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Sleep Research Laboratory, Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts 02118
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The aim of this study was to test the hypothesis that the cells in the brain stem pedunculopontine tegmentum (PPT) are critically involved in the normal regulation of wakefulness and rapid eye movement (REM) sleep. To test this hypothesis, one of four different doses of the excitatory amino acid L-glutamate (15, 30, 60, and 90 ng) or saline (control vehicle) was microinjected unilaterally into the PPT while the effects on wakefulness and sleep were quantified in freely moving chronically instrumented rats. All microinjections were made during wakefulness and were followed by 6 h of polygraphic recording. Microinjection of 15- ng (0.08 nmol) and 30-ng (0.16 nmol) doses of L-glutamate into the PPT increased the total amount of REM sleep. Both doses of L-glutamate increased REM sleep at the expense of slow-wave sleep (SWS) but not wakefulness. Interestingly, the 60-ng (0.32 nmol) dose of L-glutamate increased both REM sleep and wakefulness. The total increase in REM sleep after the 60-ng dose of L-glutamate was significantly less than the increase from the 30-ng dose. The 90-ng (0.48 nmol) dose of L-glutamate kept animals awake for 2-3 h by eliminating both SWS and REM sleep. These results show that the L-glutamate microinjection into the PPT can increase wakefulness and/or REM sleep depending on the dosage. These findings support the hypothesis that excitation of the PPT cells is causal to the generation of wakefulness and REM sleep in the rat. In addition, the results of this study led to the identification of the PPT dosage of L-glutamate that optimally induces wakefulness and REM sleep. The knowledge of this optimal dose will be useful in future studies investigating the second messenger systems involved in the regulation of wakefulness and REM sleep.
brain stem; rapid eye-movement sleep
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE PEDUNCULOPONTINE TEGMENTUM (PPT), situated in the dorsolateral mesopontine tegmentum, contains a prominent group of cholinergic neurons, which project widely throughout the brain stem and forebrain (1, 16, 20, 21, 26, 29, 36-38, 41, 42, 45, 47, 51, 56-58). All of these PPT cholinergic cells are capable of synthesizing nitric oxide (NO) as well (5-7, 23, 52-53). Single cell recordings from the PPT of behaving cats have identified several different classes of cells whose firing rates correlate with both wakefulness and rapid eye movement (REM) sleep (8, 9, 12, 17, 43, 50). Some of these PPT neurons, called REM-on cells, progressively increase their firing rates as the animal moves from wakefulness to slow-wave sleep (SWS) and then to REM sleep. Others, constituting the majority of these cells in the PPT, called wake-REM-on cells, are tonically active during both wakefulness and REM sleep (8). Brain stem lesion studies in cats have demonstrated that lesions of the PPT neurons reduced and/or eliminated physiological signs of REM sleep, (10, 44, 49). Microinjection studies in cats have demonstrated that chemical excitation of PPT cells increased both wakefulness and REM sleep by eliminating SWS (15). Although there is strong evidence in the cat suggesting that PPT cells regulate the behavioral states of wakefulness and REM sleep, there is no single study that directly shows that the excitation of PPT cells is causal to the generation of wakefulness or REM sleep in the rat. To understand, at the level of PPT cells, the detailed biochemical and molecular mechanisms involved in the normal regulation of wakefulness and sleep in the rat, the changes in wakefulness and REM sleep resulting from the excitation of PPT cells must be investigated and documented.
In the present study we examined the hypothesis that PPT cell activation is causal to the generation of wakefulness and REM sleep in the rat. This hypothesis was tested by microinjection of the excitatory amino acid L-glutamate into the PPT while simultaneously quantifying wake-sleep signs.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals. Experiments were performed on 23 male Sprague-Dawley rats (Charles River, Wilmington, MA) weighing between 250 and 350 g. The rats were housed individually at 24°C with food and water provided ad libitum with lights on from 0700 to 1900 (light cycle) and off from 1900 to 0700 (dark cycle). Principles for the care and the use of laboratory animals in research, as outlined by the National Institute of Health (1985), were strictly followed.
Surgical procedures and implantation of electrodes. Treatment of the animals and surgical procedures were in accordance with an approved institutional animal welfare protocol. Rats were anesthetized with pentobarbital sodium (40 mg/kg ip), placed in the stereotaxic apparatus, and secured using blunt rodent ear bars. With the use of sterile procedures, cortical electroencephalogram (EEG), dorsal neck muscle electromyogram, electrooculogram, hippocampal EEG (to record theta wave), and pontine EEG (to record pontine wave) recording electrodes were chronically implanted as described elsewhere (14). In addition, bilateral stainless steel guide tubes (26 gauge) with a fitted stylet of equal length inside were stereotaxically implanted 2 mm above the PPT (anterior, 0.70-1.30; lateral, 1.5-2.0; height, 2.4-3.2) (40) as described previously (11). The tips of the guide tubes were left 2 mm above the targets to minimize cellular damage at the injection sites. Rats were postsurgically treated with butorphanol (0.2 mg/kg im) to control any possible pain on recovery from anesthesia.
Habituation and polygraphic recordings. During recovery, habituation, and free-moving recording periods all rats were housed under a 12:12-h light-dark cycle with free access to food and water. After a postsurgical recovery period of 3-7 days, rats were habituated to a sound-attenuated recording cage (2.5 × 1.5 × 1.5 ft) and free-moving polygraphic recording conditions for 10 days. All adaptation recording sessions were performed between 1000 and 1600, when rats are normally sleeping.
Intracerebral microinjections and experimental design. After the adaptation-recording sessions, microinjection sessions began. Six-hour (between 1000 and 1600) microinjection recording sessions were begun after a single, unilateral microinjection of 100 nl control saline or one of the four different doses of L-glutamate (15, 30, 60, or 90 ng in 100 nl sterile saline) into the PPT. In individual rats, each microinjection was separated by at least 2 days. Each PPT site received no more than two microinjections in two different recording sessions at least 96 h apart. In these two recording sessions microinjections of control saline or the dose of L-glutamate were never repeated in a single site. The sequence of these microinjections was random.
The microinjection system consisted of a 32-gauge stainless steel injector cannula with a 26-gauge collar that extended 2.0 mm beyond the implanted guide tube. The collar was connected to a 1.0-µl motor-driven Hamilton microsyringe with polyethylene-20 tubing. The L-glutamate (RBI, Natick, MA) solutions in control saline were prepared fresh under sterile conditions before each use, and they were filtered through a sterile microfilter. After the injection system was filled, a small air bubble was introduced into the polyethylene tubing to monitor the movement of the fluid during the injection. While the animal was connected to the recording system, the stylet was removed, and a control saline- or L-glutamate solution-filled injector was introduced through the guide tube. One minute after the insertion of the injector cannula, the microinjection was performed over a 60-s period while polygraphic recordings continued. The cannula was withdrawn gently 2 min after the injection, and the stylet was reintroduced inside the guide tube. At the end of all experimental sessions and 30 min before perfusion, with the use of the same injector used for glutamate microinjection, 100 nl of black ink were microinjected 1 mm dorsal to each injection site for localizing glutamate injection sites.Determination of behavioral states and data analysis. For the purpose of determining possible effects on sleep and wakefulness, three behavioral states were distinguished based on the visual scoring of polygraphic records as described earlier (14). The behavioral states of wakefulness (W), SWS, and REM sleep were scored in successive 10-s epochs. The polygraphic measures provided the following dependent variables that are quantified for each trial: 1) percentage of recording time spent in W, SWS, and REM sleep, 2) latencies to the onset of the first episode of REM sleep after the onset of injection, 3) total number of REM sleep episodes in 6-h recording session, and 4) mean duration of REM sleep episodes in 6-h recording session. Statistical analyses were performed with the use of StatView statistical software (Abacus Concepts, Berkeley, CA). Analysis of variance (2-way ANOVA) and post hoc t-tests (one-factor ANOVA, Scheffé's F test) were used to examine the effects of microinjection of L-glutamate vs. control saline on behavioral states of W, SWS, and REM sleep.
Histological localization of injection site. At the conclusion of the microinjection experiments, rats were deeply reanesthetized with pentobarbital sodium (60 mg/kg ip) and perfused transcardially with heparinized cold phosphate buffer (0.1 M, pH 7.4) followed by 4% paraformaldehyde in 0.1 M phosphate buffer. The brains were removed and processed for the NADPH-diaphorase staining and histological localization of injection sites as described earlier (13, 15).
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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A total of 66 microinjections was made in 46 PPT injection sites
(Fig. 1). Histological identification
showed that 20 of the 46 sites were placed within
NADPH-diaphorase-positive cell compartments (Fig. 1) and thus were
considered to be within the PPT. Histological methods for the
identification of PPT for this study are in agreement with previous
reports (13, 15, 30, 52, 53). Another nine sites were
0.5-1.0 mm away from the PPT (Fig. 1). The effects of
microinjections of glutamate into these nine negative sites were
compared with control vehicle and glutamate microinjections into the
anatomically positive sites. The results of these negative sites
enabled us to determine the site specificity of glutamate-induced changes in sleep and wakefulness. The remaining 17 injection sites were
more than 1 mm away from the PPT (Fig. 1). Because these 17 injection
sites were substantially outside of the target area they are not
included in this analysis. The analysis below quantifies the effects on
W, SWS, and REM sleep resulting from the differ concentrations of
glutamate injected into the PPT.
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Effects of glutamate on sleep-wake architecture.
Figure 2 illustrates representative
sleep-wake architectures for the 6-h recording session (10 AM to 4 PM)
starting immediately after microinjections of control saline or
different doses of glutamate. The figure shows that the latency between
microinjection and the first episode of REM sleep is much shorter after
microinjections of 15 (0.08 nmol)-, 30 (0.16 nmol)-, and 60-ng (0.32 nmol) doses of glutamate than control saline into the PPT. The REM
sleep episodes are more frequent after microinjection of 15-, 30-, and
60-ng doses of glutamate than after microinjection of control saline. In contrast, the 90-ng (0.48 nmol) dose of glutamate microinjection into the PPT eliminated REM sleep for about 3-4 h.
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Effects of glutamate on the total amount of W, SWS, and REM sleep
states.
To determine the optimum dose of glutamate in the PPT, 15 (n = 6), 30 (n = 10), 60 (n = 8), and 90 ng (n = 7)
microinjection-induced changes in W, SWS, and REM sleep were compared
with control saline microinjection-induced changes (n = 9). In 6-h postinjection recording sessions, the total percentage of W
was significantly higher after 60-ng
[F(1,15) = 8.722; P < 0.001] and 90-ng [F(1,14) = 25.33; P < 0.001] doses of glutamate compared with the
control saline (Fig. 3). Microinjections
of 15- and 30-ng doses of glutamate into the PPT did not significantly
change the percentage of time in W compared with control microinjection
of saline (Fig. 3).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The principal findings of this study are that 1) microinjections of 15-, 30-, and 60-ng doses of the excitatory amino acid L-glutamate into the PPT increase the total amount of REM sleep, 2) of those three doses of glutamate the 30-ng dose showed the highest increase in the amount of REM sleep, and 3) microinjections of 60- and 90-ng doses of L-glutamate increase the total amount of wakefulness when injected into the same site. As a consequence of this glutamate-induced increase in wakefulness and REM sleep, SWS is suppressed and/or eliminated. The results show for the first time that the glutamatergic excitation of the PPT cells in rats causes wakefulness and/or REM sleep. The results presented here strengthen and extend the hypothesis that the activity of PPT cells is important for the generation of REM sleep as well as wakefulness (8, 15).
Methodological considerations. In the present study all of our pharmacologically effective injection sites were in the middle of the NADPH-diaphorase-positive cell compartment of the PPT. With use of the specific monoclonal antibodies to choline acetyltransferase, the PPT has been shown to be one of the major aggregations of cholinergic neurons in the mammalian brain stem (1, 26, 29, 36-38, 42, 45, 47, 51, 56). All of these choline acetyltransferase-positive cells also displayed intense NADPH-diaphorase activity (52, 53). Thus mesopontine NADPH-diaphorase-positive cells are unequivocally considered to be cholinergic cells (13, 50, 52, 53, 55). These NADPH-diaphorase-positive PPT cells contain NO synthase (NOS) enzyme mRNA (5-7). The presence of NADPH-diaphorase together with NOS enzyme indicates that the PPT cells are capable of synthesizing NO (6, 7, 23). Thus our effective injections were made in the middle of the PPT region where cells synthesize acetylcholine (ACh) and NO (13, 15).
In this study we used local microinjections of L-glutamate to increase the activity of cells located within the NADPH-diaphorase-positive cell compartments of the PPT. To study the structure-function relationship at the system level, cerebral microinjection of the excitatory amino acid L-glutamate has certain advantages over traditional lesion and electrical stimulation techniques, especially in the study of the wake-sleep cycle. Local application of L-glutamate excites mostly cell bodies of that particular diffusion site (35), whereas electrolytic lesion and electrical stimulation include not only a larger area, they also include processes of the cell body and passing fibers through that particular region (44, 49, 54). The level of excitation of a population of neurons (multiunit activity) could be changed in a dose-dependent manner by changing the concentration of injected L-glutamate (35). Thus L-glutamate application to excite particular cell groups that affect wake-sleep patterns could be accurately evaluated for causality. A major limitation of the L-glutamate microinjection method relates to the diversity in the neurochemical nature of the neuronal population affected by its application (15, 35). L-Glutamate is a nonspecific excitatory amino acid that excites all types of neuronal cells with different neurochemical signatures. In this study, we have injected glutamate into the part of the PPT where most cells are NADPH-diaphorase-positive cholinergic type. We acknowledge that if there are noncholinergic cells within those cholinergic cell groups, they also may be excited by the application of glutamate.Role of the PPT in REM sleep generation. The results of the present study demonstrate that the microinjection of L-glutamate into the cholinergic/nitric-oxergic (Ch/NO) cell compartments of the PPT increases REM sleep in a dose-dependent manner. These results are consistent with the results obtained after L-glutamate microinjection into the Ch/NO cell compartments of the PPT in the cat (15). However, there are three important species differences between the cat and the rat in glutamate-induced REM sleep increase. First, the optimum dose of L-glutamate for inducing the maximum amount of REM sleep is much higher in the cat (1,000 ng) compared with the rat (30 ng). Second, the mean latency for the induction of REM sleep after microinjection of the optimum dose of L-glutamate is much shorter in the rat (11.57 min) compared with the cat (38.0 min). Third, glutamate-induced increase in the total amount of REM sleep in the cat is mainly due to the increase in the duration of individual REM sleep episodes. But in the rat, the total amount of REM sleep increase was contributed by increase in both duration and total number of REM sleep episodes. Despite these important species differences, these results demonstrate that increased extracellular concentration of glutamate in the Ch/NO cell compartment of the PPT successfully induced REM sleep in the rat.
To explain the observation, we suggest that the glutamatergic excitation of Ch/NO cells of the PPT-induced REM sleep possibly by two different mechanisms. First, excitation of Ch/NO cells caused release of ACh in the anterodorsal pontine reticular formation (32), and this increased level of ACh in the anterodorsal pons induced REM sleep. In support of this possible explanation, neuroanatomic studies in which retrograde tracers were used have shown that the axons of the PPT Ch/NO cells project to the cholinoceptive REM sleep generating structures in the anterodorsal pons of the rat (41, 42, 46, 57). These anatomic connectivity studies indicate that the PPT Ch/NO cells could release ACh to the cholinoceptive REM sleep generating structures in the anterodorsal pons. Several neuropharmacological studies have shown that the microinjection of cholinergic agonist (carbachol) into the anterodorsal pons induces REM sleep in the rat (4, 19, 24, 33, 34, 39, 48). Together, these pharmacological and anatomic studies support that the PPT Ch/NO cells could induce REM sleep by releasing ACh to the anterodorsal pons. Another line of evidence supporting this suggestion that the excitation of PPT Ch/NO neurons is involved in the generation of REM sleep comes from extracellular single-cell recording studies. Although no studies have attempted to correlate single-cell activity patterns of the PPT cells and the normal sleep-wake cycle in the rat, several studies in the cat have shown that a group of PPT Ch/NO cells increases their firing rates during REM sleep (8, 17, 43). Second, possibly glutamatergic excitation of Ch/NO cells increased REM sleep by releasing NO within the extracellular space of the PPT. Indeed, increased concentration of NO within the Ch/NO cell compartment of the PPT increased REM sleep in the cat (13). This cat study also demonstrated that the NO-induced increase in REM sleep was mainly due to the increase in number of REM sleep episodes. In the present study, increase in the number of REM sleep episodes was a main contributor for the glutamate-induced increase in REM sleep. Thus it is possible that the glutamate-induced REM sleep in the present study was also due to the local release of NO in the Ch/NO cell compartment of the PPT. This interpretation also supports the hypothesis that diffusible NO acts as a paracrine agent in the PPT for the regulation of sleep-wake behavior (27, 28).Role of the PPT in wakefulness. The results of the present study demonstrate that microinjection of higher doses (60 and 90 ng) of L-glutamate into the Ch/NO cell compartments of the PPT induces wakefulness. At present there is no evidence in the rat implicating involvement of the PPT cells in wakefulness. However, in the cat there are two lines of evidence implicating involvement of the PPT cells in wakefulness. The first comes from extracellular single-cell recording studies. One group of PPT cells is active both during wakefulness and REM sleep (8, 12, 17, 43, 50). These cells have a much higher firing rate during active waking than during REM sleep. The second line of evidence comes from local microinjection studies in the cat. Microinjection of a higher dose of L-glutamate (3,000 ng) into the Ch/NO cell compartments of the PPT induced wakefulness (15).
We suggest that the high dose of L-glutamate maximally activates PPT Ch/NO cells. Maximal excitation of cholinergic cells released ACh to the locus ceruleus and other structures involved in wakefulness. It is already known that the locus ceruleus receives afferent inputs from the PPT cholinergic cells (31, 57). It is also known that the cholinergic agonist directly excites locus ceruleus cells (3). Excitation of the locus ceruleus noradrenergic cells ultimately causes wakefulness (2, 18, 22, 25).Limitations and future studies. The present data cannot address the involvement of specific glutamate receptor subtypes by which PPT cholinergic cells were stimulated to produce their effects on sleep and wakefulness. The excitatory amino acid glutamate is a mixed agonist for the N-methyl-D-aspartate (NMDA), non-NMDA, and metabotropic receptors (35). The present results point to the need for future studies to specify the receptor subtypes involved for the glutamatergic excitation of the PPT cholinergic cell.
Another limitation, which can be confirmed and quantified by future studies, is the amount of ACh release in the locus ceruleus and REM sleep sign generating structures of the brain stem after glutamate microinjection into the PPT cholinergic cell compartments. The present results also encourage the measurement of norepinephrine levels in the REM sleep sign generating structures of the brain stem following microinjection of a high dose of L-glutamate into the cholinergic cell compartments of the PPT. Despite the above limitations, our results suggest for the first time in the rat that the increased activity of the PPT cells may be causal for the generation of REM sleep as well as for wakefulness. By determining optimal doses of L-glutamate in the Ch/NO cell compartment of the PPT for the induction of REM sleep and wakefulness, the present study provides an important pharmacological tool to study the cellular and neurochemical mechanisms of these two behavioral states.Perspectives
The current findings together with previous correlative observations that PPT cells are active during wakefulness and REM sleep (reviewed in Ref. 8) suggest that glutamate may regulate wakefulness and REM sleep by regulating the levels of activation in the PPT cell compartment. Although the half-life of glutamate is very short, it produced a long-lasting REM sleep effect when microinjected into the PPT. This long-lasting REM sleep effect suggests that the glutamate microinjection into the PPT possibly activated a second messenger system(s) to sustain REM sleep effect.| |
ACKNOWLEDGEMENTS |
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We thank Sanford H. Auerbach, J. Allan Hobson, and Bernat Kocsis for helpful discussions.
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FOOTNOTES |
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This research was supported by the National Institutes of Health Research Grants MH-59839 and NS-34004.
Address for reprint requests and other correspondence: S. Datta, Sleep Research Laboratory, Dept. of Psychiatry, Boston Univ. School of Medicine, M-913, 715 Albany St., Boston, MA 02118 (E-mail: subimal{at}bu.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 11 July 2000; accepted in final form 27 October 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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, n = 20: sites of injections
that produced changes in wakefulness and sleep after glutamate
microinjection. 
, n = 9 and
, n = 17: sites of injection that did
not induce any change in wakefulness and sleep after glutamate
microinjection. 
) and 30 ng glutamate (