoked by LPS are minimally affected by age, whereas the
stimulation of the deep sleep-associated, slow-frequency components in
the EEG within non-REMS declines as a function of age in the rat. This
observation indicates age-related changes in the sleep response to LPS
and, possibly, also other immune challenges. Because the promotion of
especially deep sleep is assumed to support host defense, the present
findings may suggest an aging-associated reduction in the ability to
recuperate from immune challenge during sleep. Further studies are
needed to delineate whether this is the case and to determine the
underlying neuroendocrine mechanisms.
| |
ACKNOWLEDGEMENTS |
We thank Arnold Höhne for excellent technical assistance as
well as Thomas Pollmächer and Elisabeth Friess for valuable comments on an earlier version of this manuscript.
| |
FOOTNOTES |
Address for reprint requests and other correspondence: M. Lancel, Sleep Pharmacology, Max-Planck Institute of Psychiatry, Kraepelinstrasse 2, D-80804 München, Germany (E-mail:
lancel{at}mpipsykl.mpg.de).
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 30 May 2000; accepted in final form 27 September 2000.
| |
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INTRODUCTION
