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The different effects of maternal separation on spatial learning and reversal learning in rats
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Research report
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The different effects of maternal separation on spatial learning and reversal learning in rats
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Qiong Wang a , Man Li a , Wei Du a , Feng Shao a,∗ , Weiwen Wang b,∗∗ a
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Department of Psychology, Peking University, Beijing 100871, China Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing 100101, China
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h i g h l i g h t s
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MS increased locomotor activity in the open field of all three ages of rats. MS induced less anxiety-behaviors in the open field of adolescent rats. MS slightly disrupted spatial learning of MWM in adolescent and young adult rats. MS improved reversal learning of MWM in adolescent and young adult rats.
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Article history: Received 19 September 2014 Received in revised form 20 November 2014 Accepted 25 November 2014 Available online xxx
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Keywords: Maternal separation Locomotor activity Anxiety Spatial learning Reversal learning
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1. Introduction
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Early postnatal maternal separation (MS) can play an important role in the development of psychopathologies during ontogeny. In the present study, we investigated the effects of repeated MS (4 h per day from postnatal day (PND) 1 to 21) on locomotor activity and anxiety behavior in open field, spatial learning and reversal learning in Morris water maze of male and female juvenile (PND 21), adolescent (PND 35) and early adult (PND 56) Wistar rats. The results indicated that MS increased locomotor activity of rats across all ages and reduced anxiety behavior of adolescent rats in open field test. MS also increased swim distance in spatial learning and decreased escape latency in reversal learning in adolescent and early adult rats. Additionally, for socially reared rats, there was increased spontaneous locomotion with age, decreased reversal learning ability with age. The present study provides novel insights into the consequences of MS and demonstrates unique age-dependent changes at the behavioral levels. © 2014 Published by Elsevier B.V.
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Adverse early life events are considered risk factors for the development of psychiatric diseases [1,2]. In rats, maternal separation (MS), which deprives pups of their mothers, has often been used as a model for adverse early life experiences [3,4]. MS has been demonstrated to induce behavioral and cognitive abnormalities, such as increased locomotor activities [5,6], anxiety-related behaviors [7,8], prepulse inhibition (PPI) deficits [9,10], and impaired spatial learning in the Morris water maze test [11,12].
∗ Corresponding author at: Department of Psychology, Peking University, 5 Yiheyuan Road, Beijing 100871, China. Tel.: +86 10 62755262; fax: +86 10 62761081. ∗∗ Corresponding author at: Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, 4A Datun Road, Beijing 100101, China. Tel.: +86 10 64864516; fax: +86 10 64872070. E-mail addresses: [email protected] (F. Shao), [email protected] (W. Wang).
Reversal learning measures cognitive flexibility, which is defined as the ability to rapidly adjust established patterns of behavior according to changing circumstances [13]. Reversal learning has been considered a suitable model for measuring the cognitive rigidity in schizophrenia and other neuropsychiatric disorders. It has been demonstrated that adverse life experiences, such as social isolation, can disrupt the reversal learning performance of rats [14–18]. However, it is unclear whether MS can affect reversal learning in animals. To date, only one study has reported that a single 24 h MS at postnatal day 8 reduced reversal learning in the Morris water maze (MWM) of adult CD1 mice [19]. Successful reversal learning performance depends on normal prefrontal cortico-striatal functioning, which includes the prefrontal cortex (PFC) [20,21] and nucleus accumbens (NAc) [22,23]. It is well known that these brain regions are related to the neural substrates of neuropsychiatric diseases. It has been demonstrated that there are age-related differences among several behavioral and physiological repertoire. For
http://dx.doi.org/10.1016/j.bbr.2014.11.040 0166-4328/© 2014 Published by Elsevier B.V.
Please cite this article in press as: Wang Q, et al. The different effects of maternal separation on spatial learning and reversal learning in rats. Behav Brain Res (2014), http://dx.doi.org/10.1016/j.bbr.2014.11.040
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example, elevations in emotional reactivity, reward processing, locomotor and explorative activity follow an inverted U shape, with the peak occurring during adolescence [24,25]. While the ontogeny of rat social play is characterized by an inverted-U-shaped function, with a peak existing between 32 and 40 days of age, especially in 35-day rats [26,27]. Furthermore, the dopaminergic activity in the prefrontal cortex has been reached a peak during adolescence [28]. Furthermore, other studies have indicated that the developmental period of animals may be another important factor for the MS effects. For example, Roceri et al. reported that MS produced a short-term-up-regulation of Brain-derived neurotrophic factor (BDNF) expression in the hippocampus and PFC when measured on postnatal day (PND) 17 and a reduction of BDNF expression in the PFC at adulthood [29]. Our lab identified that long term MS (one daily period of 4 h from PND 1 to 21) had different effects on the serotonergic activity in juvenile, adolescent and young adult rats [30]. However, to date, there is no study that has investigated the effects of MS on spatial learning and reversal learning in juvenile, adolescent and young adult rats. Thus, a MS procedure was utilized for this research in a dynamic and developmental view. In the present study, we aimed to investigate the effects of repeated MS (4 h/day from PND 1 to 21) on the open-field activity, spatial learning and reversal learning of the MWM in juvenile (PND 21), adolescent (PND 35) and early adult (PND 56) rats [31].
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2. Materials and methods
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2.1. Experimental subjects and maternal separation
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Male and female adult Wistar rats were obtained from the Academy of Chinese Military Medical Science and were housed under controlled environmental conditions (ambient temperature 22 ◦ C, 12 h light/12 h dark cycle, lights on at 7:00 a.m.) with free access to food and water. The experiments were performed in accordance with the guidelines of the Beijing Laboratory Animal Center and the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 80-23). The rats were mated to produce litters that consisted of 8–12 pups. This MS procedure has been previously described [32]. Briefly, the pups were randomly separated into two experimental groups. The MS procedure was performed on one group (maternal separation, MS group, 48 pups), and the second group was left undisturbed from PND 1 to 21 (non-maternal separation, NMS group, 48 pups); each group had 24 male and 24 female pups. All experimental subjects were derived from different mothers. The MS procedure consisted of separating the rat pups from their mothers for 4 h per day from PND 1 to 21. This separation was regularly performed each day between 10:00 and 14:00. During these 4 h of separation, each pup was maintained separately from its littermates on heated sawdust at 28–30 ◦ C. The dams of the separated litters remained in the home cage during the 4 h pup isolation period. The pups from the control litters remained in the cage with the dam and litter during this period. After weaning at PND 21, 16 MS (8 males and 8 females) and 16 NMS (8 males and 8 females) animals were examined in the behavioral tests. The other siblings were allocated to different cages (4 animals per cage). Then, at PND 35, another 16 MS (8 males and 8 females) and 16 NMS (8 males and 8 females) animals were examined in the behavioral tests. At PND 56, the last 16 MS (8 males and 8 females) and 16 NMS (8 males and 8 females) animals were examined in the behavioral tests.
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2.2. Open field test
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The testing apparatus included a circular arena of 180 cm in diameter with a 50 cm high wall. The central area of the open field
was defined as a circular arena of 60 cm in diameter in the middle zone of the apparatus. The test room had a dim illumination (40 W) to decrease the anxiety of the rats. An animal was placed in the center of the field, and the horizontal activity (distance traveled) and time spent in the central arena were recorded for 5 min and analyzed by a computer-based system (Etho Vision; Noldus Information Technology, Wageningen, Netherlands). The open field was cleaned after each test. 2.3. Morris water maze test 2.3.1. Apparatus Testing was conducted in a circular pool with a 150 cm diameter and filled to a depth of 22 cm with water (23 ± 2 ◦ C). A circular Plexiglas platform (8 cm diameter) was placed 2 cm beneath the water level at different locations depending on which test was currently employed. The water was made cloudy by adding milk. Distinctive visual cues were set up on the wall surrounding the pool. A video camera was positioned above the water maze. The swim paths of the rats were tracked, digitized, and stored for later behavioral analysis using Etho Vision 3.1 (Noldus). The water maze was divided into four logical quadrants—north, south, east, and west—that served as starting positions for the rats. All animals were tested in the spatial learning and reversal learning. 2.3.2. Spatial learning The spatial learning task consisted of 4 days of acquisition using the hidden platform. This was followed by a probe test on the fifth day without the platform. The platform was fixed in the middle of the west quadrant, 45 cm from the maze wall. During the first 4 days, four swim trials were given per day, in which each animal was released from a different quadrant in each trial. This was done in a pseudo-random manner and the start quadrant used was varied across the sessions. A maximum of 60 s was allowed for each trial. If the rat did not find the platform within 60 s, it was guided to the platform and allowed to remain there for 10 s. After each training trial, the rats were dried with paper towels and returned to their home cages for 50 s before the next trial, so the intertrial interval was approximately 60 s. Both the latency to escape onto the platform and distance traveled were recorded. 2.3.3. Reversal learning After the spatial learning task was completed in each subject, they were examined using the reversal learning test. For this test, the platform was located in a novel position in the middle of the east quadrant, 45 cm from the wall opposite to the location used for the spatial memory task. The rats were also tested for four trials separated by 60-s inter-trial interval for 4 days. Otherwise, this test was similar to the spatial learning test. 2.4. Statistical analyses All data are shown as the mean ± standard error of the mean (SEM). The analyses were performed using SPSS 16 software. The Open field test results were analyzed using multivariate analysis of variance (MANOVA). Repeated measures MANOVA was used for the analysis of MWM escape latencies with rearing condition, sex and age as the independent factors and test day as the within-subject factor. Comparisons with two and three groups were analyzed using Student’s t-test and one-way analysis of variance (ANOVA) followed by LSD post hoc tests, respectively. The significance level was defined as p < 0.05.
Please cite this article in press as: Wang Q, et al. The different effects of maternal separation on spatial learning and reversal learning in rats. Behav Brain Res (2014), http://dx.doi.org/10.1016/j.bbr.2014.11.040
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82) = 179.405, p = 0.017], and the overall effect of MS was significant [F(1, 84) = 5.93, p < 0.001]. However, the overall effect of sex and age were not significant, and all interactions were also not significant. Further analysis (t-test) showed that MS significantly increased the distance traveled for the 35d and 56d rats on the first and second test days [35d: Day 1: t = (30), p = 0.001; Day 2: t = (30), p = 0.002]; [56d: Day 1: t = (30), p = 0.029; Day 2: t = (30), p = 0.005]. For escape latency of the rats in each group, the effect of test day was significant [F(3, 82) = 180.799, p < 0.001]. The overall effect of MS, age and sex were not significant. All interactions were also not significant. The results are summarized in Fig. 3A–C. The results of the probe test are illustrated in Fig. 4. The results indicated that both the MS and NMS rats had the highest spatial preference for the target quadrant. 3.3. Reversal learning in the MWM test
Fig. 1. Effects of MS on behavior in the open field test at different ages, including the distance traveled (A) and the time spent in the central area (B). Results are expressed as the mean ± S.E.M. (*Compared with NMS, p < 0.05).
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The distance traveled in the open field is summarized in Fig. 1A. The results showed that there were significant effects of MS [F(1, 84) = 42.707, p < 0.001] and age [F(2, 84) = 160.788, p < 0.001], but not sex. There was no significant interaction between MS and age, MS and sex, or age and sex. The interaction between MS, age and sex was also not significant. For age, post hoc (LSD) comparisons revealed that the distance of the 21d rats was significantly less compared with the 35d and 56d rats, and the distance of the 35d rats was significantly less compared with the 56d rats. For MS, the rats in the MS group showed an increased distance traveled compared with the rats in NMS group for all three ages [21d: t(30) = −3.088, p = 0.005; 35d: t(30) = −5.177, p < 0.001; 56d: t(30) = −3.017, p = 0.005]. The time spent in the central area is summarized in Fig. 1B. There was a significant effect of MS [F(1, 84) = 7.421, p = 0.008], but not age or sex. There was a significant interaction between MS and age [F(2, 84) = 3.400, p = 0.038] and between age and sex [F(2, 84) = 7.421, p = 0.048], but not between MS and sex. The interaction among MS, age and sex was not significant. Post hoc analysis revealed that the MS rats spent significantly more time in the central area compared with the NMS rats only in the PND 35 age group [t(30) = −2.650, p = 0.009].
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3.2. Spatial learning in the MWM test
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The average distance traveled for the rats in each group during the initial spatial learning are summarized in Fig. 2A–C. The results showed that the effect of test day was significant [F(3,
The results of the distance traveled for the rats in each group during the reversal learning indicated that the effect of test day was significant [F(3, 82) = 19.320, p < 0.001]. The overall effect of MS, age and sex were not significant. All interactions were also not significant. The results are summarized in Fig. 5A–C. The results of the average escape latency for the rats in each group during the reversal learning indicated that the effect of test day was significant [F(3, 82) = 30.07, p < 0.001], the overall effect of MS was significant [F(1, 84) = 13.414, p < 0.001], and there was a significant interaction between MS and age [F(2, 84) = 3.532, p = 0.034]. However, the other interactions were not significant. Further analysis (t-test) showed that MS significantly reduced the escape latency of the 56d rats on all four days [Day 1: t = (30), p = 0.013; Day 2: t = (30), p = 0.019; Day 3: t = (30), p < 0.001; Day 4: t = (30), p = 0.010]. For the 35d rats, MS only reduced their escape latency significantly on Day 1 [t = (30), p = 0.03]. The results are summarized in Fig. 6A–C. Furthermore, the escape latency was significantly different between the three age groups of rats in the NMS group on Day 2 and Day 3 [Day 2: F(2, 45) = 4.532, p = 0.016; Day 3: F(2, 45) = 6.474, p = 0.003]. Post hoc (LSD) comparisons within each day revealed significant differences between the different aged rats: on day 2, the 56d and 35d rats had a significantly longer escape latency compared with the 21d rats; on day 3, the 56d rats had a significantly longer escape latency compared with the 35d and 21d rats. However, this difference was not observed in the MS group. The results are summarized in Fig. 7A and B.
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4. Discussion
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4.1. Locomotor activity and anxiety in the open field test
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The open field data in the current study indicated that repeated MS (one daily period of 4 h from PND 1 to 21) increased spontaneous locomotor activity in juvenile, adolescent and young adult rats. Young adult rats displayed the highest locomotion compared with juvenile and adolescent rats, and MS only induced less anxiety in adolescent rats. However, there was no significant sex difference for locomotor activity or anxiety in the open field test. First, the present data demonstrated that MS increased open field locomotor activity in juvenile, adolescent and early adult rats. Similarly, Bouet et al. reported that MS (24 h MS on PND 9) in adult mice displayed a significant increase in horizontal activity in the open field test [33]. Sanders et al. also indicated that after repeated MS (3 h MS from PND 1 to 14), the MS adult rats had significantly increased locomotor activity [34]. However, Shalev et al. found that 3 h MS from PND 3 to 14 did not affect the locomotor response of rats (PND 70) [35].
Please cite this article in press as: Wang Q, et al. The different effects of maternal separation on spatial learning and reversal learning in rats. Behav Brain Res (2014), http://dx.doi.org/10.1016/j.bbr.2014.11.040
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Fig. 2. Effects of MS on distance traveled of spatial learning in the Morris water maze at different ages, including the 21d (A), 35d (B) and 56d (C) rats. Results are expressed as the mean ± S.E.M. (*Compared with NMS, p < 0.05).
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Second, the results also indicated that for the NMS and MS rats, spontaneous locomotor activity was enhanced with the increase of age, with the highest activity exhibited at PND 56. Several studies have investigated the developmental characteristics of locomotor activity, but the results were controversial. For example, characteristic inverted U-shaped patterns for adolescent rats have been reported, with a peak during adolescence [24,25]. In contrast, less
activity in the open field was reported in five-week-old CD-1 mice [36] and six-week-old C57BL/6J mice [37] compared with adults, which is consistent with our data. Different behavioral phenotypes have been reported depending on the different MS protocols that were used. Third, the present study demonstrated that only at PND 35, MS rats spent more time in the center of the open field, which indicates
Fig. 3. Effects of MS on escape latency of spatial learning in the Morris water maze at different ages, including the 21d (A), 35d (B) and 56d (C) rats. Results are expressed as the mean ± S.E.M.
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rats [30]. These characteristic neurochemical changes during adolescence might induce an enhanced adolescent sensitivity to early life stress, such as repeated MS, compared with juvenile and adult rats.
4.2. Spatial learning in MWM
Fig. 4. Probe test of spatial learning in the Morris water maze. Results are expressed as the mean ± S.E.M. (*p < 0.05).
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less anxiety compared with NMS rats. This finding is consistent with previous studies that described increased impulsive behavior in the open-field induced by MS. For example, Suchecki et al. reported that after 24 h MS on PND 11, MS rats (PND 30) ambulated more in the center of the open field [38]. Romeo et al. also reported that 3 h MS from PND 1 to 14 reduced anxiety and fear behavior in the open field test of adult mice [39]. However, other studies have reported increased anxiety-related behaviors in the open-field test in MS exposed adult rats [8,40]. Adolescence is a critical interval in life that is particularly susceptible to the onset of specific neuropsychiatric diseases. It has been demonstrated that the dopaminergic activity in the prefrontal cortex [28] and DRD2 maturation [41] peak during adolescence. Our previous data also demonstrated that 5-HT activity was significantly increased in the mPFC and NAc in PND 35 rats compared with PND 21 and PND 56
Spatial learning data of the MWM in the present study showed that compared to NMS rats, 35d and 56d MS rats had significant increased distance traveled on the first and second test days, suggesting that MS for 4 h/day from PND 1 to 21 slightly disrupted spatial learning in adolescent and young adult rats. Consistently, several previous studies have found that 12 h MS on PND 9 [44], and MS for 6 h/day from PND 1 to 14 [12] or for 3 h/day from PND 2 to 14 [11] decreased spatial learning of adult rats. However, other previous studies have reported that 24 h maternal deprivation (MD) on PND 9 improve spatial learning in Morris water maze of rats [45] and 24 h MD on PND 8 does not affect spatial learning of mice [19]. And there is no significant sex and age difference in the spatial learning test. However, Hill et al. found that male rats showed disruptions in spatial memory (Y-maze), induced by MS, which were absent in females [42], and this may be due to the different effects of sex steroid hormones on BDNF-TrkB signaling [43]. The discrepancies may be due to differences in experimental design, strain differences, the control group examined, or all of these factors.
4.3. Reversal learning in the MWM The present data regarding reversal learning in the MWM revealed that repeated MS improved cognitive flexibility, especially for young adult rats; with increased age, the reversal learning ability of NMS rats decreased, especially for young adult rats. There was no significant sex difference for reversal learning in the MWM.
Fig. 5. Effects of MS on distance traveled of reversal learning in the Morris water maze at different ages, including the 21d (A), 35d (B) and 56d (C) rats. Results are expressed as the mean ± S.E.M.
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Fig. 6. Effects of MS on escape latency of reversal learning in the Morris water maze at different ages, including the 21d (A), 35d (B) and 56d (C) rats. Results are expressed as the mean ± S.E.M. (*Compared with NMS, p < 0.05).
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First, the current results indicate the reversal learning in the MWM of MS young adult rats was significantly improved from 1 to 4 testing days compared with social young adult rats. These findings are inconsistent with a previous study that reported a single 24 h MS at postnatal day 8 reduced reversal learning in the MWM of adult CD1 mice [19]. It is well known that the effects of MS on cognitive function are related to differences in the experimental design, animal strain, age, or other factors. Similarly, it has been reported that social isolation can induce the impairment [14] or enhancement [46] of the reversal learning ability in the MWM. Our study is the first observation that investigated the effects of long term repeated MS on reversal learning in the MWM in rats. Second, the present data indicated that there was a negative relationship between cognitive flexibility and age for NMS rats, and the performance of reversal learning declined with age. However, young adult rats displayed the highest locomotor activity compared with juvenile and adolescent rats, which suggests the decreased performance of reversal learning in young adult rats may be induced by decreased cognitive function not locomotion ability. The MWM can be used to measure age-related cognitive function. For example, Lindner et al. found that performance in the water maze declined with age from 1.5 to 26 months of age in F-344 rats [47]. Our study is the first to report a decline of reversal learning with age from PND 21, PND 35 to PND 56 in NMS rats in the MWM. However, for MS rats, there is no age-related change in cognitive flexibility. It is well known that MS rats showed different neurochemical alterations from NMS rats such as BDNF and 5-HT changes in juvenile, adolescent and young adult period which are induced by MS procedure [29,30]. And MS produced deficits in cognitive flexibility of adult rats along with an up-regulation of long term potentiation (LTP) in the mPFC [48]. The unpublished data of our lab also showed that the highest BDNF expression in the mPFC of NMS young adult rats hit bottom in it of MS rats, which may have an
influence on the disappearance of age-related changes in cognitive flexibility induced by MS, but this still need further confirmation. More importantly, the present study provides a direct evaluation of the effects of long term MS on the spatial learning and reversal learning of MWM in three different time points of development. Our study found that increased swim distance in spatial learning induced by repeated MS primarily occurred in adolescent and early adult rats. And improved reversal learning induced by MS did not emerge until adolescence. These results suggested that the adverse effects of negative early life events on the cognitive symptoms were enhanced as age increase, which is consistent with the neurodevelopmental hypothesis of neuropsychiatric diseases. Interestingly, there exists different effects of MS on spatial learning and reversal learning, that long term MS partially disrupted spatial learning but improved reversal learning of MWM. As we have mentioned above, the performance of spatial learning and reversal learning might be dependent on the different neural circuits. It is well established that hippocampus is an important brain structure for the acquisition of spatial learning performance in MWM [49,50], however PFC and striatum/NAc play critical roles in regulating different forms of behavioral and/or cognitive flexibility such as reversal learning [51–53]. And what has also been demonstrated that adverse early life events induce age-related different neurochemical changes in these brain areas. For example, Roceri et al. reported that repeated MS (3 h from PND 2 to 14) produced a short-term up-regulation of BDNF in hippocampus and PFC at PND 17, and a selective reduction of BDNF expression in hippocampus at adulthood [29]. Kuma et al. found that for MS rats, there existed a decreased expression of BDNF mRNA in hippocampus at 16 days of age and an increased expression at 30 and 60 days of age [54]. Greisen et al. indicated that BDNF protein was increased in adult hippocampus but not in PFC after 3 h MS from PND 1 to 21 [55]. Our lab identified that long term MS (4 h from PND 1 to 21) had
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Foundation of China (Grant No. 91132728), the Knowledge Innovation Program of the Chinese Academy of Sciences (KSCX2-EW-J-8) and the Key Laboratory of Mental Health, Institute of Psychology, Q4 Chinese Academy of Sciences. References
Fig. 7. Effects of age on reversal learning in the Morris water maze in the MS and in the NMS groups on the second (A) and third (B) days of the test. Results are expressed as the mean ± S.E.M. (*Compared with 21d, p < 0.05 & compared with 35d, p < 0.05).
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different effects on the serotonergic activity in hippocampus, PFC and NAc at juvenile, adolescent and young adult rats [30]. The previous experiments in our lab have also found that brief social isolation during adolescence induced an increased BDNF expression in PFC and a decreased BDNF expression in hippocampus [14]. To sum up, based on these experimental data above, the different effects of long term MS on spatial learning and reversal learning in the present study might be induced by these complex changes in some specific cortical and sub-cortical structures at different developmental periods. This is an interesting issue, as it reveals the more complicated developmental characteristics that may exist, clearly worthy of further investigation into neural mechanism to find out the more specific explanations. 5. Conclusion
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In conclusion, our current study found that repeated MS induced enhanced locomotor activity in the open field of all three ages of rats, less anxiety-like behaviors in adolescent rats, slightly disrupted spatial learning and improved reversal learning of the MWM in adolescent and young adult rats. Additionally, for socially reared rats, there were spontaneous locomotion increasing with age and reversal learning ability decreasing with age. These present findings suggest that long term repeated MS could have different effects on cognition and cognitive flexibility, modestly disrupt spatial learning and improve reversal learning of MWM, after a developmental delay.
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Acknowledgements
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This work was supported by the National Natural Science Foundation of China (Grant No. 31470988), the National Natural Science
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Contents lists available at ScienceDirect
Behavioural Brain Research journal homepage: www.elsevier.com/locate/bbr
Research report
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The different effects of maternal separation on spatial learning and reversal learning in rats
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Qiong Wang a , Man Li a , Wei Du a , Feng Shao a,∗ , Weiwen Wang b,∗∗ a
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Department of Psychology, Peking University, Beijing 100871, China Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing 100101, China
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h i g h l i g h t s
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MS increased locomotor activity in the open field of all three ages of rats. MS induced less anxiety-behaviors in the open field of adolescent rats. MS slightly disrupted spatial learning of MWM in adolescent and young adult rats. MS improved reversal learning of MWM in adolescent and young adult rats.
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Article history: Received 19 September 2014 Received in revised form 20 November 2014 Accepted 25 November 2014 Available online xxx
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Keywords: Maternal separation Locomotor activity Anxiety Spatial learning Reversal learning
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1. Introduction
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Early postnatal maternal separation (MS) can play an important role in the development of psychopathologies during ontogeny. In the present study, we investigated the effects of repeated MS (4 h per day from postnatal day (PND) 1 to 21) on locomotor activity and anxiety behavior in open field, spatial learning and reversal learning in Morris water maze of male and female juvenile (PND 21), adolescent (PND 35) and early adult (PND 56) Wistar rats. The results indicated that MS increased locomotor activity of rats across all ages and reduced anxiety behavior of adolescent rats in open field test. MS also increased swim distance in spatial learning and decreased escape latency in reversal learning in adolescent and early adult rats. Additionally, for socially reared rats, there was increased spontaneous locomotion with age, decreased reversal learning ability with age. The present study provides novel insights into the consequences of MS and demonstrates unique age-dependent changes at the behavioral levels. © 2014 Published by Elsevier B.V.
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Adverse early life events are considered risk factors for the development of psychiatric diseases [1,2]. In rats, maternal separation (MS), which deprives pups of their mothers, has often been used as a model for adverse early life experiences [3,4]. MS has been demonstrated to induce behavioral and cognitive abnormalities, such as increased locomotor activities [5,6], anxiety-related behaviors [7,8], prepulse inhibition (PPI) deficits [9,10], and impaired spatial learning in the Morris water maze test [11,12].
∗ Corresponding author at: Department of Psychology, Peking University, 5 Yiheyuan Road, Beijing 100871, China. Tel.: +86 10 62755262; fax: +86 10 62761081. ∗∗ Corresponding author at: Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, 4A Datun Road, Beijing 100101, China. Tel.: +86 10 64864516; fax: +86 10 64872070. E-mail addresses: [email protected] (F. Shao), [email protected] (W. Wang).
Reversal learning measures cognitive flexibility, which is defined as the ability to rapidly adjust established patterns of behavior according to changing circumstances [13]. Reversal learning has been considered a suitable model for measuring the cognitive rigidity in schizophrenia and other neuropsychiatric disorders. It has been demonstrated that adverse life experiences, such as social isolation, can disrupt the reversal learning performance of rats [14–18]. However, it is unclear whether MS can affect reversal learning in animals. To date, only one study has reported that a single 24 h MS at postnatal day 8 reduced reversal learning in the Morris water maze (MWM) of adult CD1 mice [19]. Successful reversal learning performance depends on normal prefrontal cortico-striatal functioning, which includes the prefrontal cortex (PFC) [20,21] and nucleus accumbens (NAc) [22,23]. It is well known that these brain regions are related to the neural substrates of neuropsychiatric diseases. It has been demonstrated that there are age-related differences among several behavioral and physiological repertoire. For
http://dx.doi.org/10.1016/j.bbr.2014.11.040 0166-4328/© 2014 Published by Elsevier B.V.
Please cite this article in press as: Wang Q, et al. The different effects of maternal separation on spatial learning and reversal learning in rats. Behav Brain Res (2014), http://dx.doi.org/10.1016/j.bbr.2014.11.040
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example, elevations in emotional reactivity, reward processing, locomotor and explorative activity follow an inverted U shape, with the peak occurring during adolescence [24,25]. While the ontogeny of rat social play is characterized by an inverted-U-shaped function, with a peak existing between 32 and 40 days of age, especially in 35-day rats [26,27]. Furthermore, the dopaminergic activity in the prefrontal cortex has been reached a peak during adolescence [28]. Furthermore, other studies have indicated that the developmental period of animals may be another important factor for the MS effects. For example, Roceri et al. reported that MS produced a short-term-up-regulation of Brain-derived neurotrophic factor (BDNF) expression in the hippocampus and PFC when measured on postnatal day (PND) 17 and a reduction of BDNF expression in the PFC at adulthood [29]. Our lab identified that long term MS (one daily period of 4 h from PND 1 to 21) had different effects on the serotonergic activity in juvenile, adolescent and young adult rats [30]. However, to date, there is no study that has investigated the effects of MS on spatial learning and reversal learning in juvenile, adolescent and young adult rats. Thus, a MS procedure was utilized for this research in a dynamic and developmental view. In the present study, we aimed to investigate the effects of repeated MS (4 h/day from PND 1 to 21) on the open-field activity, spatial learning and reversal learning of the MWM in juvenile (PND 21), adolescent (PND 35) and early adult (PND 56) rats [31].
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2. Materials and methods
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2.1. Experimental subjects and maternal separation
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Male and female adult Wistar rats were obtained from the Academy of Chinese Military Medical Science and were housed under controlled environmental conditions (ambient temperature 22 ◦ C, 12 h light/12 h dark cycle, lights on at 7:00 a.m.) with free access to food and water. The experiments were performed in accordance with the guidelines of the Beijing Laboratory Animal Center and the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 80-23). The rats were mated to produce litters that consisted of 8–12 pups. This MS procedure has been previously described [32]. Briefly, the pups were randomly separated into two experimental groups. The MS procedure was performed on one group (maternal separation, MS group, 48 pups), and the second group was left undisturbed from PND 1 to 21 (non-maternal separation, NMS group, 48 pups); each group had 24 male and 24 female pups. All experimental subjects were derived from different mothers. The MS procedure consisted of separating the rat pups from their mothers for 4 h per day from PND 1 to 21. This separation was regularly performed each day between 10:00 and 14:00. During these 4 h of separation, each pup was maintained separately from its littermates on heated sawdust at 28–30 ◦ C. The dams of the separated litters remained in the home cage during the 4 h pup isolation period. The pups from the control litters remained in the cage with the dam and litter during this period. After weaning at PND 21, 16 MS (8 males and 8 females) and 16 NMS (8 males and 8 females) animals were examined in the behavioral tests. The other siblings were allocated to different cages (4 animals per cage). Then, at PND 35, another 16 MS (8 males and 8 females) and 16 NMS (8 males and 8 females) animals were examined in the behavioral tests. At PND 56, the last 16 MS (8 males and 8 females) and 16 NMS (8 males and 8 females) animals were examined in the behavioral tests.
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2.2. Open field test
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The testing apparatus included a circular arena of 180 cm in diameter with a 50 cm high wall. The central area of the open field
was defined as a circular arena of 60 cm in diameter in the middle zone of the apparatus. The test room had a dim illumination (40 W) to decrease the anxiety of the rats. An animal was placed in the center of the field, and the horizontal activity (distance traveled) and time spent in the central arena were recorded for 5 min and analyzed by a computer-based system (Etho Vision; Noldus Information Technology, Wageningen, Netherlands). The open field was cleaned after each test. 2.3. Morris water maze test 2.3.1. Apparatus Testing was conducted in a circular pool with a 150 cm diameter and filled to a depth of 22 cm with water (23 ± 2 ◦ C). A circular Plexiglas platform (8 cm diameter) was placed 2 cm beneath the water level at different locations depending on which test was currently employed. The water was made cloudy by adding milk. Distinctive visual cues were set up on the wall surrounding the pool. A video camera was positioned above the water maze. The swim paths of the rats were tracked, digitized, and stored for later behavioral analysis using Etho Vision 3.1 (Noldus). The water maze was divided into four logical quadrants—north, south, east, and west—that served as starting positions for the rats. All animals were tested in the spatial learning and reversal learning. 2.3.2. Spatial learning The spatial learning task consisted of 4 days of acquisition using the hidden platform. This was followed by a probe test on the fifth day without the platform. The platform was fixed in the middle of the west quadrant, 45 cm from the maze wall. During the first 4 days, four swim trials were given per day, in which each animal was released from a different quadrant in each trial. This was done in a pseudo-random manner and the start quadrant used was varied across the sessions. A maximum of 60 s was allowed for each trial. If the rat did not find the platform within 60 s, it was guided to the platform and allowed to remain there for 10 s. After each training trial, the rats were dried with paper towels and returned to their home cages for 50 s before the next trial, so the intertrial interval was approximately 60 s. Both the latency to escape onto the platform and distance traveled were recorded. 2.3.3. Reversal learning After the spatial learning task was completed in each subject, they were examined using the reversal learning test. For this test, the platform was located in a novel position in the middle of the east quadrant, 45 cm from the wall opposite to the location used for the spatial memory task. The rats were also tested for four trials separated by 60-s inter-trial interval for 4 days. Otherwise, this test was similar to the spatial learning test. 2.4. Statistical analyses All data are shown as the mean ± standard error of the mean (SEM). The analyses were performed using SPSS 16 software. The Open field test results were analyzed using multivariate analysis of variance (MANOVA). Repeated measures MANOVA was used for the analysis of MWM escape latencies with rearing condition, sex and age as the independent factors and test day as the within-subject factor. Comparisons with two and three groups were analyzed using Student’s t-test and one-way analysis of variance (ANOVA) followed by LSD post hoc tests, respectively. The significance level was defined as p < 0.05.
Please cite this article in press as: Wang Q, et al. The different effects of maternal separation on spatial learning and reversal learning in rats. Behav Brain Res (2014), http://dx.doi.org/10.1016/j.bbr.2014.11.040
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82) = 179.405, p = 0.017], and the overall effect of MS was significant [F(1, 84) = 5.93, p < 0.001]. However, the overall effect of sex and age were not significant, and all interactions were also not significant. Further analysis (t-test) showed that MS significantly increased the distance traveled for the 35d and 56d rats on the first and second test days [35d: Day 1: t = (30), p = 0.001; Day 2: t = (30), p = 0.002]; [56d: Day 1: t = (30), p = 0.029; Day 2: t = (30), p = 0.005]. For escape latency of the rats in each group, the effect of test day was significant [F(3, 82) = 180.799, p < 0.001]. The overall effect of MS, age and sex were not significant. All interactions were also not significant. The results are summarized in Fig. 3A–C. The results of the probe test are illustrated in Fig. 4. The results indicated that both the MS and NMS rats had the highest spatial preference for the target quadrant. 3.3. Reversal learning in the MWM test
Fig. 1. Effects of MS on behavior in the open field test at different ages, including the distance traveled (A) and the time spent in the central area (B). Results are expressed as the mean ± S.E.M. (*Compared with NMS, p < 0.05).
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The distance traveled in the open field is summarized in Fig. 1A. The results showed that there were significant effects of MS [F(1, 84) = 42.707, p < 0.001] and age [F(2, 84) = 160.788, p < 0.001], but not sex. There was no significant interaction between MS and age, MS and sex, or age and sex. The interaction between MS, age and sex was also not significant. For age, post hoc (LSD) comparisons revealed that the distance of the 21d rats was significantly less compared with the 35d and 56d rats, and the distance of the 35d rats was significantly less compared with the 56d rats. For MS, the rats in the MS group showed an increased distance traveled compared with the rats in NMS group for all three ages [21d: t(30) = −3.088, p = 0.005; 35d: t(30) = −5.177, p < 0.001; 56d: t(30) = −3.017, p = 0.005]. The time spent in the central area is summarized in Fig. 1B. There was a significant effect of MS [F(1, 84) = 7.421, p = 0.008], but not age or sex. There was a significant interaction between MS and age [F(2, 84) = 3.400, p = 0.038] and between age and sex [F(2, 84) = 7.421, p = 0.048], but not between MS and sex. The interaction among MS, age and sex was not significant. Post hoc analysis revealed that the MS rats spent significantly more time in the central area compared with the NMS rats only in the PND 35 age group [t(30) = −2.650, p = 0.009].
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3.2. Spatial learning in the MWM test
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The average distance traveled for the rats in each group during the initial spatial learning are summarized in Fig. 2A–C. The results showed that the effect of test day was significant [F(3,
The results of the distance traveled for the rats in each group during the reversal learning indicated that the effect of test day was significant [F(3, 82) = 19.320, p < 0.001]. The overall effect of MS, age and sex were not significant. All interactions were also not significant. The results are summarized in Fig. 5A–C. The results of the average escape latency for the rats in each group during the reversal learning indicated that the effect of test day was significant [F(3, 82) = 30.07, p < 0.001], the overall effect of MS was significant [F(1, 84) = 13.414, p < 0.001], and there was a significant interaction between MS and age [F(2, 84) = 3.532, p = 0.034]. However, the other interactions were not significant. Further analysis (t-test) showed that MS significantly reduced the escape latency of the 56d rats on all four days [Day 1: t = (30), p = 0.013; Day 2: t = (30), p = 0.019; Day 3: t = (30), p < 0.001; Day 4: t = (30), p = 0.010]. For the 35d rats, MS only reduced their escape latency significantly on Day 1 [t = (30), p = 0.03]. The results are summarized in Fig. 6A–C. Furthermore, the escape latency was significantly different between the three age groups of rats in the NMS group on Day 2 and Day 3 [Day 2: F(2, 45) = 4.532, p = 0.016; Day 3: F(2, 45) = 6.474, p = 0.003]. Post hoc (LSD) comparisons within each day revealed significant differences between the different aged rats: on day 2, the 56d and 35d rats had a significantly longer escape latency compared with the 21d rats; on day 3, the 56d rats had a significantly longer escape latency compared with the 35d and 21d rats. However, this difference was not observed in the MS group. The results are summarized in Fig. 7A and B.
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4. Discussion
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4.1. Locomotor activity and anxiety in the open field test
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The open field data in the current study indicated that repeated MS (one daily period of 4 h from PND 1 to 21) increased spontaneous locomotor activity in juvenile, adolescent and young adult rats. Young adult rats displayed the highest locomotion compared with juvenile and adolescent rats, and MS only induced less anxiety in adolescent rats. However, there was no significant sex difference for locomotor activity or anxiety in the open field test. First, the present data demonstrated that MS increased open field locomotor activity in juvenile, adolescent and early adult rats. Similarly, Bouet et al. reported that MS (24 h MS on PND 9) in adult mice displayed a significant increase in horizontal activity in the open field test [33]. Sanders et al. also indicated that after repeated MS (3 h MS from PND 1 to 14), the MS adult rats had significantly increased locomotor activity [34]. However, Shalev et al. found that 3 h MS from PND 3 to 14 did not affect the locomotor response of rats (PND 70) [35].
Please cite this article in press as: Wang Q, et al. The different effects of maternal separation on spatial learning and reversal learning in rats. Behav Brain Res (2014), http://dx.doi.org/10.1016/j.bbr.2014.11.040
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Fig. 2. Effects of MS on distance traveled of spatial learning in the Morris water maze at different ages, including the 21d (A), 35d (B) and 56d (C) rats. Results are expressed as the mean ± S.E.M. (*Compared with NMS, p < 0.05).
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Second, the results also indicated that for the NMS and MS rats, spontaneous locomotor activity was enhanced with the increase of age, with the highest activity exhibited at PND 56. Several studies have investigated the developmental characteristics of locomotor activity, but the results were controversial. For example, characteristic inverted U-shaped patterns for adolescent rats have been reported, with a peak during adolescence [24,25]. In contrast, less
activity in the open field was reported in five-week-old CD-1 mice [36] and six-week-old C57BL/6J mice [37] compared with adults, which is consistent with our data. Different behavioral phenotypes have been reported depending on the different MS protocols that were used. Third, the present study demonstrated that only at PND 35, MS rats spent more time in the center of the open field, which indicates
Fig. 3. Effects of MS on escape latency of spatial learning in the Morris water maze at different ages, including the 21d (A), 35d (B) and 56d (C) rats. Results are expressed as the mean ± S.E.M.
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rats [30]. These characteristic neurochemical changes during adolescence might induce an enhanced adolescent sensitivity to early life stress, such as repeated MS, compared with juvenile and adult rats.
4.2. Spatial learning in MWM
Fig. 4. Probe test of spatial learning in the Morris water maze. Results are expressed as the mean ± S.E.M. (*p < 0.05).
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less anxiety compared with NMS rats. This finding is consistent with previous studies that described increased impulsive behavior in the open-field induced by MS. For example, Suchecki et al. reported that after 24 h MS on PND 11, MS rats (PND 30) ambulated more in the center of the open field [38]. Romeo et al. also reported that 3 h MS from PND 1 to 14 reduced anxiety and fear behavior in the open field test of adult mice [39]. However, other studies have reported increased anxiety-related behaviors in the open-field test in MS exposed adult rats [8,40]. Adolescence is a critical interval in life that is particularly susceptible to the onset of specific neuropsychiatric diseases. It has been demonstrated that the dopaminergic activity in the prefrontal cortex [28] and DRD2 maturation [41] peak during adolescence. Our previous data also demonstrated that 5-HT activity was significantly increased in the mPFC and NAc in PND 35 rats compared with PND 21 and PND 56
Spatial learning data of the MWM in the present study showed that compared to NMS rats, 35d and 56d MS rats had significant increased distance traveled on the first and second test days, suggesting that MS for 4 h/day from PND 1 to 21 slightly disrupted spatial learning in adolescent and young adult rats. Consistently, several previous studies have found that 12 h MS on PND 9 [44], and MS for 6 h/day from PND 1 to 14 [12] or for 3 h/day from PND 2 to 14 [11] decreased spatial learning of adult rats. However, other previous studies have reported that 24 h maternal deprivation (MD) on PND 9 improve spatial learning in Morris water maze of rats [45] and 24 h MD on PND 8 does not affect spatial learning of mice [19]. And there is no significant sex and age difference in the spatial learning test. However, Hill et al. found that male rats showed disruptions in spatial memory (Y-maze), induced by MS, which were absent in females [42], and this may be due to the different effects of sex steroid hormones on BDNF-TrkB signaling [43]. The discrepancies may be due to differences in experimental design, strain differences, the control group examined, or all of these factors.
4.3. Reversal learning in the MWM The present data regarding reversal learning in the MWM revealed that repeated MS improved cognitive flexibility, especially for young adult rats; with increased age, the reversal learning ability of NMS rats decreased, especially for young adult rats. There was no significant sex difference for reversal learning in the MWM.
Fig. 5. Effects of MS on distance traveled of reversal learning in the Morris water maze at different ages, including the 21d (A), 35d (B) and 56d (C) rats. Results are expressed as the mean ± S.E.M.
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Fig. 6. Effects of MS on escape latency of reversal learning in the Morris water maze at different ages, including the 21d (A), 35d (B) and 56d (C) rats. Results are expressed as the mean ± S.E.M. (*Compared with NMS, p < 0.05).
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First, the current results indicate the reversal learning in the MWM of MS young adult rats was significantly improved from 1 to 4 testing days compared with social young adult rats. These findings are inconsistent with a previous study that reported a single 24 h MS at postnatal day 8 reduced reversal learning in the MWM of adult CD1 mice [19]. It is well known that the effects of MS on cognitive function are related to differences in the experimental design, animal strain, age, or other factors. Similarly, it has been reported that social isolation can induce the impairment [14] or enhancement [46] of the reversal learning ability in the MWM. Our study is the first observation that investigated the effects of long term repeated MS on reversal learning in the MWM in rats. Second, the present data indicated that there was a negative relationship between cognitive flexibility and age for NMS rats, and the performance of reversal learning declined with age. However, young adult rats displayed the highest locomotor activity compared with juvenile and adolescent rats, which suggests the decreased performance of reversal learning in young adult rats may be induced by decreased cognitive function not locomotion ability. The MWM can be used to measure age-related cognitive function. For example, Lindner et al. found that performance in the water maze declined with age from 1.5 to 26 months of age in F-344 rats [47]. Our study is the first to report a decline of reversal learning with age from PND 21, PND 35 to PND 56 in NMS rats in the MWM. However, for MS rats, there is no age-related change in cognitive flexibility. It is well known that MS rats showed different neurochemical alterations from NMS rats such as BDNF and 5-HT changes in juvenile, adolescent and young adult period which are induced by MS procedure [29,30]. And MS produced deficits in cognitive flexibility of adult rats along with an up-regulation of long term potentiation (LTP) in the mPFC [48]. The unpublished data of our lab also showed that the highest BDNF expression in the mPFC of NMS young adult rats hit bottom in it of MS rats, which may have an
influence on the disappearance of age-related changes in cognitive flexibility induced by MS, but this still need further confirmation. More importantly, the present study provides a direct evaluation of the effects of long term MS on the spatial learning and reversal learning of MWM in three different time points of development. Our study found that increased swim distance in spatial learning induced by repeated MS primarily occurred in adolescent and early adult rats. And improved reversal learning induced by MS did not emerge until adolescence. These results suggested that the adverse effects of negative early life events on the cognitive symptoms were enhanced as age increase, which is consistent with the neurodevelopmental hypothesis of neuropsychiatric diseases. Interestingly, there exists different effects of MS on spatial learning and reversal learning, that long term MS partially disrupted spatial learning but improved reversal learning of MWM. As we have mentioned above, the performance of spatial learning and reversal learning might be dependent on the different neural circuits. It is well established that hippocampus is an important brain structure for the acquisition of spatial learning performance in MWM [49,50], however PFC and striatum/NAc play critical roles in regulating different forms of behavioral and/or cognitive flexibility such as reversal learning [51–53]. And what has also been demonstrated that adverse early life events induce age-related different neurochemical changes in these brain areas. For example, Roceri et al. reported that repeated MS (3 h from PND 2 to 14) produced a short-term up-regulation of BDNF in hippocampus and PFC at PND 17, and a selective reduction of BDNF expression in hippocampus at adulthood [29]. Kuma et al. found that for MS rats, there existed a decreased expression of BDNF mRNA in hippocampus at 16 days of age and an increased expression at 30 and 60 days of age [54]. Greisen et al. indicated that BDNF protein was increased in adult hippocampus but not in PFC after 3 h MS from PND 1 to 21 [55]. Our lab identified that long term MS (4 h from PND 1 to 21) had
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Foundation of China (Grant No. 91132728), the Knowledge Innovation Program of the Chinese Academy of Sciences (KSCX2-EW-J-8) and the Key Laboratory of Mental Health, Institute of Psychology, Q4 Chinese Academy of Sciences. References
Fig. 7. Effects of age on reversal learning in the Morris water maze in the MS and in the NMS groups on the second (A) and third (B) days of the test. Results are expressed as the mean ± S.E.M. (*Compared with 21d, p < 0.05 & compared with 35d, p < 0.05).
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different effects on the serotonergic activity in hippocampus, PFC and NAc at juvenile, adolescent and young adult rats [30]. The previous experiments in our lab have also found that brief social isolation during adolescence induced an increased BDNF expression in PFC and a decreased BDNF expression in hippocampus [14]. To sum up, based on these experimental data above, the different effects of long term MS on spatial learning and reversal learning in the present study might be induced by these complex changes in some specific cortical and sub-cortical structures at different developmental periods. This is an interesting issue, as it reveals the more complicated developmental characteristics that may exist, clearly worthy of further investigation into neural mechanism to find out the more specific explanations. 5. Conclusion
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In conclusion, our current study found that repeated MS induced enhanced locomotor activity in the open field of all three ages of rats, less anxiety-like behaviors in adolescent rats, slightly disrupted spatial learning and improved reversal learning of the MWM in adolescent and young adult rats. Additionally, for socially reared rats, there were spontaneous locomotion increasing with age and reversal learning ability decreasing with age. These present findings suggest that long term repeated MS could have different effects on cognition and cognitive flexibility, modestly disrupt spatial learning and improve reversal learning of MWM, after a developmental delay.
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Acknowledgements
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This work was supported by the National Natural Science Foundation of China (Grant No. 31470988), the National Natural Science
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