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Previous Article | Next Article
The Journal of Neuroscience, April 1, 1998, 18(7):2653-2666
Differential Modulation of High-Frequency
-Electroencephalogram Activity and Sleep-Wake State by Noradrenaline and Serotonin Microinjections into the Region of Cholinergic Basalis Neurons
Edmund G. Cape and Barbara E. Jones Department of Neurology and Neurosurgery, McGill University, Montréal Neurological Institute, Montréal, Québec H3A 2B4, Canada
ABSTRACT
Top
Abstract
Introduction
Several lines of evidence indicate that cholinergic basalis neurons play an important role in cortical activation. The present study was undertaken to determine the effect of noradrenergic and serotonergic modulation of the cholinergic neurons on cortical EEG activity and sleep-wake states. The neurotransmitters were injected into the region of the basalis neurons by remote control in freely moving, naturally sleeping-waking rats during the day when the rats are normally asleep the majority of the time. Effects were observed on behavior and EEG activity, including high-frequency
activity (30-60 Hz), which has been demonstrated to reflect behavioral and cortical arousal in the rat. Noradrenaline, which has been shown in previous in vitro studies to depolarize and excite the cholinergic cells, produced a dose-dependent increase in
activity, and an increase in waking. Serotonin, which has been found in previous in vitro studies to hyperpolarize the cholinergic neurons, produced a dose-dependent decrease in
These results demonstrate that noradrenaline and serotonin exert differential modulatory effects on EEG activity through the basal forebrain, the one facilitating
Key words: waking; slow wave sleep; paradoxical sleep; locus coeruleus; raphe; basal forebrain; acetylcholine
INTRODUCTION
Early studies, which investigated the effects of pharmacological manipulation of cholinergic transmission or examined the release of acetylcholine (ACh) from the cerebral cortex across sleep-wake states, clearly indicated that cholinergic neurons play an important role in cortical activation that occurs during the states of wake and paradoxical sleep (Celesia and Jasper, 1966
; Longo, 1966
Cholinergic basal forebrain neurons lie in the path of the major ascending fiber system from the brainstem reticular activating system and thus serve as the ventral extrathalamic relay to the cerebral cortex (Moruzzi and Magoun, 1949
Preliminary results of this study were reported previously (Cape and Jones, 1994
MATERIALS AND METHODS
Animals and surgery. A total of 24 male Wistar rats (Charles River Canada, Montréal, Canada), weighing between 200 and 250 gm at the time of surgery, were used in this study. Nine animals were used for pilot studies, and 15 were used for experimental studies. For implantation of electrodes and cannulae, animals were anesthetized with barbiturate anesthesia (Somnotol, 67 mg/kg, i.p.) and placed in the stereotaxic instrument with the tooth bar set at
0.33 mm. For EEG recording, jeweller's screws (1 mm diameter at exposed tip and 3 mm in length) were threaded into burr holes in the skull to come into minimal contact with the dura. They were placed bilaterally by reference to Bregma over frontal (2.7-3.0 mm anterior, 0.6 mm lateral), retrosplenial (3.5 mm posterior, 0.6 mm lateral), parietal (0.5 mm posterior, 5.0 mm lateral), and occipital (7.5 mm posterior, 5.0 mm lateral) cortical regions. A reference electrode was cemented in bone rostral to the frontal cortex and caudal to the olfactory bulbs (5.5 mm anterior, 0.6 mm lateral). EMG was recorded by means of two stainless steel wires inserted in the neck musculature. A ground electrode was implanted over the cerebellum (~1 mm posterior to lambda and 2 mm from the midline). The electrodes were joined to a small female connector.
For microinjections, stainless-steel cannulae (Plastics One, Roanoke, VA) were used and included guide cannulae (26 gauge, 0.46 mm outer diameter) with fitted dummy stylets and internal cannulae (33 gauge, 0.20 mm outer diameter). The guide cannulae were placed bilaterally such that when the internal cannulae were lowered 2.0 mm below the tip of the guides, they reached the target site in the basal forebrain [using anterior-posterior (AP), lateral (L), and vertical (V) coordinates with reference to ear bar zero: AP +7.7 mm, L 2.5 mm, and V +1.5 mm] (see Fig. 1). The guide cannulae were implanted and maintained with dummy stylets that extended beyond the guides by 0.5 mm. The guide cannulae and electrodes were fixed to the skull with dental cement.
After a minimum of 2 d recovery after surgery, each rat was housed individually in a Plexiglas box inside a large electrically shielded recording chamber in which they were maintained on a 12:12 light-dark cycle (lights on from 7:00 A.M. to 7:00 P.M.). They had free access to rat chow and water. For the duration of the experiment, the connector on the rat's head was attached to a cable connected to a commutator that was suspended with a balanced boom to allow free movement of the animal in the chamber. Baseline recording was initiated after a minimum of 2 d habituation to the chamber and cable.
At the end of the experiments, the animals were killed under barbiturate anesthesia (Somnotol, ~120 mg/kg). Most (20 of 24) were perfused through the heart with a fixative solution [3.0% paraformaldehyde, as published previously (Gritti et al., 1993
EEG recording and behavioral observations. The EEG and EMG signals were recorded with a Grass model 78D polygraph. All signals were filtered between 1.0 and 100 Hz. The EEG signals were recorded with a gain that was adjusted to be the same on each channel and to remain the same for the duration of the study. The amplifier output was sent to an IBM compatible computer running Stellate Systems software (Montréal, Québec, Canada) for on-line analog-to-digital (A/D) conversion and off-line analysis of EEG. The signals were sampled at a rate of 512 Hz and filtered with a Finite Impulse Response (FIR) filter with a cut-off frequency at 128 Hz. The data were stored at a sampling rate of 256 Hz.
The rat's behavior was observed with the aid of a video monitor and marked on-line by annotations on the computer record. Behavioral annotations included the following in the order in which they frequently occur during a normal sleep-wake cycle in association with a waking (W) or sleep (S) posture: Wattentive (when the animal was immobile and seemingly attending to a stimulus), Wmoving (including walking), Weating, Wgrooming, Wquiet (when the animal was lying down but with eyes open), Suncurled (outstretched with eyes closed), Scurled (curled up with eyes closed), Smoving (adjusting posture with eyes closed), and Stwitch (showing rapid movements of eyes, ears, or whiskers while asleep with eyes closed) (Maloney et al., 1997
Recording was performed beginning in the late morning and usually ending by 3:00 P.M. in the afternoon. The EEG computer file consisted of a morning recording period (~11:00 A.M.-11:30 A.M., taken before handling) and an afternoon recording period (~12:30 P.M.-3:00 P.M., taken after handling and the placement of the inner cannulae for microinjections). The afternoon recording was not begun until the animal had recovered from the handling, as evidenced behaviorally by the resumption of sleep. For baseline recording that was performed before any injections, the animal was picked up and handled during the time that the injection cannulae would be inserted.
Injection procedure. Ringer's and chemical injections proceeded in several stages (see Fig. 1A). After the 30 min morning recording (defined as the preinjection period), the animal was picked up for removal of the stylets and manual placement of the filled internal cannulae. The filled cannulae were inserted into the guide cannulae and held there in a position ~2 mm above the tissue (i.e., ~4 mm dorsal to their eventual target; Fig. 1A) to avoid premature contact of the chemical solution with the brain. After the rat's recovery from the handling procedure, evidenced behaviorally by the apparent resumption of sleep, the afternoon recording session was begun. After the appearance of a full sleep cycle, evidenced on the EEG by the passage through slow wave sleep into transition into paradoxical sleep (tPS) or PS (usually over a ~30 min period), the filled inner cannulae were lowered into the brain. This was accomplished without disturbing the rat by use of a remotely controlled mechanism consisting of inner tubing connected to the inner cannula that slid within outer tubing connected to the cap of the outer cannula on the rat's head. From outside the cage, the inner tubing was slid forward to a point determined by the fitting of the hub of the inner cannulae into the cap of the outer cannula, which corresponds to the point of full descent of the inner cannula into the brain. The left and right cannulae were lowered in sequence. The injections subsequently were begun ~2 min after the cannulae came into contact with the brain tissue. They were made bilaterally with a syringe pump (Sage Instruments, Cambridge, MA) that simultaneously advanced both syringe plungers over a period of ~5 min. The postinjection condition was defined for statistical analysis as the 30 min period immediately after the injection and was based on the period during which the chemicals would diffuse maximally within the restricted radius of the injection site (Martin, 1991
Chemical microinjections. Chemicals were delivered via two 1 µl Hamilton syringes (Reno, NV) simultaneously driven by a syringe pump (model 341 A, Sage Instruments, Orion Research, Cambridge, MA). Connected to the syringes, polyethylene tubing (~50 cm) was filled with paraffin oil up to the last ~1 cm (or ~1.5 µl) of each inner cannula, which was filled with the chemical solution. The chemicals were dissolved in buffered Ringer's containing (in mM) 156.14 NaCl, 3.35 KCl, 2.70 CaCl2, and 2.38 NaHCO3.
All solutions were injected in volumes of 0.5 µl (at a rate of ~0.1 µl/min) that, on the basis of previous injections of neuroanatomical tracers into the basal forebrain (Jones and Yang, 1985
Subsequently, another series of experiments was conducted in five rats to establish if the effects observed were dose-dependent. In addition to Ringer's, four doses of each drug were administered, with the dose used in the main study as the maximum dose. For noradrenaline, the low dose was established as that producing a lesser but apparent effect, and the range represented doses at 100, 67, 50, and 33% of the dose used in the main study. For serotonin, the drug was administered at doses representing 100, 50, 25, and 12.5% of the dose used in the main study to include doses overlapping with those of noradrenaline. In these animals the order in which noradrenaline and serotonin were administered was varied across rats, and the interval separating the two drug administrations was at least 48 hr.
Data analysis. The EEG was examined by off-line analysis on a computer screen and scored by visual assessment according to sleep-wake states in 20 sec epochs. State was classified as one of five states: (1) wake, (2) transition into slow wave sleep (tSWS), (3) slow wave sleep (SWS), (4) transition into paradoxical sleep (tPS), and (5) paradoxical sleep (PS) (Maloney et al., 1997
Spectra were computed by using Stellate Systems software by Fast Fourier Transform (FFT), which was based on 512 points corresponding to 2 sec epochs, with a resolution of 0.5 Hz. A seven-point smoothing window was applied by this program, thus allowing a minimum of 1.5 Hz and a maximum 63.5 Hz in the spectral computation. Frequency bands were set at the following ranges: for
, 4.5-8.5 Hz; for
, 9.0-14.0 Hz; for
1, 14.5-18.5 Hz; for
EEG records and hypnograms displaying sleep-wake state and frequency band activity were examined after recording to establish, first, a normal EEG and, second, an effective microinjection. Data were excluded from analysis if any signs of abnormal EEG activity were evident as indicative of seizure-like activity common to rodents (Vergnes et al., 1982
Statistical comparisons were performed for the average percentage sleep-wake state and for EEG and EMG activity. For EEG activity, statistics were presented from the right retrosplenial cortical lead for
RESULTS
In histology, tracks of the injection cannulae were evident passing through the caudate putamen and globus pallidus into the substantia innominata [at the border between the anterior (SIa) and posterior (SIp) sectors] and above the magnocellular preoptic nucleus, where the cholinergic cell bodies are located (Fig. 1B). They were bilaterally symmetric in all animals.
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Figure 1. A, Schematic drawing of the rat brain (in sagittal view) illustrating chemical microinjections into the region of cholinergic basalis neurons (open circles), which are known to project to the cerebral cortex (dashed lines) and to receive input from noradrenergic and serotonergic afferents (solid lines), respectively, arriving from the dorsal raphe (DR) and locus coeruleus (LC) nuclei in the brainstem [adapted with permission from Jones (1995) part; GiV, gigantocellular reticular field, ventral part; GP, globus pallidus; ic, internal capsule; LC, locus coeruleus; LD, laterodorsal thalamic nucleus; LH, lateral hypothalamic area; LP, lateral posterior thalamic nucleus; MCPO, magnocellular preoptic nucleus; oc, optic chiasm; opt, optic tract; OTuD, olfactory tubercle, deep layer; PC, paracentral thalamic nucleus; PF, parafascicular thalamic nucleus; PnC, pontine reticular field, caudal part; PnO, pontine reticular field, oral part; PnV, pontine reticular field, ventral part; PPTg, pedunculopontine tegmental nucleus; R, red nucleus; RRF, retrorubral field; Rt, reticular thalamic nucleus; SIa, substantia innominata, anterior part; SIp, substantia innominata, posterior part; SN, substantia nigra; st, stria terminalis; VL, ventrolateral thalamic nucleus; VM, ventromedial thalamic nucleus; VTA, ventral tegmental area; ZI, zona incerta.
Baseline
During baseline recording periods, rats manifested brief waking episodes with alternating more prolonged periods of sleep. During the 30 min recording period of the afternoon (generally occurring between ~1:00 P.M. and 2:00 P.M.), they all passed through at least one complete sleep cycle, as marked by the appearance of tPS and PS after tSWS and SWS (n = 8; Fig. 2). The alternation of waking and sleeping and the full cycle passing from wake through tSWS-SWS into tPS-PS were associated with differential changes in EEG frequency bands (Fig. 2). As shown previously (Maloney et al., 1997
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Figure 2. Hypnogram (top) and EEG and EMG frequency band activities (bottom) per 20 sec epoch during morning (left) and afternoon (right) recording periods (rat B10). For EEG, 79 µV); the maximum ratio of Th/De is 2.4. Time lines indicate the baseline periods corresponding to 30 min pre- and postinjection recording periods. PS, Paradoxical sleep; SWS, slow wave sleep; tPS, transition into paradoxical sleep; tSWS, transition into slow wave sleep.
During the 30 min afternoon recording period in the baseline condition, which would correspond approximately to the postinjection period in the experimental condition, the rats were asleep, on average, the majority of the time (>70%; Fig. 3). They spent ~55% of the time in tSWS and SWS and >15% in tPS and PS.
0.05). Th/De also varied significantly as a function of state and, like
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Figure 3. Average percentage of state and EEG and EMG activities from baseline recording during the 30 min afternoon (equivalent postinjection) recording period (see Fig. 2), demonstrating the amounts of each state and the associated changes in EEG and EMG activities. The % State reflects the relative amounts of time spent in each state; Ga and De are frequency band activities, Th/De is the ratio of band activities, and EMG is the total spectral activity across sleep-wake states (EEG activities are taken from the right retrosplenial lead and are reported together with EMG as amplitude in A/D units, in which 100 units
Microinjections
Whereas microinjections of Ringer's solution did not appear to alter the sleep-wake states or EEG activities of the rats (Fig. 4), microinjections of noradrenaline (Fig. 5) and serotonin (Fig. 6) appeared to alter these in different ways (Figs. 7-10).
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Figure 4. Hypnogram and EEG and EMG activities (per 20 sec epoch) during Ringer's pre- and postinjection recording periods (rat B10). After the preinjection recording period, the filled inner cannulae were inserted in the guide cannulae (see Fig. 1), and the animal was allowed to resume sleeping before recording was reinitiated. With the appearance of a normal sleep cycle, marked by SWS and tPS, leading to PS, the cannulae were lowered via remote control into the basal forebrain (see Fig. 1); the bilateral injection was started ~2 min later and was performed over ~5 min. The postinjection recording period was defined as the 30 min period after the injection was stopped (time, 0-30 min at right). Note the minimal disturbance to the sleep-wake cycle caused by the injection procedure and the injection of Ringer's. EEG frequency band activity is from the right retrosplenial lead and, together with EMG, is displayed as amplitude units or as a ratio scaled to maximum activity. In this figure, the maximum amplitude for Ga is 180, for De is 360, and for EMG is 475 (A/D units, in which 100 units
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Figure 5. Hypnogram and EEG and EMG activities (per 20 sec epoch) during noradrenaline pre- and postinjection recording periods (rat B10). Note the immediate occurrence of wake once the filled cannulae are inserted and the maintenance of a wake state in association with moderately high
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Figure 6. Hypnogram and EEG and EMG activities (per 20 sec epoch) during serotonin pre- and postinjection recording periods (rat B20). Note the continuity of SWS during and after the injection in association with a decrease in
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Figure 7. Percentage of time spent in sleep-wake states during Ringer's (R), noradrenaline (NA), and serotonin (5-HT) postinjection periods. Values are mean ± SEM for R, n = 8; for NA, n = 5; and for 5-HT, n = 8. *Significantly different from Ringer's, according to paired comparison t tests (p
Ringer's solution
Most animals were awakened briefly when the injection cannulae were lowered into the basal forebrain, but all resumed sleeping before or during injections with Ringer's solution (n = 8; see Fig. 4). After the injection was stopped, all rats experienced some epochs of SWS within the first 5 min. In the 30 min postinjection period, all animals showed an alternation of wake and SWS and a progression through SWS to tPS-PS or tPS. During these state changes, the EEG frequency band activities varied in association with state and behavior in a manner that was not distinguishable from that in the preinjection period or that in the baseline postinjection recording period.
As compared with the baseline afternoon recording period, there were no significant changes in the average relative amounts of sleep-wake states after Ringer's injections (as examined in eight rats with paired comparison t tests). The rats were still asleep the majority of the time (>80%) and spent >65% of time in tSWS and SWS and ~15% in tPS and PS (Fig. 7), although the percentage of PS was insignificantly lower than that in baseline. Similarly, the average
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Figure 8. Average EEG and EMG activities during postinjection recording periods after Ringer's (R), noradrenaline (NA), and serotonin (5-HT) microinjections. For EEG (from right retrosplenial lead), Ga and De are expressed as absolute activities in each frequency band (reported as amplitude in A/D units, in which 100 units
Noradrenaline
On the lowering of the filled cannulae, all rats woke up and remained awake before and during the injection of noradrenaline (75 nmol per side, n = 5; see Fig. 5). In the 30 min postinjection period, all rats remained awake except for some brief episodes of tSWS or SWS in some rats (2 of 5). EEG frequency band activities showed variable but generally moderately high
Across animals, the wake state was increased significantly (to an average of >95% of recording time), tSWS and SWS were decreased significantly, and PS and tPS were absent during the postinjection recording period after noradrenaline (Fig. 7). There was a significant increase in average
The EEG during the postinjection period after noradrenaline was characterized by a low-voltage fast pattern (Fig. 9), which is normally characteristic of the wake state. In the high-frequency filtered record, relatively high amplitude
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Figure 9. EEG samples from noradrenaline and serotonin postinjection recording periods. Shown are unfiltered (top) and high-frequency
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Table 1. Relative Serotonin
As was the case for Ringer's, all animals resumed sleeping after the filled cannulae were lowered or the injection was started with serotonin (250 nmol per side, n = 8; see Fig. 6). SWS occurred in all rats in the 30 min postinjection period. PS occurred in only one rat (of eight) during this same time period. In EEG activity, serotonin microinjections were associated with an apparent decrease in
During the postinjection recording period after serotonin, the average percentage of the wake state did not differ significantly from that after Ringer's, although it did appear to be higher (see Fig. 7). Similarly, the average amount of slow wave sleep (tSWS and SWS) was not changed significantly (representing >55%). On the other hand, average tPS and PS were decreased significantly (to <3%). Across animals, the EEG was altered during the postinjection period by significantly lower average
The EEG during the postinjection period after serotonin often was characterized by high-voltage slow waves with relatively low amplitude
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Figure 10. Average spectra from epochs after the injection of noradrenaline (rat B10) and serotonin (rat B20). After noradrenaline, a small low-frequency peak is in the
Dose-response relationships
The differential effects of noradrenaline and serotonin on
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Figure 11. Dose-response relationships showing the effect of increasing doses of noradrenaline and serotonin on average EEG frequency band activity during the postinjection period (see Fig. 8). Least-squares means plots are presented from the output of ANCOVAs (with dose as the main factor and rat as the covariate). EEG activities are taken from the right retrosplenial lead and reported as amplitude in A/D units, in which 100 units
DISCUSSION
The results of the present study demonstrate that noradrenaline and serotonin, which have been shown in vitro to exert respective depolarizing versus hyperpolarizing influences on cholinergic basalis neurons (Khateb et al., 1993
Noradrenaline facilitates
Noradrenaline microinjections into the basal forebrain produced a significant and dose-dependent increase in
An important role of noradrenergic locus coeruleus neurons in the facilitation of cortical activation and waking has been recognized for many years (see Jouvet, 1972
The noradrenaline microinjections into the basal forebrain also resulted in a suppression of PS, which can be interpreted simply as attributable to the facilitation of waking but possibly also to a general opposing role of noradrenaline in the generation of this state (Hobson et al., 1975
Serotonin diminishes
Serotonin produced a significant and dose-dependent decrease in high-frequency
The role of serotonin in sleep-wake states has been debated greatly over the past 25 years. The demonstration that lesions of the serotonergic raphe neurons could result in complete insomnia originally led Jouvet to propose that serotonergic neurons play a determining role in the generation of slow wave sleep (for review, see Jouvet, 1972
Despite the continuity of slow wave sleep after serotonin microinjections, the resulting sleep and sleep cycle were not completely normal but were marked by higher EMG activity and the absence of paradoxical sleep as well as diminished
Conclusions
When injected into the basal forebrain of a naturally sleeping-waking rat during the day, noradrenaline, which is known to depolarize cholinergic neurons, diminishes
FOOTNOTES Received Sept. 15, 1997; revised Jan. 6, 1998; accepted Jan. 8, 1998.
This research was supported by a grant to B.E.J. from the Canadian Medical Research Council. E.G.C. was supported as a graduate student by the Fonds de Recherche en Santé du Québec, Reseau de Santé Mentale, Axe Sommeil et Vigilance. We thank Lynda Mainville for her technical assistance and Jean Gotman, Angel Alonso, and Michel Muhlethaler for their helpful consultation.
Correspondence should be addressed to Dr. Barbara E. Jones, Montréal Neurological Institute, 3801 University Street, Montréal, Québec H3A 2B4, Canada.
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