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EEG signals were low-pass filtered (
The Journal of Neuroscience, December 15, 2000, 20(24):9187-9194
Differential Expression of Plasticity-Related Genes in Waking and Sleep and Their Regulation by the Noradrenergic System
Chiara Cirelli and Giulio Tononi The Neurosciences Institute, San Diego, California 92121
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
Behavioral studies indicate that the ability to acquire long-term memories is severely impaired during sleep. It is unclear, however, why the highly synchronous discharge of neurons during sleep should not be followed by the induction of enduring plastic changes. Here we show that the expression of phosphorylated CRE-binding protein, Arc, and BDNF, three genes whose induction is often associated with synaptic plasticity, is high during waking and low during sleep. We also show that the induction of these genes during waking depends on the activity of the noradrenergic system, which is high in waking and low in sleep. These molecular results complement behavioral evidence and provide a mechanism for the impairment of long-term memory acquisition during sleep.
Key words: Arc; BDNF; neural plasticity; memory; norepinephrine; P-CREB; sleep; sleep deprivation; waking
INTRODUCTION
Behavioral studies have shown that sleep severely impairs the ability to acquire long-term memories (Tononi and Cirelli, 2000
). For example, a large number of studies have failed to demonstrate the transfer of any learning from sleep to consecutive waking (Simon and Emmons, 1956
From an evolutionary perspective, the suppression of long-term memory acquisition during sleep would seem to serve an adaptive purpose. In general, plastic changes leading to the acquisition of new information should occur when neural activity is related to the environment, but not when the brain is active off-line (Tononi and Cirelli, 2000
In this study, we examined the brain expression in sleep and waking of three molecular markers whose induction has been linked to the acquisition of long-term memories: phosphorylated CRE-binding protein (P-CREB) (Silva et al., 1998
MATERIALS AND METHODS
Surgery and sleep recording
Adult male WKY rats (~300 gm) were implanted with chronic electrodes for EEG and with neck muscle electrodes for electromyography. EEG electrodes were located over frontal cortex (2 mm anterior to the bregma and 2 mm lateral to the midline) and over occipital cortex (4 mm posterior to the bregma and 3.8 mm lateral to the midline). Rats were individually housed in a recording cage (12/12 hr light/dark cycle; lights on at 10 A.M.; ~150 lux; 25 ± 1°C) and polygraphically recorded until the percentages and distribution of sleep states were regular. Each day from 09:30-10:00 A.M. the rats were allowed to play with a new object to familiarize them with the sleep-deprivation procedure. Sleeping rats were killed during the light hours, at the end of a long period of sleep (>45 min; interrupted by periods of wakefulness of <2 min) and after spending at least 75% of the previous 3 or 8 hr asleep. Sleep-deprived rats were also killed during the light period, after being kept awake for 1-9 hr by introducing novel objects in their recording cage. Spontaneously awake rats were killed during the dark phase, after a long period of continuous wakefulness (>1.5 hr; interrupted by periods of sleep of <5 min) and after spending at least 70% of the previous 3-8 hr awake. All animals were anesthetized (<2 min) with isoflurane in their own cage and then killed by decapitation or perfused with 4% paraformaldehyde. Animal protocols followed the National Institutes of Health Guide for the Care and Use of Laboratory Animals and were approved by The Neurosciences Institute.3 dB at 30 Hz; 24 dB/octave), analog-to-digital converted (sampling rate, 128 Hz), and subjected to spectral analysis. EEG power density values were computed for successive 4 sec epochs (24 hr of recording for each animal) in the frequency range from 0.25 to 25 Hz (collapsed into 0.5 Hz bins between 0.25 and 5 Hz and into 1 Hz bins between 5.25 and 25 Hz).
Lesions of the noradrenergic system
N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine. Rats were pretreated with the selective serotonin uptake inhibitor fluoxetine (10 mg/kg, i.p.; Sigma, St. Louis, MO) to prevent possible effects on serotoninergic terminals and 30 min later injected intraperitoneally with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4; 50 mg/kg; n = 12; Research Biochemicals, Natick, MA). Rats fully recovered from DSP-4 injection within 24-48 hr. Rats were recorded for 1-2 weeks before and after the injection. 6-Hydroxydopamine. Under pentobarbital anesthesia (60-75 mg/kg, i.p.), rats were implanted with electrodes for EEG recording as described above. During the same surgical session, rats were infused with 6-hydroxydopamine (6-OHDA; Research Biochemicals) unilaterally into the left or right locus coeruleus by way of a 24 gauge stainless steel needle connected to a 5 µl Hamilton syringe. The stereotaxic coordinates according to the atlas of Paxinos and Watson (1986)Ribonuclease protection assay, in situ hybridization, and cDNA microarrays
After the rats were killed, the head was cooled in liquid nitrogen, and the whole brain was removed. The right cerebral cortex and hippocampus were dissected, whereas the rest of the brain was left intact for in situ hybridization experiments. Samples were immediately frozen on dry ice and stored at-32P]UTP (DuPont NEN, Boston, MA). Ribonuclease protection assays (RPAs) were performed using the RPAII kit (Ambion). In situ hybridization. The protocol for in situ hybridization was as described in Pompeiano et al. (1994)
Immunocytochemistry and ELISA
Immunocytochemistry was performed on frontal sections (50 µm) of the entire brain using the following antibodies: polyclonal anti-rat P-CREB (1:1000; Upstate Biotechnology, Lake Placid, NY), polyclonal anti-rat Arc (1:10,000; gift of Dr. Dietmar Kuhl, Max-Planck-Institut, Heidelberg, Germany) (Guthrie et al., 2000
RESULTS
The level of P-CREB in the cerebral cortex is high during waking and low during sleep, irrespective of circadian time
Rats kept on a 12/12 hr light/dark cycle are asleep for most of the light period and awake for most of the dark period. We selected rats that had been asleep for the first 3 or 8 hr of the light period, rats that had been spontaneously awake for the first 3 or 8 hr of the dark period, and rats that had been sleep-deprived during the light period for 3 or 8 hr. The use of these different groups of animals allowed us to distinguish between changes in gene expression related to sleep and waking per se as opposed to circadian time or to the sleep-deprivation procedure (Fig. 1A).
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Figure 1. CREB phosphorylation in the cerebral cortex after sleep and waking. A, The experimental conditions chosen to distinguish changes associated with sleep (S), waking (W), circadian factors, and the sleep-deprivation procedure (SD). A 12 hr light/dark cycle is indicated by the horizontal bar. Three hours (3h) and 8 hr (8h) of S, SD, and W are shown. B, Anti-P-CREB staining in coronal sections of parietal cortex (layers II-VI) from a rat that slept for 3 hr (S) and a rat that was sleep-deprived for 3 hr (SD). Scale bar, 100 µm. C, Mean number (±SEM) of P-CREB-immunoreactive neurons in entorhinal (ent), parietal (par), temporal (te), and occipital (occ) cortex after 3 or 8 hr of S (n = 4/group), 3 or 8 hr of SD (n = 4/group), and 3 or 8 hr of spontaneous W (n = 3 after 3 hr; n = 2 after 8 hr). The sampled area was 500 µm wide across all cortical layers. The number of P-CREB-immunoreactive neurons was significantly higher in SD and W with respect to S (Mann-Whitney U test, *p < 0.01). No differences were found between SD and W. For each condition, there were no differences between data from the 3 and 8 hr groups, which were therefore pooled.
We first investigated whether CREB is differentially phosphorylated depending on the behavioral state of the animals. CREB phosphorylation (P-CREB) at Ser133 follows increases in the intracellular concentration of Ca2+ or cAMP or the activation of Ras-dependent protein kinases (De Cesare et al., 1999
As shown in Figure 1B, P-CREB immunolabeling was low in rats killed after either 3 or 8 hr of sleep. The pattern of staining varied from one animal to another. In some rats, weakly stained nuclei were seen in all cortical layers, whereas in others they were present only in layers II-III and V or in layer V only (Fig. 1B). By contrast, after 3 hr of sleep deprivation or spontaneous waking, P-CREB immunostaining was consistently high in all cortical layers (Fig. 1B) and in all cortical areas (Fig. 1C). No further increase was seen after 8 hr of waking. On the basis of neutral red and methyl green counterstaining, it appeared that >95% of all cortical cells of awake rats showed a strong, dark P-CREB staining. P-CREB staining did not colocalize with glial fibrillary acidic protein staining and was present in both parvalbumin-negative (excitatory) and parvalbumin-positive (inhibitory) neurons (data not shown).
The expression of Arc in the cerebral cortex is high during waking and low during sleep and changes as a function of the duration of waking
Arc is unique among activity-regulated genes in that, after induction, its mRNA is selectively targeted near activated postsynaptic sites, where it may play a role in activity-dependent synaptic plasticity requiring protein synthesis (Steward et al., 1998
We found that Arc mRNA levels were low after either 3 or 8 hr of sleep and increased twofold after 3 hr of either spontaneous waking or sleep deprivation. This increase was maintained after 8 hr of waking (Fig. 2A,B). In situ hybridization experiments indicated that Arc induction during waking, although particularly evident in the cerebral cortex, was not limited to this brain region (Fig. 2C).
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Figure 2. Arc expression in the cerebral cortex after sleep and waking. A, cDNA microarrays showing cortical Arc mRNA levels (arrowheads) after 3 hr (3h) or 8 hr (8h) of sleep (S; n = 7), sleep deprivation (SD; n = 7), and waking (W; n = 6). B, Densitometric analysis performed by scanning the microarrays with a PhosphorImager. The y-axis values refer to signal intensity (arbitrary units). C, In situ hybridization for Arc mRNA in brain sections of a representative rat killed after 8 hr of S and of a rat killed at the same circadian time after 8 hr of SD. Scale bar, 1.5 mm. D, Arc levels measured with immunocytochemistry in the parietal cortex of rats after 3 hr of S and 3 hr of W. Scale bar, 100 µm. E, Mean number (±SEM) of Arc-immunoreactive neurons in parietal cortex after 3 hr of S (n = 8), SD (n = 8), and W (n = 5). The sampled area was a 500-µm-wide cortical column spanning all layers (Mann-Whitney U test, *p < 0.01). F, Double labeling in the parietal cortex of a rat that was sleep deprived for 3 hr. Arc immunoreactivity (black cells; left) does not colocalize with parvalbumin immunoreactivity (white cells; right). Scale bar, 50 µm.
The ability of Arc mRNA to move toward dendritic sites of recent synaptic activity, as well as the subsequent local translation of Arc, has been demonstrated so far only in the hippocampus (Steward et al., 1998
To determine whether Arc levels were higher in waking with respect to sleep, another group of animals was perfused after 3 hr of sleep, sleep deprivation, or spontaneous waking, and the brains were processed for immunocytochemistry. In agreement with mRNA levels, after 3 hr of sleep, Arc levels were found to be extremely low in most brain regions, including the cerebral cortex (Fig. 2D). In a few cases, however, a faint cytoplasmic staining was seen in large pyramidal cells of layer V, notably in parietal cortex, and vertically oriented, weakly stained fibers were observed in layers II-III and V. By contrast, after 3 hr of spontaneous waking or sleep deprivation, high levels of Arc were found in most regions of both isocortex and allocortex (Fig. 2D,E). Darkly stained cells were present in layers II-VI, but within each layer the intensity of the staining varied from one cell to another. In most cells the staining could be seen to extend from the cell body to the dendritic arbor, notably to the apical dendrites. We concluded that Arc was selectively expressed in neurons because Arc-positive cells never stained with an antibody for glial fibrillary acidic protein (data not shown). When sections were simultaneously reacted with antibodies against Arc and parvalbumin, no double-labeled neurons were seen in any cortical regions, suggesting that Arc is localized in glutamatergic but not in GABAergic neurons (Fig. 2F).
We then determined the time course of Arc expression by examining, in addition to the rats killed after 3 hr of waking (dark period), other animals killed after 1, 6, and 9 hr of spontaneous waking (dark period) or sleep deprivation (light period; Fig. 3, n = 2 for each time point). After 1 hr of waking, strong Arc staining was present in the cytoplasm of large pyramidal cells in layer V, and vertically oriented labeled fibers were clearly present throughout layers II-V (Fig. 3A). The most noticeable difference with respect to 3 hr of waking was the lower number of darkly stained cells in layers II-IV (Fig. 3A) and VI (Fig. 3B). After 6 hr of waking, the pattern of Arc expression was very similar to that observed after 3 hr of waking. After 9 hr of waking, by contrast, few darkly stained cells were present in layers II-IV (Fig. 3A) and VI (Fig. 3B). Only faint cytoplasmic staining was observed in layer V. However, long, darkly stained fibers were present in most neocortical areas, notably in layers II-IV (Fig. 3A).
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Figure 3. Arc expression in the parietal cortex as a function of the duration of waking. A, B, Arc levels measured with immunocytochemistry in cortical layers V (A) and VI (B) after 1 hr (1h), 3 hr (3h), and 9 hr (9h) of sleep deprivation (SD). Scale bar, 200 µm.
Taken together, these results show that spontaneous waking, but not sleep, is associated with the induction of Arc mRNA and the translation of Arc in excitatory cortical neurons. Arc immunostaining is both cytoplasmic and dendritic after short periods of waking and is mainly dendritic after longer periods.
The expression of BDNF in the cerebral cortex is high during waking and low during sleep, irrespective of circadian time
BDNF is thought to modulate activity-dependent plasticity on the basis of three main lines of evidence (Thoenen, 1995
It was shown recently that BDNF mRNA levels are higher during the dark period relative to the light period (Bova et al., 1998
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Figure 4. BDNF expression in the cerebral cortex after sleep and waking. A, RPA showing cortical BDNF mRNA levels after 8 hr of sleep (S; n = 7), sleep deprivation (SD; n = 7), and waking (W; n = 6). A -actin antisense riboprobe was used to normalize the amount of sample RNA. Lane 1 (from left), Molecular weight markers. Lane 2, BDNF and
We then measured BDNF protein levels in the cerebral cortex after 8 hr of sleep, spontaneous waking, and sleep deprivation using an ELISA immunoassay. We used two batches of rats, ~8 and ~16 weeks old. ANOVA showed that, irrespective of age, cortical BDNF levels were higher in waking than in sleeping rats (Fig. 4D; F = 21.11; p < 0.01). There was also a significant effect of age (F = 44.01; p < 0.01) but no interaction between age and behavioral state (F = 2.53). Therefore, both mRNA and protein levels of BDNF are increased in the cerebral cortex during waking with respect to sleep, independently of circadian factors or stress.
BDNF acts via the specific tyrosine kinase receptor TrkB. Electrical or pharmacological stimulation increases TrkB mRNA and protein levels (Nibuya et al., 1995
The expression of plasticity-related genes during waking depends on the noradrenergic system
Certain neuromodulatory systems with diffuse projections, such as the noradrenergic and serotoninergic systems, are plausible candidates for enabling the expression of P-CREB, Arc, and BDNF during waking, when they fire both tonically and phasically, but not during sleep, when their firing is reduced or ceases altogether (McGinty and Harper, 1976
The majority of noradrenergic neurons are located in the two symmetric brainstem nuclei of the locus coeruleus, which send projections to the entire brain. We used two different approaches to lesion the noradrenergic system selectively. The neurotoxin DSP-4, which can be administered systemically, destroys fibers originating in the locus coeruleus by accumulating within the noradrenergic nerve endings and depleting them of catecholamines (Fritschy and Grzanna, 1989
We first established that sleep-waking patterns had not been modified as a result of noradrenergic lesions. In agreement with previous results (Cirelli et al., 1996
We measured cortical Arc and BDNF mRNA levels after 8 hr of sleep deprivation in rats in which the cortical noradrenergic innervation had been destroyed 2 weeks earlier by DSP-4 and in control rats that had received a saline injection at the same time. The expression of Arc and of BDNF in the cerebral cortex was 50% lower in DSP-4-treated rats than in control rats (Fig. 5A,B).
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Figure 5. BDNF and Arc expression in the cerebral cortex after lesion of the noradrenergic system of the locus coeruleus. A, RPA showing cortical BDNF and Arc mRNA levels after 8 hr of sleep deprivation in control rats who received a saline injection (C; n = 4; lanes 1-3 from left) and in rats treated with DSP-4 to destroy the noradrenergic innervation of the cerebral cortex (n = 4; lanes 4-6). A
We also examined rats that had received 6-OHDA injections in the locus coeruleus of one side. As expected, after 1-2 weeks the noradrenergic neurons of the locus coeruleus of that side were completely destroyed (Fig. 5C), as was the case for the noradrenergic fibers in the ispilateral (but not contralateral) cerebral hemisphere and hippocampus (Fig. 5C). In rats that had been awake for 3 hr before being killed, Arc immunostaining was high in the cerebral cortex of the intact hemisphere, as was expected during waking, but low in the hemisphere in which noradrenergic fibers had been destroyed (Fig. 5D).
Thus, in the absence of an intact noradrenergic system, waking behavior accompanied by normal low-voltage fast activity patterns is not sufficient for the induction of P-CREB (Cirelli et al., 1996
DISCUSSION
Sleep, waking, and memory acquisition
It is well established that the acquisition of long-term memories requires the activation of gene expression in the nucleus as well as protein synthesis, which may lead to structural changes in neural circuits (Squire and Kandel, 1999
The present results demonstrate that levels of P-CREB, Arc, and BDNF in most cortical areas are much higher after waking than after sleep. The expression of Fos and NGFI-A, two transcription factors that have been variously associated with the induction of plastic changes, is also higher during waking relative to sleep (Cirelli and Tononi, 2000
These molecular findings go together with the behavioral and electrophysiological evidence indicating that the long-term acquisition of information is severely dampened if not blocked during sleep (Tononi and Cirelli, 2000
The role of neuromodulatory systems in enabling memory acquisition in different behavioral states
During sleep, locus coeruleus neurons fire regularly at very low rates, whereas during waking they fire regularly at higher rates and emit phasic, short bursts of action potentials in response to salient events (Aston-Jones and Bloom, 1981a
activity in the EEG [see Cape and Jones (1998)
As shown here in the freely behaving animal, the expression of Arc and BDNF is high during waking, when locus coeruleus firing is high, and low during sleep, when locus coeruleus firing is reduced or absent. Most important, if the noradrenergic system is lesioned, waking behavior associated with a normal waking EEG (low-voltage fast activity) is not accompanied by the induction of these molecular markers of plasticity. Thus, the activation of the EEG can be completely dissociated from the activation of gene expression. These results are consistent with previous evidence indicating that the activity of the noradrenergic system is responsible for the differential expression of P-CREB, Fos, and NGFI-A (Cirelli et al., 1996
These observations prompt the question whether differences in the expression of plasticity-related genes similar to those observed between waking and sleep also occur between other conditions associated respectively with high locus coeruleus activity, such as orienting to novel stimuli, associative learning, and exploratory behavior, and with low locus coeruleus activity, such as grooming and consummatory behavior (Aston-Jones and Bloom, 1981a
Serotoninergic neurons also fire at higher levels during waking and decrease firing during sleep (McGinty and Harper, 1976
Finally, acetylcholine release in the cerebral cortex and the activity of cholinergic neurons are higher during waking than during non-REM sleep, but they are also often higher in REM sleep than in non-REM sleep (Jasper and Tessier, 1971
Conclusions
The present results demonstrate that several molecular markers of neural plasticity, such as P-CREB, Arc, and BDNF, are induced during waking but not during sleep. They also indicate that the inactivity of the noradrenergic system is a key factor that prevents the induction of these genes during sleep, leading to an impairment of long-term memory acquisition. Although these results provide a molecular basis for the inability to acquire long-term memories during sleep, they do not exclude a contribution of sleep to other aspects of learning and memory, such as memory consolidation. Other molecular mechanisms, such as dendritic or somatic protein synthesis, receptor insertion and clustering, and synaptic capture, may occur preferentially during sleep, although at present no direct evidence is available. A better understanding of the molecular mechanisms of memory consolidation should provide an opportunity to determine whether sleep may play a specific and positive role in some aspect of memory.
FOOTNOTES Received Aug. 17, 2000; revised Sept. 28, 2000; accepted Oct. 3, 2000.
The Neurosciences Institute is supported by the Neurosciences Research Foundation, which receives major support from Novartis. We thank G. A. Davis, M. C. Gallina, and D. F. Robinson for their expert contribution and Dr. D. Kuhl for the kind gift of the anti-Arc antibody.
Correspondence should be addressed to Dr. Chiara Cirelli, The Neurosciences Institute, 10640 John J. Hopkins Drive, San Diego, CA 92121. E-mail: cirelli{at}nsi.edu.
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