Vol. 280, Issue 4, R1001-R1006, April 2001
Glial cell line-derived neurotrophic factor promotes sleep in
rats and rabbits
Tetsuya
Kushikata,
Takeshi
Kubota,
Jidong
Fang, and
James
M.
Krueger
Department of Veterinary and Comparative Anatomy, Pharmacology, and
Physiology, Washington State University, Pullman, Washington
99164-6520
 |
ABSTRACT |
Various growth factors (e.g., growth
hormone-releasing hormone, acidic fibroblast growth factor, nerve
growth factor, brain-derived neurotrophic factor, and interleukin-1)
are implicated in sleep regulation. It is hypothesized that neuronal
activity enhances the production of such growth factors, and they in
turn form part of the sleep regulatory mechanism. Glial cell
line-derived neurotrophic factor (GDNF) promotes development,
differentiation, maintenance, and regeneration of neurons, and its
production is induced by well-characterized sleep regulatory substances
such as interleukin-1 and tumor necrosis factor. Therefore, we
investigated whether GDNF would promote sleep. Twenty-six male
Sprague-Dawley rats and 30 male New Zealand White rabbits were
surgically implanted with electroencephalogram (EEG) and electromyogram
(EMG; rats only) electrodes, a brain thermistor, and a lateral
intracerebroventricular cannula. The animals were injected
intracerebroventricularly with pyrogen-free saline and on a
separate day with one of the following doses of GDNF: 5, 50, and 500 ng
in rabbits and 50 and 500 ng in rats. The EEG, brain temperature, EMG
(in rats), and motor activity (in rabbits) were recorded for 23 h
after the intracerebroventricular injection. GDNF (500-ng dose)
increased the time spent in nonrapid eye movement sleep in both rats
and rabbits. Rapid eye movement sleep was not affected by the lower
doses of GDNF but was inhibited in rabbits after the high dose. EEG
slow-wave activity was not affected by GDNF. The current results
provide further evidence that various growth factors are involved in
sleep regulation.
growth factors; rapid eye movement sleep; slow-wave sleep; fever; cytokine
| |
INTRODUCTION |
A VARIETY OF GROWTH
FACTORS are implicated in sleep regulation; the list includes
endocrines such as growth hormone (GH), GH-releasing hormone (GHRH),
prolactin (PRL), and insulin and autocrines or exocrines such as
interleukin-1
(IL-1), tumor necrosis factor (TNF)-
, acidic
fibroblast growth factor (aFGF), nerve growth factor (NGF), and
brain-derived neurotrophic factor (BDNF). All of these substances, if
injected, have the capacity to enhance either nonrapid eye movement
sleep [NREMS (insulin, IL-1, TNF-, aFGF)], rapid eye movement
sleep [REMS (GH, PRL)], or both (GHRH, NGF, and BDNF). Inhibition of
GH, IL-1, TNF, NGF, and GHRH inhibits spontaneous sleep and, in the
case of GHRH, IL-1, and TNF, sleep rebound after sleep deprivation.
These and much additional data strongly suggest that these growth
factors are involved in physiological sleep regulation (18-20 and
reviewed in Refs. 13 and 14).
Glial cell line-derived neurotrophic factor (GDNF) is another cytokine
that has the ability to promote the growth and survival of neurons (6 and reviewed in Ref. 5). GDNF, along with neurturin, persephin, and artemin, are members of the transforming growth factor- family. These molecules signal through a family of receptors [GDNF family ligands receptor- (GFR) 1, 2, 3, and 4]. GFR-1 preferentially binds GDNF and is found on neurons in many areas of the
brain (3, 22). The GDNF promoter contains a nuclear factor-
B (NF-B) site (38); NF-B also regulates
the expression of many other sleep regulatory substances (reviewed in
Ref. 15). Other sleep regulatory substances, such as IL-1
and TNF, have the capacity to enhance GDNF release and GDNF mRNA levels
(36 and 37 and reviewed in Ref. 1). We thus thought it
likely that GDNF would promote sleep; we report here that GDNF enhances
sleep in rats and rabbits.
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MATERIALS AND METHODS |
Recombinant human GDNF and recombinant rat GDNF were
purchased from R&D systems (Minneapolis, MN). The bioactivity of the GDNF (i.e., its ability to support the survival of and stimulate neurite outgrowth of cultured embryonic chick dorsal root ganglia) was
determined by the manufacturer. It contained 250 µg BSA/5 µg GDNF.
Substances were dissolved in pyrogen-free isotonic saline (PFS; Abbott,
North Chicago, IL). Injection volumes were 4 µl for rats and 25 µl
for rabbits.
Animals.
Male Sprague-Dawley rats (340-400 g) and male New Zealand White
rabbits (4.5-5.5 kg) were surgically implanted with
electroencephalogram (EEG) electrodes, a brain thermistor, a lateral
intracerebroventricular cannula, and electromyogram (EMG) electrodes
(only in rats) using ketamine-xylazine (35 and 5 mg/kg) anesthesia as
previously described (11). In rats, the patency and free
drainage of the guide cannula were verified by injecting 40 ng of ANG
II (Sigma, St. Louis, MO) in 4 µl of PFS. If the cannula placement
was correct, ANG II elicited a drinking response (31).
Only rats with a positive drinking response were used. After a 1- to
2-wk recovery period, the animals were placed in sleep-recording
chambers (model 352600; Hot Pack, Philadelphia, PA). The rats were
habituated to the recording procedure for 3 days; during this period,
the rats were connected to recording cables and injected daily with PFS
at the same time as the experimental treatments were to be done. The
rabbits were habituated to the recording chamber for 1 day. The animals
were kept on a 12:12-h light-dark cycle (lights on at 0800 with the rats or at 0600 with the rabbits) at 21 ± 1°C ambient
temperature. Water and food were available ad libitum throughout the
experiment. A flexible tether connected the electrodes and thermistor
leads to an electronic swivel. The animals were allowed relatively
unrestricted movement inside the recording cages. EEG, brain
temperature (Tbr), motor activity detected by an ultrasonic
sensor (only in rabbits; Biomedical Instrumentation, University of
Tennessee), and EMG (only in rats) were recorded. The EEG was filtered
below 0.1 and above 35 Hz. The amplified signals were digitized at a
frequency of 128 Hz for the EEG and EMG and at 2 Hz for Tbr
and motor activity. Tbr data were saved on a computer in
10-s intervals. Tbr values, averaged in 3-h intervals, were
used for statistical analysis. Some of the Tbr data were
lost because of technical problems; therefore, the sample sizes for
Tbr were lower than those for sleep data.
On-line Fourier analyses of EEG data were performed. The vigilance
states were determined off-line in 10-s epochs. The vigilance states of
wakefulness, NREMS, and REMS were visually identified in 10-s epochs
applying criteria previously reported (18). The amount of
time spent in each vigilance state was calculated for 1-h intervals and
for the entire recording period. The percent of time spent in sleep for
3-h intervals was used for statistical analyses. The EEG power density
values were summed in the delta (0.5-4.0 Hz) band, and then
average delta activity during NREMS [also called slow-wave activity
(SWA)] was calculated for 1-h time blocks. Because the EEG amplitude
was subject to the influence of subtle variations of EEG electrode
placement, the average power during NREMS throughout the entire 23-h
control recording period was normalized to 100%. The relative changes
in EEG power density values from the baseline were then calculated. In
addition, a computer program was used to determine the number of NREMS
and REMS episodes and their mean episode lengths, with the criterion that each episode lasted at least 30 s.
Experimental protocol.
Twenty-six rats and 30 rabbits were used in these experiments. Each rat
received an injection of 4 µl PFS intracerebroventricularly to obtain
control values. On a separate day, the same animals were then injected
intracerebroventricularly with one of two doses of GDNF as follows:
group 1, 50 ng (n = 6); group 2,
500 ng (n = 7). The injections took place on the dark
onset (2000). In addition, seven rats were injected
intracerebroventricularly with 500 ng GDNF at light onset (0800). Each
rabbit received 25 µl PFS intracerebroventricularly in the same
manner as rats. On the next day, the animals were injected
intracerebroventricularly with one of three doses of GDNF as follows:
group 1, 5 ng (n = 6); group 2,
50 ng (n = 8); group 3, 500 ng
(n = 8). The injections took place between 0850 and
0925. As an additional control to exclude the effects of contaminants such as endotoxin, six rats and eight rabbits were injected
intracerebroventricularly with 500 ng of heat-treated (90°C for 30 min) GDNF.
All statistical analyses were performed with two-way ANOVA for repeated
measures across the entire recording period. A significance level of
P < 0.05 was accepted.
| |
RESULTS |
Rats given heat-treated GDNF or physiological saline continued to
exhibit the normal diurnal variations of sleep and Tbr that are characteristic of this species. The lower dose of GDNF tested in
rats (50 ng) at dark onset (2000) also failed to affect any of the
parameters measured in this study. Administration of the higher dose of
GDNF (500 ng) at dark onset increased the amount of time spent in NREMS
[ANOVA; treatment effect; F(1,6) = 13.16; P < 0.05; Fig. 1 and
Table 1]. The increases in NREMS
resulted from an increase in the number of NREMS episodes [327.1 ± 8.6 control vs. 388.7 ± 12.1 during experiment, ANOVA;
treatment effect; F(1,6) = 6.04;
P < 0.05 with an interaction of treatment and time; F(7,42) = 5.45; P < 0.01]. In contrast, the higher dose of GDNF at light onset (0800)
failed to enhance NREMS, although it slightly decreased the number of
NREMS episodes [372.4 ± 10.7 control vs. 347.3 ± 5.8 during experiment, ANOVA; treatment effect;
F(1,6) = 13.26; P < 0.05]. In rats, GDNF failed to affect REMS (Tables 1 and
2) and also failed to affect EEG SWA
after any dose. The higher dose of GDNF at dark onset slightly
increased Tbr [ANOVA; treatment effect;
F(1,6) = 7.61; P < 0.05].
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Fig. 1.
Effects of icv injection of recombinant rat glial cell line-derived
neurotrophic factor (GDNF) on time spent in nonrapid eye movement sleep
(NREMS), rapid eye movement sleep (REMS), electroencephalogram (EEG)
slow-wave activity (SWA), and brain temperature (Tbr) in
rats during the 23-h postinjection period. Error bars indicate SE.
 , Results after vehicle treatment;  ,
results after GDNF treatment. Horizontal dark bars denote the dark
phase of the day. GDNF (500 ng) injected icv increased the amount of
time spent in NREMS and Tbr.
|
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Heat-treated GDNF or physiological saline failed to alter the normal
diurnal variations of sleep in rabbits (Fig.
2).
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Fig. 2.
Effects of icv injection of recombinant human GDNF on time spent in
NREMS, REMS, EEG SWA, and Tbr in rabbits during the 23-h
postinjection period. Error bars indicate SE. , Results
after vehicle treatment; , results after GDNF
treatment. Horizontal dark bars denote the dark phase of the day. GDNF
(500 ng) injected icv at dark onset increased the amount of time spent
in NREMS but decreased the amount of time spent in REMS.
|
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Intracerebroventricular administration of the lowest (5 ng) or middle
(50 ng) dose of GDNF tested also had no effect on NREMS, REMS, SWA, or
Tbr. However, intracerebroventricular administration of the
highest dose of GDNF (500 ng) increased the amount of time spent in
NREMS by ~1 h over the 23-h recording period [Fig. 2 and Table 1;
ANOVA; treatment effect; F(1,7) = 11.84;
P < 0.05; with an interaction of treatment and time;
F(7,49) = 2.94; P < 0.05]. In contrast, REMS was decreased after intracerebroventricular administration of the highest dose of GDNF [ANOVA; treatment effect; F(1,7) = 13.15; P < 0.01;
Fig. 2 and Table 1]. The decreases in REMS resulted from a decrease in
the number of REMS episodes [65.1 ± 6.3 control vs. 57.4 ± 6.0 during experiment, ANOVA; treatment effect;
F(1,7) = 7.36; P < 0.05]. The middle dose of GDNF also decreased the number of REMS
episodes [67.8 ± 5.2 control vs. 59.8 ± 5.3 during
experiment, ANOVA; treatment effect;
F(1,7) = 30.37; P < 0.01]. GDNF failed to affect SWA or Tbr after any dose in
rabbits (Fig. 2 and Table 1).
Although not systematically quantified, GDNF did not induce abnormal
behavior in either rats or rabbits in the sense that animals continued
to cycle through sleep-wake episodes, they were easily aroused if
disturbed, and they exhibited no gross abnormal motor behavior.
| |
DISCUSSION |
The current results clearly indicate that GDNF promotes sleep in
rats and rabbits. The effects of GDNF on sleep depended on the time of
administration in rats. Previously, differences in sleep responses in
rats were reported after administration of sleep-promoting or
sleep-inhibiting substances at different times of the day. For example,
administration of 10.0 ng IL-1 at dark onset enhances NREMS in rats,
whereas the same dose of IL-1 suppresses NREMS if given during the
light period (26). These differences likely resulted from
the interaction of the circadian and homeostatic processes regulating sleep.
GDNF failed to enhance EEG delta wave activity during NREMS. In
contrast, several other somnogenic growth factors, such as IL-1,
TNF-, GHRH, and aFGF, enhance EEG SWA at doses that also enhance
duration of NREMS. The mechanisms responsible for EEG SWA remain
unknown. In many circumstances, EEG SWA is thought to be indicative of
NREMS intensity. For example, after sleep deprivation,
"supranormal" EEG slow waves characterize NREMS (28) and are associated with higher arousal thresholds (27).
Nevertheless, there is an extensive literature describing the
separation of EEG SWA from state regulation. For instance,
intraperitoneal injections of IL-1 or TNF- induce increases in
NREMS and decreases in EEG SWA in rats (7) and mice
(4), whereas intracerebroventricular injections of IL-1 or
TNF enhance both of these of parameters (8, 26).
Electrolytic lesions of the hypothalamus result in long-term reduction
of EEG SWA, whereas NREMS moves toward normal duration after ~8 days
(32). Furthermore, rats restricted to a daytime diet shift
their diurnal rhythm of NREMS, becoming daytime active, but do not
shift the diurnal rhythm of EEG SWA (30). Regardless of
such considerations, it does not appear that GDNF has a major role in
the regulation of EEG SWA, although it has the capacity to enhance
NREMS, thereby suggesting that the mechanisms responsible for EEG SWA
are different, in part, from those involved in sleep regulation.
The significance of the GDNF-induced inhibition of REMS in rabbits
after the high dose is unknown. The mechanisms responsible for REMS
regulation are, in part, independent from those responsible for NREMS
(reviewed in Ref. 14), and it is possible to
differentially stimulate or inhibit NREMS or REMS (e.g., see Table 1).
Nevertheless, one possible mechanism of GDNF inhibition of REMS could
be via dopaminergic neurons. GDNF is dopaminotrophic (2,
23), and dopaminergic neurons are implicated in sleep regulation
(35). For instance, dopamine autoreceptor antagonists
inhibit REMS (24). Furthermore, GFR-1 receptors are in
many areas of brain, including the cholinergic system
(22), which is also implicated in REMS regulation
(reviewed in Ref. 33). Regardless, the effects of GDNF on
REMS were small and only occurred in one species after the highest
dose; thus, it remains to be determined whether this effect has
biological significance.
The biological significance of the enhanced Tbr in rats
after GDNF is also questionable since rabbits, a species often
considered more sensitive to pyrogens, failed to display fever after
GDNF. In rats, GDNF induced very small increases in Tbr,
and it is possible that the hyperthermia affected sleep responses.
Regardless, there is a rather extensive literature describing the
multiple links between thermoregulation and sleep. For example, there
is a regulated decrease in Tbr during the entry into NREMS,
and an acute mild increase in ambient temperature is a
well-characterized somnogen. Nevertheless, under a variety of
circumstances, thermoregulation can be separated from sleep regulation
(reviewed in Ref. 16). Some substances enhance both NREMS
and Tbr (e.g., TNF and IL-1), yet the pyrogenic actions
of IL-1 can be pharmacologically blocked without affecting sleep
responses (17). In contrast, the NREMS-promoting actions
of IL-1, but not its pyrogenic actions, are blocked by central
administration of nitric oxide synthase inhibitors (9). Furthermore, some substances (e.g., IL-6) are pyrogenic but not somnogenic (25). Collectively, such considerations clearly
indicate separate, yet linked, mechanisms for sleep and body temperature.
Microbial products such as endotoxin are common contaminants of
manufactured peptides (21). Endotoxin induces production of a variety of somnogenic cytokines, and it is, itself, somnogenic. We
thus tested heat-inactivated GDNF as a control, since endotoxin and
other pyrogenic bacterial cell wall products are heat stable. Because
the heat-inactivated GDNF had no effect on the sleep parameters studied, it seems unlikely that results obtained were due to
contaminating bacterial cell wall products.
Perspectives
That GDNF promotes NREMS provides further evidence for the
involvement of the brain cytokine network in sleep regulation. Previously, we hypothesized that cytokines and other somnogenic growth
factors are important components of sleep mechanisms and are indicative
of, and play a role in, sleep function (reviewed in Ref.
12). Thus we proposed that neuronal activation stimulates production of these sleep regulatory growth factors, e.g., GDNF mRNA
levels are enhanced by neuron excitation (29). These
growth factors alter membrane potentials of nearby neurons and thereby change their firing patterns. Thus synapses that were not activated by
the initial train of events are secondarily activated with a time delay
due to the production and diffusion times of upregulated growth factors
(modeled in Ref. 13). As a consequence, the input-output activity patterns of neuronal groups are changed and thereby divorce environmental input from output; when this occurs, we hypothesize that
the neuronal groups are in a state of sleep. Kavanau (10) also reached the conclusion that neuronal groups alter between states,
although he used different reasoning. Finally, these growth factors
also alter expression of genes involved in synaptic function. As a
consequence, the efficacy of transmission at affected synapses is
changed for longer periods of time because of structural changes. Thus
sleep function (growth factor-induced synaptic sculpturing) is
inseparable from sleep mechanisms (growth factor-induced altered circuit dynamics of neuronal groups; reviewed in Ref. 15).
| |
ACKNOWLEDGEMENTS |
This work was supported by National Institutes of Health Grants
NS-25378, NS-31453, and HD-36520.
| |
FOOTNOTES |
Address for reprint requests and other correspondence: J. M. Krueger, Dept. of VCAPP, Washington State Univ., 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 17 August 2000; accepted in final form 17 November 2000.
| |
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Copyright © 2001 the American Physiological Society
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ABSTRACT
INTRODUCTION
