LITHIUM PREVENTS REM SLEEP DEPRIVATION-INDUCED MEMORY IMPAIRMENTS http://dx.doi.org/10.5665/sleep.3126
Lithium Prevents REM Sleep Deprivation-Induced Impairments on Memory Consolidation Simone M. Ota, MSc1; Karin Di Monteiro Moreira, PhD1,2; Deborah Suchecki, PhD1; Maria Gabriela M. Oliveira, PhD1; Paula A. Tiba, PhD1,2 Departamento de Psicobiologia, Universidade Federal de São Paulo, São Paulo, Brazil; 2Centro de Matemática, Computação e Cognição, Universidade Federal do ABC, Santo André, Brazil
1
Background: Pre-training rapid eye movement sleep (REMS) deprivation affects memory acquisition and/or consolidation. It also produces major REMS rebound at the cost of waking and slow wave sleep (SWS). Given that both SWS and REMS appear to be important for memory processes, REMS rebound after training may disrupt the organization of sleep cycles, i.e., excessive amount of REMS and/or little SWS after training could be harmful for memory formation. Objective: To examine whether lithium, a drug known to increase SWS and reduce REMS, could prevent the memory impairment induced by pretraining sleep deprivation. Design: Animals were divided in 2 groups: cage control (CC) and REMS-deprived (REMSDep), and then subdivided into 4 subgroups, treated either with vehicle or 1 of 3 doses of lithium (50, 100, and 150 mg/kg) 2 h before training on the multiple trial inhibitory avoidance task. Animals were tested 48 h later to make sure that the drug had been already metabolized and eliminated. Another set of animals was implanted with electrodes and submitted to the same experimental protocol for assessment of drug-induced sleep-wake changes. Subjects: Wistar male rats weighing 300-400 g. Results: Sleep deprived rats required more trials to learn the task and still showed a performance deficit during test, except from those treated with 150 mg/kg of lithium, which also reduced the time spent in REM sleep during sleep recovery. Conclusion: Lithium reduced rapid eye movement sleep and prevented memory impairment induced by sleep deprivation. These results indicate that these phenomena may be related, but cause-effect relationship cannot be ascertained. Keywords: Multiple trial inhibitory avoidance task, slow wave sleep, lithium, sleep rebound Citation: Ota SM; Moreira KDM; Suchecki D; Oliveira MGM; Tiba PA. Lithium prevents REM sleep deprivation-induced impairments on memory consolidation. SLEEP 2013;36(11):1677-1684.
INTRODUCTION Sleep is viewed as of fundamental importance for cognitive processes, including attention, learning and memory consolidation.1-3 Important discoveries in this field come from investigations on the harmful effects of sleep deprivation—including rapid eye movement sleep (REMS) deprivation—on memory tasks, such as contextual fear conditioning, inhibitory avoidance, and place learning.4-9 Recently, however, there has been speculation on the role of slow wave sleep (SWS), and not only of REMS, on memory consolidation,2 based on studies showing post-training SWS augmentation or positive correlation between SWS amount and performance in some emotional memory tasks.10-13 Furthermore, place cells present the same firing pattern during SWS as during active state.2,14,15 Therefore, it has been hypothesized that SWS and REMS play different, yet complementary roles in memory consolidation. While neurons would replay the activity pattern in SWS with reduced external interference, plasticityrelated gene expression occurring in REMS would be important to strengthen long-term memories.2,16
Submitted for publication October, 2012 Submitted in final revised form July, 2013 Accepted for publication July, 2013 Address correspondence to: Deborah Suchecki, Departamento de Psicobiologia, Universidade Federal de São Paulo – UNIFESP, Rua Napoleão de Barros, 925, Vila Clementino, São Paulo, SP, Brazil, CEP 04024-002; Tel: + 55 11 2149-01559; Fax: + 55 11 5572-5092; E-mail: [email protected] SLEEP, Vol. 36, No. 11, 2013 1677 Downloaded from https://academic.oup.com/sleep/article-abstract/36/11/1677/2558947 by guest on 10 March 2018
One of the major consequences of REMS deprivation in rats is the sleep rebound that ensues once rats are given the opportunity to sleep. After a period of 96 h of sleep deprivation with the modified multiple platform method, rats exhibit approximately 160% increase of REMS and a 12% decrease of SWS within the 24-h rebound period.17,18 Therefore, we hypothesized that disorganized sleep architecture seen after sleep deprivation might be responsible for performance impairment in memory tasks. To test this hypothesis, we deprived rats from REMS for 96 h before training in the multiple trial inhibitory avoidance (MTIA)8; we then allowed them to recover for 48 h, when testing took place. Since in this task the animals are trained until achievement of a learning criterion, it is possible to observe the consequences of prior sleep deprivation (residual effects of sleep deprivation itself and/or the sleep rebound that occurs immediately after the training session) on memory consolidation, independent of its effects on acquisition. If this hypothesis holds true, strategies that prevent or reduce REMS rebound and/or increased SWS could be beneficial for learning and memory processes after sleep deprivation. Lithium carbonate, used for the treatment of bipolar disorder, is known to augment SWS and to reduce REMS.19-22 In the present study, we sought to prevent memory impairments induced by 96 h of REMS deprivation in animals trained and tested in the MTIA task, by a single administration of lithium a few hours before task training. METHODS Subjects Male Wistar rats (3 to 4 months old) from Centro de Desenvolvimento de Modelos Experimentais (CEDEME) of the Sleep Deprivation, Lithium, and Memory—Ota et al
Habituation 3 days (1 h/day)
Sleep Deprivation or Habituation 4 days
Division into REMSDep and CC groups
Lithium Administration
Opportunity to Sleep 2 days
MTIA Training
MTIA Training
Figure 1—Scheme of the experimental procedures used in the present study.
Universidade Federal de São Paulo (UNIFESP) were used. Animals were housed in polypropylene cages (5 per cage) and maintained under 12 h/12 h light/dark cycle (lights on at 07:00) and controlled temperature (23 ± 2ºC), receiving food and water ad libitum. This study was approved by the Ethical Committee in Research of UNIFESP (CEP 0079/10). Drugs Lithium carbonate (Eurofarma, Brazil) was prepared in 0.9% saline at doses of 50, 100, and 150 mg/kg, and administered IP in a volume of 0.2 mL/100 g of body weight. These doses were chosen based on a previous study in which they were shown to reverse mania-like behavior in REMS-deprived (REMSDep) mice.23 Sleep Deprivation Animals were submitted to the modified multiple platform method (MMPM) for 96 h. Ten rats were placed in an stainless steel tank (123 cm length × 44 cm width × 44 cm depth) containing 14 platforms (6.5 cm diameter) filled with water until approximately 2 cm below the platform surface.24 The animals stayed on the platforms; when REMS was initiated, they fell in or touched the water due to muscle atonia, and were thus awakened. This method completely suppresses REMS and reduces the time spent in SWS by 31%.18 To prevent environmental interference (such as humidity), animals in the control group were placed inside the water tanks for one hour per day.5 Multiple Trial Inhibitory Avoidance Task The task was performed in a 2-compartment shuttle box, with a white compartment connected to a black one by a sliding door. Each rat was placed in the white side of the apparatus, and 10 s later the sliding door was opened. As soon as the rat stepped in the dark compartment with its 4 paws, the sliding door was closed and a 0.7 mA shock was delivered. The first step-through latency in the training was recorded and the outliers (based on z-score) were excluded from the study. Subsequently, the animal was removed from the box and placed again in the white compartment. The procedure was repeated until the animal reached the learning criterion, e.g., remaining in the safe compartment for 120 s. The number of trials was recorded to assess the acquisition index.8 On the test session, which occurred 48 h after training, the animals were placed in the safe compartment and the latency to cross to the aversive compartment (step-through latency) was taken as a retention index to be compared between groups. If the animals did not cross the apparatus in 300 s, this latency was SLEEP, Vol. 36, No. 11, 2013 1678 Downloaded from https://academic.oup.com/sleep/article-abstract/36/11/1677/2558947 by guest on 10 March 2018
recorded. No footshock was delivered during the test session. The period of 48 h between training and testing session was chosen because this is the time that the rats require to eliminate the drug,25 ensuring that rats were not performing under the effect of the drug. Electrode Implantation and Sleep Recording A second set of animals underwent surgery for electrode implantation. Anesthesia was induced with ketamine and xylazine (50 mg/kg and 10 mg/kg, IP, respectively). For electroencephalography (EEG) recording, 4 electrodes were fixed in the rat’s skull, following coordinates: 1 mm posterior to bregma and 3 mm to the left of the sagittal suture; 3 mm anterior to bregma and 1 mm to the right of the sagittal suture; 1 mm anterior to lambda and 4 mm to the left of the sagittal suture; and 4 mm anterior to lambda and 1 mm to the right of the sagittal suture. For electromyography (EMG), one pair of nickel-chromium wire was inserted in the neck muscle. To avoid infection and pain, rats were treated with Pentabiotic (0.25 mL, IM) and the analgesic drug sodium diclofenac (25 mg/mL, IM). Sleep-wake cycle was recorded in digital polygraphs NihonKohden (Neurofax QP 223 A Nihon Kohden Co., Tokyo, Japan) and each animal was connected to 6 channels, electrodes implanted. The recordings were analyzed in epochs of 10 s26 using the program Sleepscorer in the software Matlab. Sleep stages were classified visually, in SWS (high amplitude and slow cortical waves, with low EMG activity), transition sleep ([TS] high amplitude and slow cortical waves with sleep spindles and theta hippocampal waves), and REMS (low amplitude and high frequency cortical waves, with theta hippocampal waves and muscle atonia). Waking was classified when it was observed low amplitude and high frequency cortical waves and high EMG activity, in accordance to Timo-Iaria and colleagues27 and Giuditta and colleagues.10 The data was obtained from 4 h of sleep recording, beginning immediately after the end of sleep deprivation, because it encompassed the period of drug action on sleep-wake cycle.22 Experimental Procedure (Figure 1) All animals were habituated to the sleep deprivation tank for one hour per day for 3 days. Subsequently, they were randomly assigned to cage control (CC) or REMSDep groups. REMSDep rats were submitted to the MMPM, whereas CC rats were placed in the water tanks for 1 h per day. After a period of 96 h of sleep deprivation, training in the MTIA task commenced (7 h after lights on). Sleep Deprivation, Lithium, and Memory—Ota et al
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Figure 2—Number of trials necessary for cage control (CC) and rapid eye movement sleep-deprived (REMSDep) animals, treated with vehicle (VEH) or lithium (LI 50, 100, 150 mg/kg), to achieve the acquisition criterion in the MTIA task. Values are expressed as mean ± SEM *Group effect, Two-way ANOVA; P < 0.001. MTIA, multiple trial inhibitory avoidance; SEM, standard error of mean.
0
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Figure 3—First step-through latency of cage control (CC) and rapid eye movement sleep-deprived (REMSDep) animals treated with vehicle (VEH) or lithium (LI 50, 100, 150 mg/kg), in the training of the MTIA task. Values are expressed as mean ± SEM *Group effect, Two-way ANOVA; P < 0.05. MTIA, multiple trial inhibitory avoidance; SEM, standard error of mean.
Experiment 1: Effects of Lithium on Inhibitory Avoidance Performance
Animals were treated 2 h before the onset of training session, with vehicle (VEH) or one of the lithium doses (LI 50, LI 100, LI 150 mg/kg; n = 10-15/group/dose). Lithium was administered before training, as the effects of the drug on sleep are observed 2 h post-administration.22
waking in this time block. Analysis of the subsequent period of sleep was done by a 3-way ANOVA for repeated measures, with Group, Drug (vehicle or lithium 150 mg/kg), and Hour (Hour 2, Hour 3, and Hour 4) as main factors. When necessary, the tests of Tukey and Newman-Keuls (for repeated measures) were used for post hoc analysis. Level of significance was established at P ≤ 0.05.
Experiment 2: Effects of Lithium on Sleep Pattern
RESULTS
Statistical Analysis Z-score of step-through latencies was used to remove the outliers (e.g., rats with latency > 2 standard deviation). In the memory recall experiment, the number of trials required to reach learning criterion was analyzed by a 2-way ANOVA, with Group (CC, REMSDep) and Drug (vehicle, 50, 100, 150 mg/kg) as main factors, as the drug was given before training and rats were distributed in 8 groups (CC and REMSDep subdivided into each treatment). Analysis of step-through latency was done by a 3-way repeated measures ANOVA, with Group, Drug, and Session (repeated measure: first step-through latency on training, latency on test) as main factors. A linear regression analysis was performed to observe the correlation between the “first step-through latency on training” and the “step-through latency on test.” Analysis of percentage of time spent in and number of episodes of each behavioral state in the first hour of sleep recording was done by 2-way ANOVA with Group and Drug as main factors. This was done because of the high amount of
Effects of Lithium on Memory Training: Figure 2 shows the number of trials required to reach learning criterion in the MTIA. The 2-way ANOVA showed a main effect of Group (F1,97 = 26.66; P < 0.001), with REMSDep group requiring more trials to learn the task than CC group (2.11 ± 0.36 and 2.75 ± 0.81). There was no statistical effect of Drug (F3,97 = 0.30; P = 0.83) nor interaction between the factors (F3,97 = 0.28; P = 0.84). Analysis of first step-through latency (Figure 3) pointed to a Group effect (F1,97 = 4.42; P = 0.04); REMSDep animals presented higher latency than control (29.02 ± 23.20 and 21.98 ± 13.72) and Drug (F1,97 = 2.87; P = 0.04); however, post hoc tests showed no difference among the treatments. Test (Figure 4): The 3-way ANOVA for repeated measures indicated a main effect of Session (F1,97 = 105.13; P < 0.001), an interaction between Session and Group (F1,97 = 36.43; P < 0.00001), and a triple interaction (F3,97 = 2.96; P = 0.04). The post hoc analysis showed that all CC animals, regardless of the dose of lithium, presented longer step-through latency on test than REMSDep rats (P < 0.005); the latency of REMSDep animals treated with vehicle, 50 or 100 mg/kg did not differ between training and test sessions. Treatment with 150 mg/kg, however, enhanced the latency in the test when compared to training (P < 0.01) and to REMSDep + VEH,
Twenty-four rats were submitted to electrode implantation surgery and had 10 days of recovery in separated cages. The animals were submitted to the same protocol and received either vehicle or lithium 150 mg/kg (n = 5-7/group/drug), but instead of MTIA task training, sleep-wake cycle recording began.
SLEEP, Vol. 36, No. 11, 2013 1679 Downloaded from https://academic.oup.com/sleep/article-abstract/36/11/1677/2558947 by guest on 10 March 2018
Sleep Deprivation, Lithium, and Memory—Ota et al
CC
REMSDep
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300
Latency (s)
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Transitional Sleep
0 VEH
SWS, and an interaction between Group and Drug (F1,20 = 7.03; P = 0.04). The test of Tukey showed that both REMSDep + VEH and REMSDep + LI groups spent less time in SWS than CC + VEH group (P < 0.005). The ANOVA also showed a main effect of Hour (F2,40 = 3.63; P = 0.04), and the post hoc test revealed that the rats spent less time in SWS in Hour 4 than Hour 3. For the number of episodes, main effects of Group (F1,20 = 18.27; P < 0.001) and Hour (F2,40 = 4.27; P = 0.02) were observed. Newman-Keuls test revealed that REMSDep animals presented fewer episodes than CC animals; in addition, there were fewer SWS episodes in Hours 3 and 4 than Hour 2, as can be seen in Table 2.
LI 50
Dose
LI 100
LI 150
Figure 4—Step-through latency of cage control (CC) and rapid eye movement sleep-deprived (REMSDep) animals, treated with vehicle (VEH) or lithium (LI 50, 100, 150 mg/kg), in the MTIA test. Values are expressed as mean ± SEM *Different from respective control group, P < 0.005. †Different from sleep deprived groups treated with vehicle and other doses of lithium, P < 0.05. MTIA, multiple trial inhibitory avoidance; SEM, standard error of mean.
REMSDep + LI 50 and REMSDep + LI 100 groups (P < 0.05). All REMSDep subgroups, except from the one treated with LI 150, performed poorer than their respective CC subgroups (P < 0.001). There was no correlation between the first step-through latency on training and the step-through latency on test (r = 0.06), indicating that training did not influence the performance during test. Effects of Lithium on Sleep Pattern Figure 5 shows the average amount of each sleep state in the 4 groups. At a glance one can distinguish the higher percentage of TS and REMS in the sleep deprived groups. The mean percentage of time spent, per hour, in each sleep state is shown in Table 1, and the mean number of episodes is shown in Table 2. Waking
During the first hour there was no difference between groups in any of the parameters. Analysis of the other hours revealed an interaction between Group and Drug (F1,20 = 10.14; P < 0.01), and the test of Tukey showed that CC + LI group spent more time awake than the other groups (P < 0.01). Moreover, there was a main effect of Group (F1,20 = 7.92; P = 0.01), as REMSDep groups presented fewer episodes of waking than CC groups). Slow Wave Sleep
The analysis showed no difference among the groups in the first hour. However, from the second recording hour on, the 3-way ANOVA revealed a main effect of Group (F1,20 = 43.68; P < 0.001), e.g., sleep-deprived animals spent less time in SLEEP, Vol. 36, No. 11, 2013 1680 Downloaded from https://academic.oup.com/sleep/article-abstract/36/11/1677/2558947 by guest on 10 March 2018
In the first hour there was an interaction between Group and Drug (F1,20 = 4.72; P = 0.04), and the post hoc test showed that group REMSDep + VEH presented higher percentage of TS than its respective control group (P = 0.04). Analysis of the number of episodes also pointed to an interaction between Group and Drug (F1,20 = 4.99; P = 0.04), in which sleep deprived animals treated with vehicle also presented more TS episodes than the control group (P = 0.02). In the following hours, analysis of amount of TS showed an effect of Group (F1,20 = 20.58; P < 0.001), i.e., REMSDep groups presented higher percentage of this stage. For the number of episodes, the test also showed a main effect of Group (F1,20 = 22.16; P < 0.001), as REMSDep groups presented more episodes of transition sleep than CC groups. REM Sleep
For the first hour, 2-way ANOVA showed main effect of Group (F1,20 = 23.69; P < 0.001) and an interaction between Group and Drug (F1,20 = 5.52; P = 0.03). The test of Tukey showed that REMSDep + VEH group spent more time in REM than the other groups (P < 0.05). Analysis of the number of episodes revealed main effects of Group (F1,20 = 29.59; P < 0.001) and Drug (F1,20 = 7.22; P = 0.01) and an interaction between these factors (F1,20 = 11.91; P < 0.01). The post hoc test indicated that REMSDep + VEH group presented more episodes of REMS than the other groups (P < 0.001). During the other hours of sleep recording, analysis of time spent in REMS showed an effect of Group (F1,20 = 114.11; P < 0.001), in which REMSDep groups presented more REMS than CC groups. For number of REMS episodes, the test showed main effects of Group (F1,20 = 42.07; P < 0.001) and Drug (F1,20 = 4.39; P = 0.05); REMSDep groups presented more REMS episodes, and lithium treatment reduced this parameter. DISCUSSION The present results on the effect of REMS deprivation on acquisition of inhibitory avoidance task replicated previous findings from our laboratory, i.e., REMS deprivation impairs learning and retention of the inhibitory avoidance task.6-8 In the present study, we showed that the highest dose of lithium successfully prevented the impairment of memory retention. Likewise, the study of sleep-wake recording replicated previous results from our laboratory, showing that sleepdeprived rats exhibit more REMS and less SWS than control Sleep Deprivation, Lithium, and Memory—Ota et al
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Figure 5—Visual representation of the percentage of each sleep state in cage control (CC) and rapid eye movement sleep-deprived (REMSDep) groups treated either with vehicle (A and C) or lithium 150 mg/kg (B and D).
animals when given the opportunity to sleep.17,18 Moreover, the present results also showed that the REMSDep group spent more time in TS than control rats. Acute administration of lithium enhanced waking time and number of episodes in the control group, but did not interfere with its performance compared to vehicle-treated control rats. In the last hours of recording, REMSDep + VEH and REMSDep + LI groups presented less SWS than CC + VEH group, but did not differ from CC + LI group, though a more prominent increase of SWS was expected, as is seen with lithium administration in humans.19 Furthermore, REMSDep + VEH group exhibited more TS than its respective control group during the first hour of recording, but REMSDep + LI group did not exhibit this difference from its respective control group. Lithium administration to REMSDep rats reduced the time spent in REMS during the first hour and diminished the number of episodes in the second hour of sleep recording compared to REMSDep + VEH rats, but unlike Jones and colleagues there, was no difference between non sleep-deprived groups, which could be explained by the different strain, dose administered, and time of manipulation.22 Despite the lack of lithium effect on SWS, SLEEP, Vol. 36, No. 11, 2013 1681 Downloaded from https://academic.oup.com/sleep/article-abstract/36/11/1677/2558947 by guest on 10 March 2018
the drug substantially reduced REMS in the first hour, and this effect on REMS episodes persisted during the rest of the sleep recording period. These results suggest that the high amount of REMS after training could be responsible for memory impairment and, by reducing REMS rebound, lithium might have prevented memory deficits. Interestingly, brief periods of sleep deprivation after training in context fear conditioning impairs subsequent performance,28,29 which raises the possibility that lithium prevented sleep disorganization within the time frame required for hippocampus-dependent memory consolidation. However, it is important to notice that sleep recording was performed in animals that did not undergo the behavioral test. Previous studies with REMS deprivation show that this manipulation also increases locomotor activity in rats30-32 and mice,23 and lithium reverses this behavioral alteration.23 One might think that 150 mg/kg of lithium affected the locomotor behavior of REMSDep rats leading to the interpretation of improvement of memory retention. However, even if the locomotor activity was altered on the training session leading to increased step-through latency, it did not correlate with the latency on the test session. Thus, we believe that this effect was Sleep Deprivation, Lithium, and Memory—Ota et al
Table 1—Percentage of time spent in each sleep state Waking
SWS
TS
Hour 1 CC + VEH CC + LI REMSDep + VEH REMSDep + LI
REMS
71.06 ± 24.68 69.79 ± 34.06 46.02 ± 15.37 57.17 ± 15.53
28.84 ± 24.60 27.64 ± 28.73 23.64 ± 9.93 30.89 ± 18.35
0.00 ± 0.00 0.84 ± 1.87 2.63 ± 2.48† 0.57 ± 0.59
0.09 ± 0.23 1.73 ± 3.87 27.71 ± 10.90*,† 11.37 ± 13.85*,¥
Hour 2 CC + VEH CC + LI REMSDep + VEH REMSDep + LI
23.40 ± 11.38 49.74 ± 22.41 20.75 ± 10.52* 19.26 ± 6.66*,¥
67.58 ± 10.34 44.65 ± 15.83 29.46 ± 10.67*,† 35.77 ± 14.50*,†
1.86 ± 1.04 1.00 ± 1.42 7.29 ± 6.57* 6.77 ± 4.30*
7.16 ± 4.42 4.61 ± 8.44 42.49 ± 6.92* 38.20 ± 13.40*
Hour 3 CC + VEH CC + LI REMSDep + VEH REMSDep + LI
19.46 ± 6.56 36.64 ± 11.51† 16.54 ± 9.85* 20.43 ± 4.98*,¥
66.86 ± 8.33 56.08 ± 7.91 31.90 ± 11.47*,† 37.02 ± 8.34*,†
1.95 ± 1.74 2.00 ± 2.85 7.68 ± 4.18* 6.43 ± 3.93*
11.73 ± 7.02 5.28 ± 7.31 43.88 ± 13.73* 36.13 ± 7.06*
Hour 4 CC + VEH CC + LI REMSDep + VEH REMSDep + LI
31.55 ± 15.58 45.40 ± 5.07† 24.48 ± 16.44* 21.89 ± 6.81*,¥
53.07 ± 7.97¶ 48.58 ± 6.98¶ 29.47 ± 14.44*,†,¶ 35.21 ± 6.31*,†,¶
2.56 ± 1.47 1.90 ± 1.81 6.18 ± 4.71* 5.89 ± 3.33*
12.81 ± 8.25 4.13 ± 5.08 39.87 ± 13.59* 37.01 ± 9.66*
Percentage of time spent in waking, SWS, TS and REMS, per hour, post-lithium administration (150 mg/kg, IP). Values are expressed as mean ± SD *Group effect. †Different from CC + VEH. ¥Different from REMSDep + VEH. ¶Different from Hour 3. Three-way ANOVA for repeated measures, followed by NewmanKeuls test, P ≤ 0.05. CC, cage control; IP, intraperitoneal; LI, lithium; REMS, rapid eye movement sleep; REMSDep, rapid eye movement sleep-deprived; SD, standard deviation; SWS, slow wave sleep; TS, transistion sleep; VEH, vehicle.
Table 2—Number of episodes Waking
SWS
TS
Hour 1 CC + VEH CC + LI REMSDep + VEH REMSDep + LI
REMS
11.50 ± 6.66 14.80 ± 9.98 11.86 ± 2.61 15.83 ± 7.63
10.67 ± 7.89 13.20 ± 9.93 11.86 ± 3.29 13.33 ± 7.45
0.00 ± 0.00 1.60 ± 3.58 5.14 ± 4.41† 1.33 ± 1.03
0.17 ± 0.41 1.00 ± 2.24# 9.86 ± 4.06*,† 3.17 ± 2.04*#
Hour 2 CC + VEH CC + LI REMSDep + VEH REMSDep + LI
16.83 ± 3.12 23.00 ± 6.96 17.00 ± 4.24* 13.50 ± 2.66*
18.50 ± 4.04 23.40 ± 6.73 14.00 ± 2.38* 14.50 ± 5.01*
3.67 ± 2.16 2.40 ± 3.36 13.14 ± 10.41* 14.17 ± 5.88*
3.00 ± 2.10 1.40 ± 2.61# 18.43 ± 8.06* 15.17 ± 7.25*,#
Hour 3 CC + VEH CC + LI REMSDep + VEH REMSDep + LI
15.50 ± 1.97 19.80 ± 6.69 13.71 ± 6.24* 12.50 ± 2.81*
16.00 ± 1.67¶ 20.60 ± 6.23¶ 10.43 ± 4.28*,¶ 13.33 ± 3.93*,¶
3.67 ± 2.50 3.60 ± 5.13 14.00 ± 7.12* 11.33 ± 4.93*
4.33 ± 1.63 1.40 ± 1.95# 20.57 ± 11.00* 12.33 ± 3.08*,#
Hour 4 CC + VEH CC + LI REMSDep + VEH REMSDep + LI
17.67 ± 6.65 14.40 ± 4.61 14.71 ± 3.68* 12.83 ± 3.66*
18.50 ± 6.72¶ 14.40 ± 4.93¶ 11.57 ± 2.22*,¶ 14.00 ± 3.03*,¶
5.00 ± 3.35 3.60 ± 2.88 12.00 ± 7.89* 10.33 ± 5.82*
5.50 ± 3.39 1.60 ± 2.07# 16.14 ± 7.75* 11.83 ± 3.87*,#
Number of episodes of waking, SWS, TS and REMS, per hour, post-lithium administration (150 mg/kg, IP). Values are expressed as mean ± SD *Group effect. #Drug effect. †Different from CC + VEH. ¶Different from Hour 3. Three-way ANOVA for repeated measures, followed by Newman-Keuls test, P ≤ 0.05. CC, cage control; IP, intraperitoneal; LI, lithium; REMS, rapid eye movement sleep; REMSDep, rapid eye movement sleep-deprived; SD, standard deviation; SWS, slow wave sleep; TS, transistion sleep; VEH, vehicle. SLEEP, Vol. 36, No. 11, 2013 1682 Downloaded from https://academic.oup.com/sleep/article-abstract/36/11/1677/2558947 by guest on 10 March 2018
Sleep Deprivation, Lithium, and Memory—Ota et al
a real improvement of consolidation because rats were tested two days after lithium treatment, a period of time sufficient to eliminate the drug.27 The positive effects lithium on memory, observed in our work, is in accordance with a previous study showing that sub-chronic lithium treatment reverses memory impairment in nucleus basalis magnocellularis-lesioned rats.33 However, there is still controversy as to whether lithium influences memory consolidation,34 as Tsaltas and colleagues showed an improvement in passive avoidance retention with chronic lithium treatment,35 whereas Hines and Poling reported impaired acquisition in the same task.36 Besides, there is only one other study that used acute lithium treatment, which did not find any effect on spatial reward alternation.37 An additional explanation for the effect of lithium on memory performance of sleep-deprived rats may involve its neurotrophic effect. As reviewed by Quiroz and colleagues this neurotrophic effect occurs by increasing the activity of adenylyl cyclase, and consequently, of cyclic adenosine monophosphate (cAMP), which physiologic effects are mediated by activation of protein kinase A (PKA). PKA phosphorylates and activates cAMP response element binding (CREB), which, in turn, activates the gene for brain-derived neurotrophic factor (BDNF), known for its effects on synaptic plasticity. Lithium can also increase transcription via extracellular-regulated kinase activation, which increases CREB expression. The neuroprotective effects of lithium occur via inhibition of glycogen synthase kinase 3β that regulates cell apoptosis.38 Interestingly, a recent report shows that 72 h of REMS deprivation impairs memory retention in the contextual fear conditioning test and decreases phosphorylated CREB (pCREB) in the central nucleus of the amygdala.39 Although the behavioral test was different in this study, the amygdala also plays an essential role in memory consolidation in the inhibitory avoidance task.40 Thus, lithium might have reversed REM sleep deprivation-induced reduction of pCREB in the amygdala. Importantly, it should be emphasized that the findings on the neurotrophic effects of lithium stem from studies conducted either in vitro or in chronically treated animals, although 2-day treatment with lithium has been shown to enhance long-term potentiation (LTP), a phenomenon important for learning and memory processes independent of hippocampal neurogenesis.41 Despite contradictory results regarding the effects of lithium on memory, the positive result found in this study might have been due to the prevention of the impairment in memory consolidation, rather than an enhancement to the “normal” state. Although our findings point to alterations in the sleep pattern, effects of the drug per se should not be discarded. CONCLUSION Lithium prevented memory impairment induced by sleep deprivation, and this effect could be related to reduction of rapid eye movement sleep rebound. ABBREVIATIONS BDNF, brain-derived neurotrophic factor CC, cage control cAMP, cyclic adenosine monophosphate CREB, cAMP response element binding SLEEP, Vol. 36, No. 11, 2013 1683 Downloaded from https://academic.oup.com/sleep/article-abstract/36/11/1677/2558947 by guest on 10 March 2018
EEG, electroencephalography EMG, electromyography IM, intramuscular IP, intraperitoneal LI, lithium LTP, long-term potentiation MTIA, multiple trial inhibitory avoidance pCREB, phosphorylated CREB pKA, protein kinase A REMS, rapid eye movement sleep REMSDep, rapid eye movement sleep-deprived SWS, slow wave sleep TS, transition sleep VEH, vehicle DISCLOSURE STATEMENT This was not an industry supported study. Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, São Paulo Research Foundation), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, National Science and Technology Council) and Associação Fundo de Incentivo à Pesquisa (AFIP, Funding Society for the Incentive of Research). The authors have indicated no financial conflicts of interest. REFERENCES
1. Maquet P. The role of sleep in learning and memory. Science 2001;294:1048-52. 2. Ribeiro S, Nicolelis MA. Reverberation, storage, and postsynaptic propagation of memories during sleep. Learn Mem 2004;11:686-96. 3. Stickgold R. Sleep-dependent memory consolidation. Nature 2005;437:1272-78. 4. Dametto M, Suchecki D, Bueno OF, Moreira KM, Tufik S, Oliveira MG. Social stress does not interact with paradoxical sleep deprivation-induced memory impairment. Behav. Brain Res 2002;129:171-8. 5. Tiba PA, Oliveira MGM, Rossi VC, Tufik S, Suchecki D. Glucocorticoids are not responsible for paradoxical sleep deprivation-induced memory impairments. Sleep 2008;31:505-15. 6. Bueno OF, Lobo LL, Oliveira MG, Gugliano EB, Pomarico AC, Tufik S. Dissociated paradoxical sleep deprivation effects on inhibitory avoidance and conditioned fear. Physiol Behav 1994;56:775-9. 7. Esumi LA, Palma BD, Gomes VL, Tufik S, Hipólide DC. Inflammatory markers are associated with inhibitory avoidance memory deficit induced by sleep deprivation in rats. Behav Brain Res 2011;221:7-12. 8. Moreira KM, Ferreira TL, Hipolide DC, Fornari RV, Tufik S, Oliveira MG. Modafinil prevents inhibitory avoidance memory deficit induced by sleep deprivation in rats. Sleep 2010;7:990-3. 9. Smith C, Rose GM. Evidence for a paradoxical sleep window for place learning in the Morris water maze. Physiol Behav 1996;59:93-7. 10. Giuditta A, Ambrosini MV, Montagnese P, et al. The sequential hypothesis of the function of sleep. Behav Brain Res 1995; 69:157-66. 11. Fogel SM, Smith CT. Learning-dependent changes in sleep spindles and Stage 2 sleep. J Sleep Res 2006;15:250-5. 12. Hellman K, Abel T. Fear conditioning increases NREM sleep. Behav Neurosci 2007;121:310-23. 13. Fogel SM, Smith CT, Higginson CD, Beninger RJ. Different types of avoidance behavior in rats produce dissociable post-training changes in sleep. Physiol Behav 2011;102:170-4. 14. Pavlides C, Winson J. Influences of hippocampal place cell firing in the awake state on the activity of these cells during subsequent sleep episodes. J Neurosci 1989;9:2907-18. 15. Wilson MA, McNaughton BL. Reactivation of hippocampal ensemble memories during sleep. Science 1994; 265:676-9. 16. Buzsáki G. Memory consolidation during sleep: a neurophysiological perspective. J Sleep Res 1998;7 Suppl 1:17-23. 17. Suchecki D, Duarte Palma B, Tufik S. Sleep rebound in animals deprived of paradoxical sleep by the modified multiple platform method. Brain Res 2000;875:14-22.
Sleep Deprivation, Lithium, and Memory—Ota et al
18. Machado RB, Hipolide DC, Benedito-Silva AA, Tufik S. Sleep deprivation induced by the modified multiple platform technique: quantification of sleep loss and recovery. Brain Res 2004;1004:45-51. 19. Friston KJ, Sharpley AL, Solomon RA, Cowen PJ. Lithium increases slow wave sleep: possible mediation by brain 5-HT2 receptors? Psychopharmacology (Berl) 1989;98:139-40. 20. Qureshi A Jr, Lee-Chiong T. Medications and their effects on sleep. Med Clin N Am 2004;88:751-66. 21. Zamboni G, Perez E, Amici R, Jones CA, Parmeggiani PL. Control of REM sleep: an aspect of the regulation of physiological homeostasis. Arch Ital Biol 1999;137:249-62. 22. Jones CA, Perez E, Amici R, et al. Lithium affects REM sleep occurrence, autonomic activity and brain second messengers in the rat. Behav Brain Res 2008;187:254-61. 23. Armani F, Andersen ML, Andreatini R, Frussa-Filho R, Tufik S, Galduróz JC. Successful combined therapy with tamoxifen and lithium in a paradoxical sleep deprivation-induced mania model. CNS Neurosci Ther 2011;17:1-7 24. Suchecki D, Tufik S. Social stability attenuates the stress in the modified multiple platform method for paradoxical sleep deprivation in the rat. Physiol Behav 2000;68:309-16. 25. Morrison JM Jr, Pritchard HD, Braude MC, D’Aguanno W. Plasma and brain lithium levels after lithium carbonate and lithium chloride administration by different routes in rats. Proc Soc Exp Biol Med 1971;137:889-92. 26. Gross BA, Walsh CM, Turakhia AA, Booth V, Mashour GA, Poe GR. Open-source logic-based automated sleep scoring software using electrophysiological recordings in rats. J Neurosci Methods 2009;184:10-8. 27. Timo-Iaria C, Negrão N, Schmidek WR, Hoshino K, Lobato de Menezes CE, Leme da Rocha T. Phases and states of sleep in the rat. Physiol Behav 1970;5:1057-62. 28. Graves LA, Heller EA, Pack AI, Abel T. Sleep deprivation selectively impairs memory consolidation for contextual fear conditioning. Learn Mem 2003;10:168-76. 29. Hagewoud R, Bultsma LJ, Barf RP, Koolhaas JM, Meerlo P. Sleep deprivation impairs contextual fear conditioning and attenuates subsequent behavioural, endocrine and neuronal responses. J Sleep Res 2011;20:259-66.
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30. Gessa GL, Pani L, Fadda P, Fratta W. Sleep deprivation in the rat: an animal model of mania. Eur Neuropsychopharmacol 1995; 5 Suppl:89-93. 31. Oliveira RA, Cunha GM, Borges KD, et al. The effect of venlafaxine on behaviour, body weight and striatal monoamine levels on sleep-deprived female rats. Pharmacol Biochem Behav 2004;79:499-506. 32. Dubiela FP, Messias MF, Moreira KD, et al. Reciprocal interactions between MK-801, sleep deprivation and recovery in modulating rat behaviour. Behav Brain Res 2011;216:180-5. 33. Pascual T, Gonzalez JL. A protective effect of lithium on rat behaviour altered by ibotenic acid lesions of the basal forebrain cholinergic system. Brain Res 1995;695:289-92. 34. Tsaltas E, Kontis D, Boulougouris V, Papadimitriou GN. Lithium and cognitive enhancement: leave it or take it? Psychopharmacology 2009;202:457-76. 35. Tsaltas E, Kontis D, Boulougouris V, et al. Enhancing effects of chroniclithium on memory in the rat. Behav Brain Res 2007;177:51-60. 36. Hines G, Poling TH. Lithium effects on active and passive avoidance behavior in the rat. Psychopharmacology (Berl) 1984;82:78-82. 37. Furusawa K. Drug effects on cognitive function in micedetermined by the non-matching to sample task using a 4-armmaze. Jpn J Pharmacol 1991;56:483-93. 38. Quiroz JA, Machado-Vieira R, Zarate CA Jr, Manji HK. Novel insights into lithium’s mechanism of action: neurotrophic and neuroprotective effects. Neuropsychobiology 2010;62:50-60. 39. Pinho N, Moreira KM, Hipolide DC, et al. Sleep deprivation alters phosphorylated CREB levels in the amygdala: Relationship with performance in a fear conditioning task. Behav Brain Res 2013;236:221-4 40. Wilensky AE, Schafe GE, LeDoux JE. The amygdala modulates memory consolidation of fear-motivated inhibitory avoidance learning but not classical fear conditioning. J Neurosci 2000;20:7059-66. 41. Son H, Yu IT, Hwang SJ, et al. Lithium enhances long-term potentiation independently of hippocampal neurogenesis in the rat dentate gyrus. J Neurochem 2003;85:872-81.
Sleep Deprivation, Lithium, and Memory—Ota et al
Lithium Prevents REM Sleep Deprivation-Induced Impairments on Memory Consolidation Simone M. Ota, MSc1; Karin Di Monteiro Moreira, PhD1,2; Deborah Suchecki, PhD1; Maria Gabriela M. Oliveira, PhD1; Paula A. Tiba, PhD1,2 Departamento de Psicobiologia, Universidade Federal de São Paulo, São Paulo, Brazil; 2Centro de Matemática, Computação e Cognição, Universidade Federal do ABC, Santo André, Brazil
1
Background: Pre-training rapid eye movement sleep (REMS) deprivation affects memory acquisition and/or consolidation. It also produces major REMS rebound at the cost of waking and slow wave sleep (SWS). Given that both SWS and REMS appear to be important for memory processes, REMS rebound after training may disrupt the organization of sleep cycles, i.e., excessive amount of REMS and/or little SWS after training could be harmful for memory formation. Objective: To examine whether lithium, a drug known to increase SWS and reduce REMS, could prevent the memory impairment induced by pretraining sleep deprivation. Design: Animals were divided in 2 groups: cage control (CC) and REMS-deprived (REMSDep), and then subdivided into 4 subgroups, treated either with vehicle or 1 of 3 doses of lithium (50, 100, and 150 mg/kg) 2 h before training on the multiple trial inhibitory avoidance task. Animals were tested 48 h later to make sure that the drug had been already metabolized and eliminated. Another set of animals was implanted with electrodes and submitted to the same experimental protocol for assessment of drug-induced sleep-wake changes. Subjects: Wistar male rats weighing 300-400 g. Results: Sleep deprived rats required more trials to learn the task and still showed a performance deficit during test, except from those treated with 150 mg/kg of lithium, which also reduced the time spent in REM sleep during sleep recovery. Conclusion: Lithium reduced rapid eye movement sleep and prevented memory impairment induced by sleep deprivation. These results indicate that these phenomena may be related, but cause-effect relationship cannot be ascertained. Keywords: Multiple trial inhibitory avoidance task, slow wave sleep, lithium, sleep rebound Citation: Ota SM; Moreira KDM; Suchecki D; Oliveira MGM; Tiba PA. Lithium prevents REM sleep deprivation-induced impairments on memory consolidation. SLEEP 2013;36(11):1677-1684.
INTRODUCTION Sleep is viewed as of fundamental importance for cognitive processes, including attention, learning and memory consolidation.1-3 Important discoveries in this field come from investigations on the harmful effects of sleep deprivation—including rapid eye movement sleep (REMS) deprivation—on memory tasks, such as contextual fear conditioning, inhibitory avoidance, and place learning.4-9 Recently, however, there has been speculation on the role of slow wave sleep (SWS), and not only of REMS, on memory consolidation,2 based on studies showing post-training SWS augmentation or positive correlation between SWS amount and performance in some emotional memory tasks.10-13 Furthermore, place cells present the same firing pattern during SWS as during active state.2,14,15 Therefore, it has been hypothesized that SWS and REMS play different, yet complementary roles in memory consolidation. While neurons would replay the activity pattern in SWS with reduced external interference, plasticityrelated gene expression occurring in REMS would be important to strengthen long-term memories.2,16
Submitted for publication October, 2012 Submitted in final revised form July, 2013 Accepted for publication July, 2013 Address correspondence to: Deborah Suchecki, Departamento de Psicobiologia, Universidade Federal de São Paulo – UNIFESP, Rua Napoleão de Barros, 925, Vila Clementino, São Paulo, SP, Brazil, CEP 04024-002; Tel: + 55 11 2149-01559; Fax: + 55 11 5572-5092; E-mail: [email protected] SLEEP, Vol. 36, No. 11, 2013 1677 Downloaded from https://academic.oup.com/sleep/article-abstract/36/11/1677/2558947 by guest on 10 March 2018
One of the major consequences of REMS deprivation in rats is the sleep rebound that ensues once rats are given the opportunity to sleep. After a period of 96 h of sleep deprivation with the modified multiple platform method, rats exhibit approximately 160% increase of REMS and a 12% decrease of SWS within the 24-h rebound period.17,18 Therefore, we hypothesized that disorganized sleep architecture seen after sleep deprivation might be responsible for performance impairment in memory tasks. To test this hypothesis, we deprived rats from REMS for 96 h before training in the multiple trial inhibitory avoidance (MTIA)8; we then allowed them to recover for 48 h, when testing took place. Since in this task the animals are trained until achievement of a learning criterion, it is possible to observe the consequences of prior sleep deprivation (residual effects of sleep deprivation itself and/or the sleep rebound that occurs immediately after the training session) on memory consolidation, independent of its effects on acquisition. If this hypothesis holds true, strategies that prevent or reduce REMS rebound and/or increased SWS could be beneficial for learning and memory processes after sleep deprivation. Lithium carbonate, used for the treatment of bipolar disorder, is known to augment SWS and to reduce REMS.19-22 In the present study, we sought to prevent memory impairments induced by 96 h of REMS deprivation in animals trained and tested in the MTIA task, by a single administration of lithium a few hours before task training. METHODS Subjects Male Wistar rats (3 to 4 months old) from Centro de Desenvolvimento de Modelos Experimentais (CEDEME) of the Sleep Deprivation, Lithium, and Memory—Ota et al
Habituation 3 days (1 h/day)
Sleep Deprivation or Habituation 4 days
Division into REMSDep and CC groups
Lithium Administration
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Figure 1—Scheme of the experimental procedures used in the present study.
Universidade Federal de São Paulo (UNIFESP) were used. Animals were housed in polypropylene cages (5 per cage) and maintained under 12 h/12 h light/dark cycle (lights on at 07:00) and controlled temperature (23 ± 2ºC), receiving food and water ad libitum. This study was approved by the Ethical Committee in Research of UNIFESP (CEP 0079/10). Drugs Lithium carbonate (Eurofarma, Brazil) was prepared in 0.9% saline at doses of 50, 100, and 150 mg/kg, and administered IP in a volume of 0.2 mL/100 g of body weight. These doses were chosen based on a previous study in which they were shown to reverse mania-like behavior in REMS-deprived (REMSDep) mice.23 Sleep Deprivation Animals were submitted to the modified multiple platform method (MMPM) for 96 h. Ten rats were placed in an stainless steel tank (123 cm length × 44 cm width × 44 cm depth) containing 14 platforms (6.5 cm diameter) filled with water until approximately 2 cm below the platform surface.24 The animals stayed on the platforms; when REMS was initiated, they fell in or touched the water due to muscle atonia, and were thus awakened. This method completely suppresses REMS and reduces the time spent in SWS by 31%.18 To prevent environmental interference (such as humidity), animals in the control group were placed inside the water tanks for one hour per day.5 Multiple Trial Inhibitory Avoidance Task The task was performed in a 2-compartment shuttle box, with a white compartment connected to a black one by a sliding door. Each rat was placed in the white side of the apparatus, and 10 s later the sliding door was opened. As soon as the rat stepped in the dark compartment with its 4 paws, the sliding door was closed and a 0.7 mA shock was delivered. The first step-through latency in the training was recorded and the outliers (based on z-score) were excluded from the study. Subsequently, the animal was removed from the box and placed again in the white compartment. The procedure was repeated until the animal reached the learning criterion, e.g., remaining in the safe compartment for 120 s. The number of trials was recorded to assess the acquisition index.8 On the test session, which occurred 48 h after training, the animals were placed in the safe compartment and the latency to cross to the aversive compartment (step-through latency) was taken as a retention index to be compared between groups. If the animals did not cross the apparatus in 300 s, this latency was SLEEP, Vol. 36, No. 11, 2013 1678 Downloaded from https://academic.oup.com/sleep/article-abstract/36/11/1677/2558947 by guest on 10 March 2018
recorded. No footshock was delivered during the test session. The period of 48 h between training and testing session was chosen because this is the time that the rats require to eliminate the drug,25 ensuring that rats were not performing under the effect of the drug. Electrode Implantation and Sleep Recording A second set of animals underwent surgery for electrode implantation. Anesthesia was induced with ketamine and xylazine (50 mg/kg and 10 mg/kg, IP, respectively). For electroencephalography (EEG) recording, 4 electrodes were fixed in the rat’s skull, following coordinates: 1 mm posterior to bregma and 3 mm to the left of the sagittal suture; 3 mm anterior to bregma and 1 mm to the right of the sagittal suture; 1 mm anterior to lambda and 4 mm to the left of the sagittal suture; and 4 mm anterior to lambda and 1 mm to the right of the sagittal suture. For electromyography (EMG), one pair of nickel-chromium wire was inserted in the neck muscle. To avoid infection and pain, rats were treated with Pentabiotic (0.25 mL, IM) and the analgesic drug sodium diclofenac (25 mg/mL, IM). Sleep-wake cycle was recorded in digital polygraphs NihonKohden (Neurofax QP 223 A Nihon Kohden Co., Tokyo, Japan) and each animal was connected to 6 channels, electrodes implanted. The recordings were analyzed in epochs of 10 s26 using the program Sleepscorer in the software Matlab. Sleep stages were classified visually, in SWS (high amplitude and slow cortical waves, with low EMG activity), transition sleep ([TS] high amplitude and slow cortical waves with sleep spindles and theta hippocampal waves), and REMS (low amplitude and high frequency cortical waves, with theta hippocampal waves and muscle atonia). Waking was classified when it was observed low amplitude and high frequency cortical waves and high EMG activity, in accordance to Timo-Iaria and colleagues27 and Giuditta and colleagues.10 The data was obtained from 4 h of sleep recording, beginning immediately after the end of sleep deprivation, because it encompassed the period of drug action on sleep-wake cycle.22 Experimental Procedure (Figure 1) All animals were habituated to the sleep deprivation tank for one hour per day for 3 days. Subsequently, they were randomly assigned to cage control (CC) or REMSDep groups. REMSDep rats were submitted to the MMPM, whereas CC rats were placed in the water tanks for 1 h per day. After a period of 96 h of sleep deprivation, training in the MTIA task commenced (7 h after lights on). Sleep Deprivation, Lithium, and Memory—Ota et al
CC
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Figure 2—Number of trials necessary for cage control (CC) and rapid eye movement sleep-deprived (REMSDep) animals, treated with vehicle (VEH) or lithium (LI 50, 100, 150 mg/kg), to achieve the acquisition criterion in the MTIA task. Values are expressed as mean ± SEM *Group effect, Two-way ANOVA; P < 0.001. MTIA, multiple trial inhibitory avoidance; SEM, standard error of mean.
0
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Figure 3—First step-through latency of cage control (CC) and rapid eye movement sleep-deprived (REMSDep) animals treated with vehicle (VEH) or lithium (LI 50, 100, 150 mg/kg), in the training of the MTIA task. Values are expressed as mean ± SEM *Group effect, Two-way ANOVA; P < 0.05. MTIA, multiple trial inhibitory avoidance; SEM, standard error of mean.
Experiment 1: Effects of Lithium on Inhibitory Avoidance Performance
Animals were treated 2 h before the onset of training session, with vehicle (VEH) or one of the lithium doses (LI 50, LI 100, LI 150 mg/kg; n = 10-15/group/dose). Lithium was administered before training, as the effects of the drug on sleep are observed 2 h post-administration.22
waking in this time block. Analysis of the subsequent period of sleep was done by a 3-way ANOVA for repeated measures, with Group, Drug (vehicle or lithium 150 mg/kg), and Hour (Hour 2, Hour 3, and Hour 4) as main factors. When necessary, the tests of Tukey and Newman-Keuls (for repeated measures) were used for post hoc analysis. Level of significance was established at P ≤ 0.05.
Experiment 2: Effects of Lithium on Sleep Pattern
RESULTS
Statistical Analysis Z-score of step-through latencies was used to remove the outliers (e.g., rats with latency > 2 standard deviation). In the memory recall experiment, the number of trials required to reach learning criterion was analyzed by a 2-way ANOVA, with Group (CC, REMSDep) and Drug (vehicle, 50, 100, 150 mg/kg) as main factors, as the drug was given before training and rats were distributed in 8 groups (CC and REMSDep subdivided into each treatment). Analysis of step-through latency was done by a 3-way repeated measures ANOVA, with Group, Drug, and Session (repeated measure: first step-through latency on training, latency on test) as main factors. A linear regression analysis was performed to observe the correlation between the “first step-through latency on training” and the “step-through latency on test.” Analysis of percentage of time spent in and number of episodes of each behavioral state in the first hour of sleep recording was done by 2-way ANOVA with Group and Drug as main factors. This was done because of the high amount of
Effects of Lithium on Memory Training: Figure 2 shows the number of trials required to reach learning criterion in the MTIA. The 2-way ANOVA showed a main effect of Group (F1,97 = 26.66; P < 0.001), with REMSDep group requiring more trials to learn the task than CC group (2.11 ± 0.36 and 2.75 ± 0.81). There was no statistical effect of Drug (F3,97 = 0.30; P = 0.83) nor interaction between the factors (F3,97 = 0.28; P = 0.84). Analysis of first step-through latency (Figure 3) pointed to a Group effect (F1,97 = 4.42; P = 0.04); REMSDep animals presented higher latency than control (29.02 ± 23.20 and 21.98 ± 13.72) and Drug (F1,97 = 2.87; P = 0.04); however, post hoc tests showed no difference among the treatments. Test (Figure 4): The 3-way ANOVA for repeated measures indicated a main effect of Session (F1,97 = 105.13; P < 0.001), an interaction between Session and Group (F1,97 = 36.43; P < 0.00001), and a triple interaction (F3,97 = 2.96; P = 0.04). The post hoc analysis showed that all CC animals, regardless of the dose of lithium, presented longer step-through latency on test than REMSDep rats (P < 0.005); the latency of REMSDep animals treated with vehicle, 50 or 100 mg/kg did not differ between training and test sessions. Treatment with 150 mg/kg, however, enhanced the latency in the test when compared to training (P < 0.01) and to REMSDep + VEH,
Twenty-four rats were submitted to electrode implantation surgery and had 10 days of recovery in separated cages. The animals were submitted to the same protocol and received either vehicle or lithium 150 mg/kg (n = 5-7/group/drug), but instead of MTIA task training, sleep-wake cycle recording began.
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Sleep Deprivation, Lithium, and Memory—Ota et al
CC
REMSDep
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300
Latency (s)
250 200 150
†
100 50
*
*
*
Transitional Sleep
0 VEH
SWS, and an interaction between Group and Drug (F1,20 = 7.03; P = 0.04). The test of Tukey showed that both REMSDep + VEH and REMSDep + LI groups spent less time in SWS than CC + VEH group (P < 0.005). The ANOVA also showed a main effect of Hour (F2,40 = 3.63; P = 0.04), and the post hoc test revealed that the rats spent less time in SWS in Hour 4 than Hour 3. For the number of episodes, main effects of Group (F1,20 = 18.27; P < 0.001) and Hour (F2,40 = 4.27; P = 0.02) were observed. Newman-Keuls test revealed that REMSDep animals presented fewer episodes than CC animals; in addition, there were fewer SWS episodes in Hours 3 and 4 than Hour 2, as can be seen in Table 2.
LI 50
Dose
LI 100
LI 150
Figure 4—Step-through latency of cage control (CC) and rapid eye movement sleep-deprived (REMSDep) animals, treated with vehicle (VEH) or lithium (LI 50, 100, 150 mg/kg), in the MTIA test. Values are expressed as mean ± SEM *Different from respective control group, P < 0.005. †Different from sleep deprived groups treated with vehicle and other doses of lithium, P < 0.05. MTIA, multiple trial inhibitory avoidance; SEM, standard error of mean.
REMSDep + LI 50 and REMSDep + LI 100 groups (P < 0.05). All REMSDep subgroups, except from the one treated with LI 150, performed poorer than their respective CC subgroups (P < 0.001). There was no correlation between the first step-through latency on training and the step-through latency on test (r = 0.06), indicating that training did not influence the performance during test. Effects of Lithium on Sleep Pattern Figure 5 shows the average amount of each sleep state in the 4 groups. At a glance one can distinguish the higher percentage of TS and REMS in the sleep deprived groups. The mean percentage of time spent, per hour, in each sleep state is shown in Table 1, and the mean number of episodes is shown in Table 2. Waking
During the first hour there was no difference between groups in any of the parameters. Analysis of the other hours revealed an interaction between Group and Drug (F1,20 = 10.14; P < 0.01), and the test of Tukey showed that CC + LI group spent more time awake than the other groups (P < 0.01). Moreover, there was a main effect of Group (F1,20 = 7.92; P = 0.01), as REMSDep groups presented fewer episodes of waking than CC groups). Slow Wave Sleep
The analysis showed no difference among the groups in the first hour. However, from the second recording hour on, the 3-way ANOVA revealed a main effect of Group (F1,20 = 43.68; P < 0.001), e.g., sleep-deprived animals spent less time in SLEEP, Vol. 36, No. 11, 2013 1680 Downloaded from https://academic.oup.com/sleep/article-abstract/36/11/1677/2558947 by guest on 10 March 2018
In the first hour there was an interaction between Group and Drug (F1,20 = 4.72; P = 0.04), and the post hoc test showed that group REMSDep + VEH presented higher percentage of TS than its respective control group (P = 0.04). Analysis of the number of episodes also pointed to an interaction between Group and Drug (F1,20 = 4.99; P = 0.04), in which sleep deprived animals treated with vehicle also presented more TS episodes than the control group (P = 0.02). In the following hours, analysis of amount of TS showed an effect of Group (F1,20 = 20.58; P < 0.001), i.e., REMSDep groups presented higher percentage of this stage. For the number of episodes, the test also showed a main effect of Group (F1,20 = 22.16; P < 0.001), as REMSDep groups presented more episodes of transition sleep than CC groups. REM Sleep
For the first hour, 2-way ANOVA showed main effect of Group (F1,20 = 23.69; P < 0.001) and an interaction between Group and Drug (F1,20 = 5.52; P = 0.03). The test of Tukey showed that REMSDep + VEH group spent more time in REM than the other groups (P < 0.05). Analysis of the number of episodes revealed main effects of Group (F1,20 = 29.59; P < 0.001) and Drug (F1,20 = 7.22; P = 0.01) and an interaction between these factors (F1,20 = 11.91; P < 0.01). The post hoc test indicated that REMSDep + VEH group presented more episodes of REMS than the other groups (P < 0.001). During the other hours of sleep recording, analysis of time spent in REMS showed an effect of Group (F1,20 = 114.11; P < 0.001), in which REMSDep groups presented more REMS than CC groups. For number of REMS episodes, the test showed main effects of Group (F1,20 = 42.07; P < 0.001) and Drug (F1,20 = 4.39; P = 0.05); REMSDep groups presented more REMS episodes, and lithium treatment reduced this parameter. DISCUSSION The present results on the effect of REMS deprivation on acquisition of inhibitory avoidance task replicated previous findings from our laboratory, i.e., REMS deprivation impairs learning and retention of the inhibitory avoidance task.6-8 In the present study, we showed that the highest dose of lithium successfully prevented the impairment of memory retention. Likewise, the study of sleep-wake recording replicated previous results from our laboratory, showing that sleepdeprived rats exhibit more REMS and less SWS than control Sleep Deprivation, Lithium, and Memory—Ota et al
Waking
SWS
TS
A
B
CC + VEH
CC + LI 150
100
100
80
80
60
%
60
%
40
40
20
20
0
1
C
%
REMSDep
2
Hour
3
0
4
D
REMSDep + VEH
100
80
80
60
%
40
20
20
2
Hour
3
4
Hour
3
4
60
40
1
2
REMSDep + LI 150
100
0
1
0
1
2
Hour
3
4
Figure 5—Visual representation of the percentage of each sleep state in cage control (CC) and rapid eye movement sleep-deprived (REMSDep) groups treated either with vehicle (A and C) or lithium 150 mg/kg (B and D).
animals when given the opportunity to sleep.17,18 Moreover, the present results also showed that the REMSDep group spent more time in TS than control rats. Acute administration of lithium enhanced waking time and number of episodes in the control group, but did not interfere with its performance compared to vehicle-treated control rats. In the last hours of recording, REMSDep + VEH and REMSDep + LI groups presented less SWS than CC + VEH group, but did not differ from CC + LI group, though a more prominent increase of SWS was expected, as is seen with lithium administration in humans.19 Furthermore, REMSDep + VEH group exhibited more TS than its respective control group during the first hour of recording, but REMSDep + LI group did not exhibit this difference from its respective control group. Lithium administration to REMSDep rats reduced the time spent in REMS during the first hour and diminished the number of episodes in the second hour of sleep recording compared to REMSDep + VEH rats, but unlike Jones and colleagues there, was no difference between non sleep-deprived groups, which could be explained by the different strain, dose administered, and time of manipulation.22 Despite the lack of lithium effect on SWS, SLEEP, Vol. 36, No. 11, 2013 1681 Downloaded from https://academic.oup.com/sleep/article-abstract/36/11/1677/2558947 by guest on 10 March 2018
the drug substantially reduced REMS in the first hour, and this effect on REMS episodes persisted during the rest of the sleep recording period. These results suggest that the high amount of REMS after training could be responsible for memory impairment and, by reducing REMS rebound, lithium might have prevented memory deficits. Interestingly, brief periods of sleep deprivation after training in context fear conditioning impairs subsequent performance,28,29 which raises the possibility that lithium prevented sleep disorganization within the time frame required for hippocampus-dependent memory consolidation. However, it is important to notice that sleep recording was performed in animals that did not undergo the behavioral test. Previous studies with REMS deprivation show that this manipulation also increases locomotor activity in rats30-32 and mice,23 and lithium reverses this behavioral alteration.23 One might think that 150 mg/kg of lithium affected the locomotor behavior of REMSDep rats leading to the interpretation of improvement of memory retention. However, even if the locomotor activity was altered on the training session leading to increased step-through latency, it did not correlate with the latency on the test session. Thus, we believe that this effect was Sleep Deprivation, Lithium, and Memory—Ota et al
Table 1—Percentage of time spent in each sleep state Waking
SWS
TS
Hour 1 CC + VEH CC + LI REMSDep + VEH REMSDep + LI
REMS
71.06 ± 24.68 69.79 ± 34.06 46.02 ± 15.37 57.17 ± 15.53
28.84 ± 24.60 27.64 ± 28.73 23.64 ± 9.93 30.89 ± 18.35
0.00 ± 0.00 0.84 ± 1.87 2.63 ± 2.48† 0.57 ± 0.59
0.09 ± 0.23 1.73 ± 3.87 27.71 ± 10.90*,† 11.37 ± 13.85*,¥
Hour 2 CC + VEH CC + LI REMSDep + VEH REMSDep + LI
23.40 ± 11.38 49.74 ± 22.41 20.75 ± 10.52* 19.26 ± 6.66*,¥
67.58 ± 10.34 44.65 ± 15.83 29.46 ± 10.67*,† 35.77 ± 14.50*,†
1.86 ± 1.04 1.00 ± 1.42 7.29 ± 6.57* 6.77 ± 4.30*
7.16 ± 4.42 4.61 ± 8.44 42.49 ± 6.92* 38.20 ± 13.40*
Hour 3 CC + VEH CC + LI REMSDep + VEH REMSDep + LI
19.46 ± 6.56 36.64 ± 11.51† 16.54 ± 9.85* 20.43 ± 4.98*,¥
66.86 ± 8.33 56.08 ± 7.91 31.90 ± 11.47*,† 37.02 ± 8.34*,†
1.95 ± 1.74 2.00 ± 2.85 7.68 ± 4.18* 6.43 ± 3.93*
11.73 ± 7.02 5.28 ± 7.31 43.88 ± 13.73* 36.13 ± 7.06*
Hour 4 CC + VEH CC + LI REMSDep + VEH REMSDep + LI
31.55 ± 15.58 45.40 ± 5.07† 24.48 ± 16.44* 21.89 ± 6.81*,¥
53.07 ± 7.97¶ 48.58 ± 6.98¶ 29.47 ± 14.44*,†,¶ 35.21 ± 6.31*,†,¶
2.56 ± 1.47 1.90 ± 1.81 6.18 ± 4.71* 5.89 ± 3.33*
12.81 ± 8.25 4.13 ± 5.08 39.87 ± 13.59* 37.01 ± 9.66*
Percentage of time spent in waking, SWS, TS and REMS, per hour, post-lithium administration (150 mg/kg, IP). Values are expressed as mean ± SD *Group effect. †Different from CC + VEH. ¥Different from REMSDep + VEH. ¶Different from Hour 3. Three-way ANOVA for repeated measures, followed by NewmanKeuls test, P ≤ 0.05. CC, cage control; IP, intraperitoneal; LI, lithium; REMS, rapid eye movement sleep; REMSDep, rapid eye movement sleep-deprived; SD, standard deviation; SWS, slow wave sleep; TS, transistion sleep; VEH, vehicle.
Table 2—Number of episodes Waking
SWS
TS
Hour 1 CC + VEH CC + LI REMSDep + VEH REMSDep + LI
REMS
11.50 ± 6.66 14.80 ± 9.98 11.86 ± 2.61 15.83 ± 7.63
10.67 ± 7.89 13.20 ± 9.93 11.86 ± 3.29 13.33 ± 7.45
0.00 ± 0.00 1.60 ± 3.58 5.14 ± 4.41† 1.33 ± 1.03
0.17 ± 0.41 1.00 ± 2.24# 9.86 ± 4.06*,† 3.17 ± 2.04*#
Hour 2 CC + VEH CC + LI REMSDep + VEH REMSDep + LI
16.83 ± 3.12 23.00 ± 6.96 17.00 ± 4.24* 13.50 ± 2.66*
18.50 ± 4.04 23.40 ± 6.73 14.00 ± 2.38* 14.50 ± 5.01*
3.67 ± 2.16 2.40 ± 3.36 13.14 ± 10.41* 14.17 ± 5.88*
3.00 ± 2.10 1.40 ± 2.61# 18.43 ± 8.06* 15.17 ± 7.25*,#
Hour 3 CC + VEH CC + LI REMSDep + VEH REMSDep + LI
15.50 ± 1.97 19.80 ± 6.69 13.71 ± 6.24* 12.50 ± 2.81*
16.00 ± 1.67¶ 20.60 ± 6.23¶ 10.43 ± 4.28*,¶ 13.33 ± 3.93*,¶
3.67 ± 2.50 3.60 ± 5.13 14.00 ± 7.12* 11.33 ± 4.93*
4.33 ± 1.63 1.40 ± 1.95# 20.57 ± 11.00* 12.33 ± 3.08*,#
Hour 4 CC + VEH CC + LI REMSDep + VEH REMSDep + LI
17.67 ± 6.65 14.40 ± 4.61 14.71 ± 3.68* 12.83 ± 3.66*
18.50 ± 6.72¶ 14.40 ± 4.93¶ 11.57 ± 2.22*,¶ 14.00 ± 3.03*,¶
5.00 ± 3.35 3.60 ± 2.88 12.00 ± 7.89* 10.33 ± 5.82*
5.50 ± 3.39 1.60 ± 2.07# 16.14 ± 7.75* 11.83 ± 3.87*,#
Number of episodes of waking, SWS, TS and REMS, per hour, post-lithium administration (150 mg/kg, IP). Values are expressed as mean ± SD *Group effect. #Drug effect. †Different from CC + VEH. ¶Different from Hour 3. Three-way ANOVA for repeated measures, followed by Newman-Keuls test, P ≤ 0.05. CC, cage control; IP, intraperitoneal; LI, lithium; REMS, rapid eye movement sleep; REMSDep, rapid eye movement sleep-deprived; SD, standard deviation; SWS, slow wave sleep; TS, transistion sleep; VEH, vehicle. SLEEP, Vol. 36, No. 11, 2013 1682 Downloaded from https://academic.oup.com/sleep/article-abstract/36/11/1677/2558947 by guest on 10 March 2018
Sleep Deprivation, Lithium, and Memory—Ota et al
a real improvement of consolidation because rats were tested two days after lithium treatment, a period of time sufficient to eliminate the drug.27 The positive effects lithium on memory, observed in our work, is in accordance with a previous study showing that sub-chronic lithium treatment reverses memory impairment in nucleus basalis magnocellularis-lesioned rats.33 However, there is still controversy as to whether lithium influences memory consolidation,34 as Tsaltas and colleagues showed an improvement in passive avoidance retention with chronic lithium treatment,35 whereas Hines and Poling reported impaired acquisition in the same task.36 Besides, there is only one other study that used acute lithium treatment, which did not find any effect on spatial reward alternation.37 An additional explanation for the effect of lithium on memory performance of sleep-deprived rats may involve its neurotrophic effect. As reviewed by Quiroz and colleagues this neurotrophic effect occurs by increasing the activity of adenylyl cyclase, and consequently, of cyclic adenosine monophosphate (cAMP), which physiologic effects are mediated by activation of protein kinase A (PKA). PKA phosphorylates and activates cAMP response element binding (CREB), which, in turn, activates the gene for brain-derived neurotrophic factor (BDNF), known for its effects on synaptic plasticity. Lithium can also increase transcription via extracellular-regulated kinase activation, which increases CREB expression. The neuroprotective effects of lithium occur via inhibition of glycogen synthase kinase 3β that regulates cell apoptosis.38 Interestingly, a recent report shows that 72 h of REMS deprivation impairs memory retention in the contextual fear conditioning test and decreases phosphorylated CREB (pCREB) in the central nucleus of the amygdala.39 Although the behavioral test was different in this study, the amygdala also plays an essential role in memory consolidation in the inhibitory avoidance task.40 Thus, lithium might have reversed REM sleep deprivation-induced reduction of pCREB in the amygdala. Importantly, it should be emphasized that the findings on the neurotrophic effects of lithium stem from studies conducted either in vitro or in chronically treated animals, although 2-day treatment with lithium has been shown to enhance long-term potentiation (LTP), a phenomenon important for learning and memory processes independent of hippocampal neurogenesis.41 Despite contradictory results regarding the effects of lithium on memory, the positive result found in this study might have been due to the prevention of the impairment in memory consolidation, rather than an enhancement to the “normal” state. Although our findings point to alterations in the sleep pattern, effects of the drug per se should not be discarded. CONCLUSION Lithium prevented memory impairment induced by sleep deprivation, and this effect could be related to reduction of rapid eye movement sleep rebound. ABBREVIATIONS BDNF, brain-derived neurotrophic factor CC, cage control cAMP, cyclic adenosine monophosphate CREB, cAMP response element binding SLEEP, Vol. 36, No. 11, 2013 1683 Downloaded from https://academic.oup.com/sleep/article-abstract/36/11/1677/2558947 by guest on 10 March 2018
EEG, electroencephalography EMG, electromyography IM, intramuscular IP, intraperitoneal LI, lithium LTP, long-term potentiation MTIA, multiple trial inhibitory avoidance pCREB, phosphorylated CREB pKA, protein kinase A REMS, rapid eye movement sleep REMSDep, rapid eye movement sleep-deprived SWS, slow wave sleep TS, transition sleep VEH, vehicle DISCLOSURE STATEMENT This was not an industry supported study. Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, São Paulo Research Foundation), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, National Science and Technology Council) and Associação Fundo de Incentivo à Pesquisa (AFIP, Funding Society for the Incentive of Research). The authors have indicated no financial conflicts of interest. REFERENCES
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