Laboratoire de Neurobiologie de l'Apprentissage, de la Mémoire et de la Communication, Centre National de la Recherche Scientifique, Université Paris-Sud, Orsay, France;
Catherine Maho
Laboratoire de Neurobiologie de l'Apprentissage, de la Mémoire et de la Communication, Centre National de la Recherche Scientifique, Université Paris-Sud, Orsay, France
Acknowledgement: We warmly thank Jean-Marc Edeline for his constructive criticisms concerning this article.
The idea that sleep is involved in memory processing has received considerable attention in the recent years, rekindling interest in a potential link between sleep and brain plasticity (see
As in most of our previous studies, the learning paradigm was classical fear conditioning, the most commonly used model to study emotional memory and neuronal plasticity. A tone (conditioned stimulus; CS) was paired with a footshock (unconditioned stimulus; US) during waking, and it was subsequently presented, at a nonawakening intensity, during SWS episodes. Multiunit recordings were collected in the medial division of the medial geniculate nucleus (MGm), a nonlemniscal division of the auditory thalamus, and in the primary auditory cortex (ACx). Indeed, an extensive literature has established that the learned behavioral significance of an acoustic stimulus is encoded as early as the thalamocortical auditory system (reviewed in
Male Wistar rats (Iffa-Credo, Saint Germain-sur-l'Arbresle, France) weighing 300 to 350 g at the time of surgery were used. They were housed in individual cages, with continuous access to food and water, in a temperature-controlled room (23 ± 1 °C) on a 12-hr light–dark cycle (lights on at 8 a.m.). The experiments were conducted in the afternoon. All procedures were in accordance with the European legislation (86/609/EEC) on animal experimentation.
The surgery was conducted under sodium pentobarbital anesthesia (60 mg/kg ip), supplemented as necessary during implantation. Two extraduralcortical electrodes, made of small silver spheres, were placed along the interhemispheric suture with a large frontoparietal contralateral derivation for the recording of electrocorticographic (ECoG) activity. Two silver wires were inserted into the dorsal neck muscles for the recording of electromyographic (EMG) activity. A small brass screw fixed into the frontal bone was used as the ground. The recording electrodes implanted in MGm and ACx were Teflon-insulated tungsten wires (50 μm, ≈ 0.5–1 MΩ; A-M Systems, Everett, WA); two of them were inserted into a stainless steel microtube (outer diameter = 300 μm). Relative to bregma, the target sites for electrode placements were for MGm 5.8 mm posterior, 3 mm lateral, 6 mm ventral, and for ACx 4.8 mm posterior, 6.5 mm lateral, 4 mm ventral (
The experimental box (25 cm long × 25 cm wide × 50 cm high) was located in a sound-attenuating chamber; both had a transparent front door that allowed the rat to be seen. Counterbalanced recording cables were relayed at the top of the experimental box through a multichannel rotating connector. The top of the box was equipped with a loudspeaker (5 cm in diameter, bandpass = 20–20000 kHz). The grid floor of the box was made of stainless steel rods, 0.5 cm in diameter, spaced 1.5 cm center to center. The scrambled electrical footshock used as US was delivered through the grid floor via an isolation unit placed in the sound-attenuating chamber on the side of the experimental box.
Neuronal activity was recorded through subminiature operational amplifiers (TL074 surface-mount package, Texas Instruments, Dallas, TX; input = 15 pA) located on the rats' heads at the extremity of the recording cables. The activity was amplified (Model P511K, Grass, Quincy, MA; gain = 10000), filtered (600–10000 Hz), displayed on an oscilloscope, and sent to voltage window discriminators (two-threshold triggers with temporal windows; see
The output pulses of all of the triggers were stored on each trial by a laboratory microcomputer during the 1-s pretone period and the 2-s-after-tone onset. The time of occurrence of each pulse was recorded by the acquisition board at a precision of 50 μs. On each trial, custom-made software provided online rasters for four channels of neuronal activity (two from ACx, two from MGm) and for EMG activity. Off-line analysis allowed construction of standard peristimulus time histograms using any selected time bin, as well as quantification of tone responses on each channel by selection of temporal windows after tone onset. Trials on which a movement was detected in the awake rat during the 1-s pretone period, as well as trials on which the sleeping rat woke up during the pretone period or the 1-s period after tone onset, were discarded from analysis.
Familiarization period
For 2 days, each rat was familiarized with the experimental conditions. On the 2nd day, ECoG and EMG activities were monitored, and tone intensity that would be used subsequently was determined as follows. The tone (8 kHz, 2 s) was presented at different intensities (delivered in a random order) during SWS episodes. Ten to 15 tone presentations were given, and the highest intensity that did not wake the rat was determined. The intensity used during all subsequent experimental phases was 15 dB below that highest intensity; it varied among rats between 50 and 60 dB SPL.
Habituation and conditioning in wakefulness
For 4 consecutive days, at the same time of day, each rat was placed into the experimental box, and ECoG and EMG activities were permanently monitored. On the 1st day, all rats were submitted to a habituation session during which the tone (8 kHz, 2 s) was presented alone; 10 tone presentations were given. For the next 3 days, rats in the conditioned group were submitted to a session of classical conditioning during which the tone (2 s in duration) was immediately followed by a footshock (0.25–0.35 mA, 0.5 s); there were 10 tone–footshock pairings per session with variable intertrial intervals (range = 2–6 min). Rats in the pseudoconditioned group were given explicitly unpaired presentations of tone and footshock; there were 10 tone presentations separated by a varying interval of 2–6 min, and footshocks occurred randomly between the tones with a delay of 1 to 5 min after the tone; two successive tones or two successive shocks occasionally occurred.
Test trials in SWS
After the habituation session and each conditioning or pseudoconditioning session, the rat was kept in the experimental box and monitored for sleep phases. Ten test tones, 100 ms in duration, were presented during SWS. Tone duration was shortened compared with that used during conditioning in order to avoid any awakening during tone presentation. Indeed, in a pilot experiment, a 2-s tone was found to awake the rats too often. Tones were presented only when ECoG activity exhibited continuous high-voltage slow waves for a period of at least 30 s. They were distributed among several SWS episodes; the shortest intertone interval was 30 s. The duration of postsession recordings varied between 1.30 and 3 hr.
As in previous experiments (
The output pulses generated by triggering the EMG activity were analyzed in the same way as were the neuronal data. EMG reactivity to the tone was assessed by subtracting the number of counts per bin during the 1-s pretone period from the number of counts per bin during and after (for SWS) tone presentation, for each selected temporal window.
All statistical comparisons were performed on the averaged values obtained at a given block of trials, using contrast analysis of variance (
At the end of the experiment, the rats were given an overdose of pentobarbital (100 mg/kg ip) and were perfused transcardially with 0.9% (wt/vol) saline (100 μl) followed by 500 μl cold (4 °C) fixative (4% [wt/vol] paraformaldehyde in 0.1 M phosphate buffer). The brains were removed and postfixed in the same fixative solution for a week. They were subsequently placed in 0.1 M phosphate buffer containing 10% (wt/vol) sucrose for 1 day, then 20% (wt/vol) sucrose for 3 days, both at 4 °C. Serial 50-μm coronal sections were cut on a freezing microtome and stained with cresyl violet.
The results were derived from a total of 19 rats, of which 15 had electrodes implanted in both the MGm and the ACx and 4 had electrodes implanted in only the MGm or only the ACx. Multiunit recordings were obtained from 15 electrodes in the MGm and from 14 electrodes in the ACx in the conditioned group (n = 11); they were from 11 electrodes in the MGm and from 11 electrodes in the ACx in the pseudoconditioned group (n = 8).
Behavioral data
As can be seen in
Tone responses in MGm
The 26 sites from which recordings were collected were located in the caudal part of MGm. Most of them (13 in the conditioned group and 9 in the pseudoconditioned group) were 6 mm posterior to bregma; the other four (two in each group) were 5.6 mm posterior to bregma (
In the conditioned group, the “on” response evoked during the first 40 ms after tone onset changed across sessions, F(3, 42) = 10.01, p < .001. It was higher during conditioning (the three sessions pooled together) than during habituation, F(1, 14) = 15.82, p < .005. As shown in
None of these changes were observed in the pseudoconditioned group. The “on” response did not change across sessions, F(3, 30) < 1; it did not differ between pseudoconditioning and habituation, F(1, 10) = 1.03, ns. Significant Group × Session interactions confirmed the difference between the two groups, F(3, 72) = 3.88, p = .012, and F(1, 24) = 6.57, p = .017.
Tone responses in ACx
The 25 recording sites were located in the temporal area TE1, from 4.3 to 5.3 mm posterior to bregma, which corresponds to the primary auditory cortical field (
In the conditioned group, the “on” response evoked during the first 40 ms of tone changed across sessions, F(3, 39) = 18.70, p < .001. It was higher during conditioning than during habituation, F(1, 13) = 45.34, p < .001. As shown in
In the pseudoconditioned group, the “on” response remained unchanged: It was not modified across sessions, F(3, 30) = 1.10, ns; it was comparable during pseudoconditioning and habituation, F(1, 10) < 1. The difference between the two groups was corroborated by significant Group × Session interactions, F(3, 69) = 8.30, and F(1, 23) = 16.10; p < .001 for each comparison.
Electromyographic data
In the conditioned group, tone presentation elicited no significant EMG change on the habituation day: The activity recorded during each time bin did not differ from mean pretone level: higher F value, F(1, 10) = 3.20, p = .10, for the 200-to-500-ms bin, during which EMG activity was lower than pretone value. Reactivity to the tone did not change across the 4 days: higher F value, F(3, 30) = 2.25, p = .11 for the 200-to-500-ms bin, p > .21 for all the other bins. It was not significantly different after conditioning and after habituation: higher F value, F(1, 10) = 4.03, p = .073 for the 200-to-500-ms bin; F(1, 10) < 1 for all the other bins.
In the pseudoconditioned group, EMG reactivity to the neutral tone was slightly higher than in the conditioned group during the 0-to-100-ms bin, F(1, 17) = 3.93, p = .064, and during the 200-to-500-ms bin, F(1, 17) = 7.77, p = .012. This reactivity did not significantly change across days: higher F value, F(3, 21) = 2.66, p = .074, for the 200-to-500-ms bin. It was not different after pseudoconditioning and after habituation: higher F value, F(1, 7) = 2.15, ns, for the 500-to-1,000-ms bin.
Thus, no change in EMG reactivity occurred during the 100 ms of tone presentation. Further, over the whole second after tone onset, reactivity to the conditioned tone remained similar to that expressed to the neutral tone, F(1, 10) < 1, for the comparison between EMG responses after conditioning and after habituation, and it was comparable to that expressed after pseudoconditioning, F(1, 17) < 1, for the interaction between the factors of group and treatment day (habituation vs. conditioning or pseudoconditioning).
Tone responses in MGm: Group data
On the habituation day and for the whole set of 26 recordings, the evoked activity recorded during the 100 ms of the tone was reduced compared with wakefulness, F(1, 25) = 7.22, p = .012. The discharges occurring during the first 40 ms were not significantly decreased, F(1, 25) = 2.20, ns, but those occurring during each of the next three 20-ms bins were (all ps < .05). As can be seen in
Spontaneous activity recorded during the 1-s pretone period did not change across days in either group, F(3, 42) < 1, and F(3, 30) = 2.04, ns, for the conditioned and the pseudoconditioned group, respectively. This was also the case for the tone-evoked response. In the conditioned group, the “on” response evoked in the first 40 ms of tone remained unchanged across days, F(3, 42) < 1, and was comparable after conditioning and after habituation, F(1, 14) = 1.18, ns. Similarly, no change was observed after pseudoconditioning, F(3, 30) < 1, and F(1, 10) < 1. Therefore, the responses of MGm neurons in SWS did not differ after conditioning and after pseudoconditioning, F(3, 72) < 1, and F(1, 24) < 1, for the Group × Day interactions. Similar results were obtained when the whole response evoked during the 100 ms of the tone was considered, F(3, 72) < 1, and F(1, 24) < 1.
Tone responses in ACx: Group data
On the habituation day and for the whole set of 25 recordings, the evoked activity recorded during the 100 ms of the tone was reduced compared with waking, F(1, 24) = 33.42, p < .001. Evoked discharges were not significantly decreased during the first 20-ms bin, F(1, 24) = 1.15, ns, but they were during each of the subsequent three bins (all ps ≤ .014; for the fifth 20-ms bin, p = .085). As in MGm, offset responses were also observed after habituation, conditioning, and pseudoconditioning (see
In the conditioned and the pseudoconditioned group, spontaneous pretone activity did not change across days, F(3, 39) < 1, and F(3, 30) < 1, respectively. The response evoked in the first 40 ms of the tone was also unchanged, F(3, 39) < 1, and F(3, 30) = 1.96, ns. It did not differ before and after conditioning, F(1, 13) = 2.33, ns, or before and after pseudoconditioning, F(1, 10) = 2.36, ns. There was therefore no between-groups difference, F(3, 69) < 1, and F(1, 23) < 1, for the Group × Day interactions. It was also the case when the whole tone duration was considered, F(3, 69) = 1.22, ns, and F(1, 23) < 1. Thus, contrasting with the results obtained during waking, group data did not show enhanced responsiveness to the tone CS during SWS, whether in MGm or in ACx.
Tone responses in MGm and ACx: Further analyses
A possibility that could account for the absence of response changes during posttraining SWS is that neuronal plasticity induced during wakefulness was not sufficiently robust to be maintained and expressed in another behavioral state. To address this issue, we compared the conditioned changes obtained in MGm during waking with those obtained in a previous experiment. In that study (
Nonetheless, further analyses indicated that the expression of conditioned responses in SWS did depend on the strength of the conditioned changes. First, the response changes observed in MGm during posttraining SWS were correlated with those observed during conditioning, r(15) = .691, p = .003. This contrasts with the total absence of correlation between the changes occurring during SWS and those occurring during waking in the pseudoconditioned group, r(11) = −.007. Therefore, on the basis of the scatter diagram presented in
The same analyses were performed for the cortical responses. Although there was no correlation between the changes observed during SWS and during conditioning, r(14) = .041, ACx recordings were divided into two subsets: One included the six recordings that exhibited the largest response increases during conditioning (in B
Although tone responses in MGm and ACx were enhanced during the three conditioning sessions, overall they failed to show any significant changes during SWS. This failure contrasts with previous results demonstrating that fear-conditioning-induced plasticity in MGm was expressed during PS (
During wakefulness, increases in evoked responses were observed only in the conditioned group, not in the pseudoconditioned group, which attested to their associative nature. As these increases were already present in the first 40 ms of tone, they did not result from movements and/or behavioral feedback: Myographic activities did not change in the first 100 ms of tone, conditioned motor responses starting only in the subsequent 100 ms. Furthermore, in line with pioneering studies (
Tone responses were reduced during SWS. This decrease was mainly due to suppression of the sustained activity that followed the “on” response in waking; the early response component occurring in the first 40 ms was less affected. Most of the single-unit studies that examined sleep-dependent changes in sensory systems showed that evoked activity in SWS was predominantly depressed at the thalamic level (
Admittedly, testing tone responses during SWS after fear conditioning without awaking the rat was far from being simple. The arousing properties of a stimulus closely depend on its emotional salience and behavioral relevance. Thereby, sensory thresholds for awakening from sleep in general and SWS in particular are lowered after a stimulus has acquired significance through associative learning (
On the basis of a systematic and careful inspection of ECoG tracings and on quantification of nuchal EMG activity, no awakening from SWS was detected during tone presentation and even over the 1-s period after tone onset. Obviously, we cannot assert that microarousals never occurred. Quantitative analysis would have possibly revealed subtle modifications in the spectral composition of the ECoG. However, the overall absence of changes in the pattern and amplitude of evoked responses in MGm and ACx, as well as in posttone firing activity, suggests that microarousal reactions to the conditioned tone, if any, were rare. Actually, the question of possible arousal effects on tone responsiveness is pertinent only for the recordings that displayed response changes in postlearning SWS, particularly the five MGm recordings that exhibited the largest discharge increases during conditioning and enhanced responses during SWS. It is improbable that the enhancement observed in that subset was due to arousal from SWS, for the following reason. In the 4 rats from which these five recordings were obtained, two other MGm recordings and five ACx recordings were simultaneously collected. If arousal from SWS had occurred, then response changes should have been observed also for those other recordings. This was not the case: Compared with habituation levels, the response changes observed after conditioning for the two MGm recordings were –0.01 and 0.38 spikes/20 ms; the mean change obtained for the five ACx recordings was 0.14 spikes/20 ms. Therefore, we can reasonably assume that the enhanced responding expressed by the five-MGm-recording subset did reflect learning-induced plasticity.
No ACx recording subset showed increased responses during SWS. This difference between ACx and MGm is probably more apparent than real. First, because the robustness of associative plasticity in ACx has been largely demonstrated (
That neuronal plasticity is or is not transferred across physiological states depending on the strength of conditioning-induced plastic changes is per se far from surprising, of course. However, in previous studies we systematically found that response plasticity was transferred from waking to PS; this was observed for conditioned responses in the hippocampus, the amygdala, and the MGm (
It might be speculated that an extinction process, due to repeated tones in the absence of the US, developed during SWS. As a result, conditioned responses would have diminished over trials and days; only the strongest of them would have been partially preserved and, thus, detected. This possibility is unlikely for several reasons. First, fear-conditioning-induced responses do not easily extinguish: For example, in awake rats, conditioned onset responses in ACx were still retained after 30 extinction trials (
The other possibility, much more likely, is that the physiological conditions prevailing in the thalamocortical system during SWS make the expression of response plasticity difficult. Whereas waking and PS are similar in a number of respects (
An increasing amount of evidence supports the view that SWS facilitates the consolidation of memories by providing suitable conditions for reactivating memory traces and reinforcing neural plasticity initiated during waking (e.g.,
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Submitted: February 28, 2005 Revised: May 11, 2005 Accepted: May 23, 2005