Pharmacology, Biochemistry and Behavior 129 (2015) 14–18
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Pharmacology, Biochemistry and Behavior journal homepage: www.elsevier.com/locate/pharmbiochembeh
Nicotine enhances the reconsolidation of novel object recognition memory in rats Shaowen Tian a,b,1, Si Pan c,1, Yong You c,⁎ a b c
Department of Physiology, College of Medicine, University of South China, Hengyang, Hunan 421001, PR China Institute of Neuroscience, College of Medicine, University of South China, Hengyang, Hunan 421001, PR China Department of Neurology, First Affiliated Hospital, University of South China, Hengyang, Hunan 421001, PR China
a r t i c l e
i n f o
Article history: Received 4 September 2014 Received in revised form 24 November 2014 Accepted 29 November 2014 Available online 4 December 2014 Keywords: Nicotine Object recognition memory Reactivation Reconsolidation Locomotor activity Rats
a b s t r a c t There is increasing evidence that nicotine is involved in learning and memory. However, there are only few studies that have evaluated the relationship between nicotine and memory reconsolidation. In this study, we investigated the effects of nicotine on the reconsolidation of novel object recognition memory in rats. Behavior procedure involved four training phases: habituation (Days 1 and 2), sample (Day 3), reactivation (Day 4) and test (Day 6). Rats were injected with saline or nicotine (0.1, 0.2 and 0.4 mg/kg) immediately or 6 h after reactivation. The discrimination index was used to assess memory performance and calculated as the difference in time exploring on the novel and familiar objects. Results showed that nicotine administration immediately but not 6 h after reactivation significantly enhanced memory performance of rats. Further results showed that the enhancing effect of nicotine on memory performance was dependent on memory reactivation, and was not attributed to the changes of the nonspecific responses (locomotor activity and anxiety level) 48 h after nicotine administration. The results suggest that post-reactivation nicotine administration enhances the reconsolidation of novel object recognition memory. Our present finding extends previous research on the nicotinic effects on learning and memory. © 2014 Elsevier Inc. All rights reserved.
1. Introduction According to the traditional memory consolidation hypothesis, newly acquired memory is initially present in a transient unstable state in which the memory trace can be disrupted by various treatments, but becomes resistant to disruption over time (Alberini, 2005). This process is called memory consolidation. However, a wellconsolidated memory could be again rendered labile and susceptible to disruption upon its reactivation. Memory reconsolidation refers to the process by which memories that have been destabilized by reactivation are restabilized (Dudai, 2006). It is proposed that memory reconsolidation is a vital mechanism of memory modification by which the memory maintains relevant to present and future behaviors (Lee, 2009). Although the issue of memory reconsolidation remains controversial (Lattal and Abel, 2004; Miller and Matzel, 2000), the reconsolidation of memories has been observed in many species including invertebrates and vertebrates (Reichelt and Lee, 2013). Numerous studies have suggested that consolidation and reconsolidation share brain circuits and molecular processes, but the neuronal mechanisms
⁎ Corresponding author. Tel.: +86 13974709033; fax: +86 734 8281389. E-mail address: [email protected] (Y. You). 1 These authors contributed to this paper equally.
http://dx.doi.org/10.1016/j.pbb.2014.11.019 0091-3057/© 2014 Elsevier Inc. All rights reserved.
involved do not completely overlap (Lee et al., 2004; Lee and Hynds, 2012; Taubenfeld et al., 2001). Declarative memory refers to a conscious memory for events and facts and is often subdivided into semantic memory (memory for general information) and episodic memory (memory for personal events) (Squire and Zola, 1996). Declarative memory is usually thought to be acquired with relatively few exposures to the material to be learned. The novel object recognition (NOR) memory task is a simple behavioral assay of memory that relies primarily on the spontaneous tendency of rats to explore a novel object more than a familiar one in the absence of externally applied rules or reinforcement (Antunes and Biala, 2012). Currently the NOR task has become a widely used paradigm for the investigation of the neurobiology of mammalian declarative memory (Winters et al., 2008). Similar to other types of memories, NOR memory can be modified by various pharmacological treatments. For example, microinfusion of a protein synthesis inhibitor anisomycin into the dorsal hippocampus or the ventromedial prefrontal cortex impaired consolidation and reconsolidation of NOR memory (Akirav and Maroun, 2006; Rossato et al., 2007). Recent studies have suggested an important role of nicotinic acetylcholine receptors (nAChRs) in a variety of learning and memory, such as fear conditioning (Tian et al., 2008), spatial learning (Sharifzadeh et al., 2005), trace eyeblink conditioning (Brown et al., 2010), and various forms of recognition memories (Boess et al., 2007; Froeliger et al.,
S. Tian et al. / Pharmacology, Biochemistry and Behavior 129 (2015) 14–18
2009; Kenney et al., 2011; Puma et al., 1999; Tinsley et al., 2011). Activation of nAChRs typically enhances the NOR memory by promoting stronger memory encoding, consolidation or/and retrieval (Boess et al., 2007; Melichercik et al., 2012; Obinu et al., 2002; Puma et al., 1999). To date, however, whether nicotine affects the reconsolidation of NOR memory remains to be elucidated. In the present study, we explored the effects of post-reactivation nicotine administration on the reconsolidation of NOR memory in rats. 2. Material and methods 2.1. Subject The subjects were adult male Sprague-Dawley rats (230–250 g) obtained from the Laboratory Animal Center of University of South China, Hengyang, China. After arrival, the rats were housed individually in a temperature- and humidity-controlled room with ad libitum access to food and water. Animals were maintained on a 12 h light/dark schedule, with lights on at 7 A.M. After being housed, the rats were handled (3–5 min per rat per day) for 1 week to habituate them to the experimenter. Experiments were conducted according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals, and experimental protocols were approved by the animal care and use committee of University of South China. 2.2. Behavioral apparatus As we have previously described (He et al., 2013), the training apparatus consisted of two similar black Plexiglas boxes (50 × 50 × 40 cm) which were used to test 2 animals at the same time respectively. Each box was placed in a sound-attenuating cabinet which was located in a brightly lit and isolated room. Illumination was provided by a 15 W white house light mounted on the ceiling of cabinet, and a 65 dB background noise was supplied by a ventilation fan in the cabinet. The floor of the box was covered with sawdust. The objects used in the test were made of water-repellant materials such as glass and plastic with differences in shape and color. The sizes of the objects were about 6 × 6 × 8 cm. Objects were fixed to the floor of the training apparatus, 10 cm from the walls. The location and objects were counterbalanced to control for any preferences that the rats might have had for one of the corners or of the objects. The sawdust was stirred and the box and the objects were cleaned with 40% ethanol solution between trials. Exploration of an object was defined as pointing the nose to the object at a distance of b1 cm and/or touching it with the nose.
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The time spent on exploring each object and the total time spent on exploring both objects were recorded. The discrimination index used to assess memory performance was expressed as the difference in time exploring on the novel and familiar objects divided by the total time spent on exploring both objects (Ennaceur and Delacour, 1988). As described below in experiment 1, we observed that rats treated with nicotine at doses of 0.1 and 0.2 mg/kg presented an enhancement of memory performance on Day 6, which implies that nicotine may enhance the reconsolidation of NOR memory. To further strengthen our conclusion, three additional experiments (2, 3 and 4) were added. Experiment 2 was designed to evaluate the effects of nicotine administration 6 h after reactivation on NOR memory reconsolidation. Training procedures were as described in experiment 1, except that rats were injected intraperitoneally with saline or nicotine at a dose of 0.1 mg/kg, 6 h after reactivation on Day 4. According to a previous note (Nader et al., 2000), a valid criterion to consider a potential effect on reconsolidation is that such manipulation must be effective only following memory reactivation rather than when memory is not reactivated. Thus, Experiment 3 was designed to assess whether nicotine enhances NOR memory performance without the reactivation of memory. Training procedures were as described in experiment 1, except that on Day 4 rats were transported from their home cages and only received intraperitoneally saline or nicotine at a dose of 0.1 mg/kg (no reactivation). Experiment 4 was designed to study whether nicotine affects the nonspecific responses (locomotor activity and anxiety level) of rats 48 h after nicotine administration. The rats received intraperitoneally saline or nicotine at a dose of 0.1 mg/kg. Forty-eight hours after injection, rats were taken from their home cages and transported to the open field test chambers (60 × 60 × 50 cm) (Shanghai Jiliang Software Technology Co. Ltd., Shanghai, China) for 5 min and their behaviors were recorded as digital videos. The digital videos were then analyzed offline. The distance of rat traveling (defined as locomotor activity index) and the ratio of the time spent in the central zone to the time spent in the peripheral zone (defined as the anxiety level index) in the open field test chamber were analyzed by the commercial software provided by Shanghai Jiliang Software Technology Co. Ltd., Shanghai, China. 2.4. Statistical analyses Statistical analyses were performed using one-way ANOVA (SigmaStat 3.1). Post-hoc comparisons were performed with the Tukey HSD method. All data were represented as mean ± SEM. Significant level was set at p b 0.05.
2.3. Experiment design and procedure
3. Results
Experiment 1 was designed to evaluate the effects of nicotine administration immediately after reactivation on NOR memory reconsolidation. The behavioral procedure involved four phases: habituation, sample, reactivation and the test phase. On Days 1 and 2 (habituation phase), rats were taken from their home cages and transported to the training box for 5 min with no objects presented to habituate them to the training box. On Day 3 (sample phase), rats were transported from their home cages to the training box, and were exposed to 2 objects (A and B) for 4 min as described above. The total time spent on exploring both objects was recorded. On Day 4 (reactivation phase), rats were exposed to the same 2 sample objects (A and B) for a 2-min period to reactivate the memory trace. The total time spent on exploring both objects was recorded. Immediately after reactivation, rats were injected intraperitoneally with saline or nicotine hydrogen tartrate salt (Sigma Co., St. Louis, USA) at doses of 0.1, 0.2 and 0.4 mg/kg respectively. All nicotine doses are expressed as those of the freebase. On Day 6 (test phase), rats were exposed to a duplicate of an object from the sample/reactivation trial and a novel object for 2 min.
3.1. Experiment 1: effects of nicotine administration immediately after reactivation on NOR memory performance Fig. 1 shows the effects of nicotine administration immediately after reactivation on NOR memory performance in experiment 1. During the sample phase (Fig. 1A), a one-way ANOVA of the total time spent on exploring both objects found no significant differences between groups (F(3, 28) = 0.165, p N 0.05), indicating that the four groups showed equivalent levels of exploring objects. During the reactivation phase (Fig. 1B), a one-way ANOVA of the total time spent on exploring both objects found no significant differences between groups (F(3, 28) = 0.222, p N 0.05). During the test phase (Fig. 1C), a one-way ANOVA revealed a significant group effect (F(3, 28) = 6.199, p b 0.01). Post hoc comparisons showed that compared with saline treated rats, rats injected with nicotine at 0.1 and 0.2 mg presented a significantly higher discrimination index (p b 0.01 and p b 0.05, respectively). There was no significant difference in the discrimination index between saline and nicotine injected at 0.4 mg (p N 0.05).
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S. Tian et al. / Pharmacology, Biochemistry and Behavior 129 (2015) 14–18
Fig. 1. Nicotine administration immediately after reactivation enhances NOR memory performance in experiment 1. (A) The total time spent on exploring both objects is shown for the four groups on the sample phase. (B) The total time spent on exploring both objects is shown for the four groups on the reactivation phase. (C) The discrimination index is shown for the four groups on the test phase. ⁎p b 0.05 and ⁎⁎p b 0.01 versus saline group. N = 8 per treatment. All data are represented as mean ± SEM.
3.2. Experiment 2: effects of nicotine administration 6 h after reactivation on NOR memory performance Fig. 2 shows the effects of nicotine administration 6 h after reactivation on NOR memory performance. During the sample phase (Fig. 2A), a one-way ANOVA of the total time spent on exploring both objects revealed no significant group effect (F(1, 17) = 0.0316, p N 0.05), indicating that the two groups showed equivalent levels of exploration of objects. During the reactivation phase (Fig. 2B), a one-way ANOVA of the total time spent on exploring both objects revealed no significant group effect (F(1, 17) = 0.379, p N 0.05). During the test phase (Fig. 2C), a one-way ANOVA of discrimination index found no significant differences between groups (F(1, 17) = 0.0234, p N 0.05). 3.3. Experiment 3: effects of nicotine administration on NOR memory performance without memory reactivation Fig. 3 shows the effects of nicotine administration on NOR memory performance without memory reactivation in experiment 3. During the sample phase (Fig. 3A), a one-way ANOVA of the total time spent on exploring both objects found no significant differences between groups (F(1, 17) = 0.122, p N 0.05), indicating that the two groups showed equivalent levels of exploring both objects. During the test phase (Fig. 3B), a one-way ANOVA of discrimination index found no significant differences between groups (F(1, 17) = 0.215, p N 0.05). 3.4. Experiment 4: effects of nicotine administration on nonspecific responses Fig. 4 shows the effects of nicotine on nonspecific responses (locomotor activity and anxiety level) 48 h after nicotine administration.
For locomotor activity (Fig. 4A), a one-way ANOVA of the distance of rat traveling revealed no significant differences between groups (F(1, 22) = 0.0921, p N 0.05). For anxiety level (Fig. 4B), a one-way ANOVA of the ratio of time spent in the central zone to time spent in the peripheral zone found no significant differences between groups (F(1, 22) = 0.865, p N 0.05). 4. Discussion The aim of the present study was to explore the effects of postreactivation nicotine administration on the reconsolidation of NOR memory. In experiment 1, rats treated with nicotine at doses of 0.1 and 0.2 mg/kg but not 0.4 mg/kg immediately after reactivation presented a significantly higher discrimination index. The results are consistent with the suggestion that the nicotine administration or nicotinic receptor stimulation produces an inverted “U”-shaped dose– response curve on cognitive performance (Newhouse et al., 2004). It was important to rule out the possibility that nicotine may enhance memory performance without the reactivation of memory. To control for this possible effect (experiment 3), rats received nicotine (0.1 mg/kg) at the same time interval without reexposure to the training boxes (no reactivation) on Day 4. On Day 6, we found that there was no significant difference in the level of discrimination index between saline and nicotine-treated rats, indicating that the behavioral effect of nicotine on memory performance is dependent on memory reactivation. Another possibility is that nicotine may induce change of nonspecific responses (locomotor activity and anxiety level) of rats 48 h after nicotine administration. In order to further evaluate this possibility (experiment 4), nonspecific responses were assessed 48 h after rats received nicotine at a dose of 0.1 mg/kg. We found that saline and nicotine-treated rats showed a comparable level of locomotor activity
Fig. 2. Nicotine administration at a dose of 0.1 mg/kg 6 h after reactivation does not affect NOR memory performance in experiment 2. (A) The total time spent on exploring both objects was shown for the two groups on the sample phase. (B) The total time spent on exploring both objects was shown for the two groups on the reactivation phase. (C) The discrimination index was shown for the two groups on the test phase. N = 9–10 per treatment. All data are represented as mean ± SEM.
S. Tian et al. / Pharmacology, Biochemistry and Behavior 129 (2015) 14–18
Fig. 3. Nicotine administration at a dose of 0.1 mg/kg does not affect NOR memory performance without memory reactivation in experiment 3. (A) The total time spent on exploring both objects was shown for the two groups on the sample phase. (B) The discrimination index is shown for the two groups on the test phase. N = 9–10 per treatment. All data are represented as mean ± SEM.
and anxiety, indicating that the administration of nicotine at a dose of 0.1 mg does not result in the change of the nonspecific response 48 h after nicotine administration. Taken together, the data suggest that post-reactivation nicotine administration does enhance the reconsolidation of NOR memory. Previous studies have suggested that various agents affect the consolidation of new memories when administered during a specific time window (which varies from minutes to hours) after reactivation (Jobim et al., 2012; Nader et al., 2000). Administration of these drugs after this time window does not affect memory reconsolidation. For example, rapamycin impaired NOR memory reconsolidation when infused immediately but not 6 h after reactivation (Jobim et al., 2012). In the present study we found that nicotine administration immediately after reactivation enhanced NOR memory reconsolidation in experiment 1. We next asked whether a time window also exists for nicotinic effects on reconsolidation by delaying nicotine administration for 6 h after reactivation. In contrast to nicotine administration immediately after reactivation, nicotine administration 6 h after reactivation had no effect on reconsolidation in experiment 2. Thus, there is a specific time window that is critical for the nicotinic effect on the reconsolidation of NOR memory. There are a number of studies examining the effects of nAChR activation on NOR memory performance. The NOR task usually involves two phases: sample and test. The novel α7 nAChR agonists, such as EVP5141, EVP-6124 and ABBF, enhance NOR memory performance when administered before the sample phase in mice (Boess et al., 2007; Boess et al., 2013; Prickaerts et al., 2012). α7pep2, an interfering peptide
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that disrupts the α7 nAchR–NMDAR interaction, impairs NOR memory performance when administered before the test phase in mice (Li et al., 2013). Acute systemic nicotine administration enhances the acquisition, consolidation and retrieval of NOR memory (Puma et al., 1999). The enhancing effect of nicotine on the acquisition of NOR memory was further confirmed by a recent study; acute intra-perirhinal cortex or intrahippocampal infusions of nicotine facilitated NOR memory performance by promoting stronger encoding and/or consolidation of memory in rats (Melichercik et al., 2012). These studies suggest that nAChR activation typically enhances memory performance by affecting the acquisition, consolidation and retrieval of NOR memory. To date, however, there are no studies which explored the roles of nAChR activation in the reconsolidation of NOR memory. Our present results confirm previous findings in which nAChR activation by nicotine enhances NOR memory performance. Moreover, the enhancing effect of nicotine is mediated by affecting the reconsolidation of NOR memory. This is consistent with a previous study showing that nicotine enhanced memory performance when injected immediately after reactivation to rats subjected to a contextual fear conditioning task (Tian et al., 2011). The specific mechanism by which nicotine exerts its enhancing effect on memory reconsolidation remains unclear. It has been suggested that there is a set of brain structures involved in the acquisition, consolidation and retrieval of object recognition memory (Antunes and Biala, 2012; Winters et al., 2008). Early data from animal studies suggest that the hippocampus and/or amygdala are critical for object recognition memory (Melichercik et al., 2012; Murray and Mishkin, 1984; Zola-Morgan et al., 1982). Subsequent studies further suggest a vital role of the medial temporal lobe (especially the perirhinal cortex) in the performance of object recognition tasks (Melichercik et al., 2012; Murray and Mishkin, 1986; Winters et al., 2008). The involvement of nAChRs in cognitive function has been assessed widely in several brain regions such as the hippocampus, perirhinal cortex, amygdala and frontal cortex (Levin et al., 2006; Melichercik et al., 2012). Nicotine promotes the release of several neurotransmitters important for cognitive function including acetylcholine, dopamine, serotonin, gammaaminobutyric acid and glutamate (Wonnacott et al., 1989). Furthermore, a growing number of evidence demonstrates an important role of nAChR activation in synaptic plasticity mechanisms widely believed to underlie long-term memory formation and maintenance (Kenney and Gould, 2008). Possibly, nAChR activation triggers a variety of cellular and molecular processes that may contribute to the nicotinic effects on memory reconsolidation. It is interesting to explore this point in future studies. In conclusion, we demonstrated in this study that nicotine administration immediately but not 6 h after reactivation significantly enhances NOR memory performance. The results suggest that post-reactivation nicotine administration enhances the reconsolidation of NOR memory. Our present finding extends previous studies on the effects of nicotine on learning and memory. Acknowledgments This study was supported by the National Natural Science Foundation of China (81171281), the Science and Technology Project of Hunan Province (2013FJ3133), the Construct Program of the Key Discipline in Hunan Province and the Construct Program of the Key Discipline in University of South China. The authors wish to thank Dr. Moshe Laudon and Dr. Shujun Zhang for their editorial help.
Fig. 4. Nicotine administration at a dose of 0.1 mg/kg does not affect nonspecific responses (locomotor activity and anxiety level) 48 h after nicotine administration in experiment 4. (A) The distance of rat traveling (as locomotor activity index) in the open field test chamber is shown for the two groups. (B) The ratio of time spent in the central zone to time spent in the peripheral zone (defined as anxiety level index) in the open field test chamber is shown for the two groups. N = 12 per treatment. All data are represented as mean ± SEM.
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Contents lists available at ScienceDirect
Pharmacology, Biochemistry and Behavior journal homepage: www.elsevier.com/locate/pharmbiochembeh
Nicotine enhances the reconsolidation of novel object recognition memory in rats Shaowen Tian a,b,1, Si Pan c,1, Yong You c,⁎ a b c
Department of Physiology, College of Medicine, University of South China, Hengyang, Hunan 421001, PR China Institute of Neuroscience, College of Medicine, University of South China, Hengyang, Hunan 421001, PR China Department of Neurology, First Affiliated Hospital, University of South China, Hengyang, Hunan 421001, PR China
a r t i c l e
i n f o
Article history: Received 4 September 2014 Received in revised form 24 November 2014 Accepted 29 November 2014 Available online 4 December 2014 Keywords: Nicotine Object recognition memory Reactivation Reconsolidation Locomotor activity Rats
a b s t r a c t There is increasing evidence that nicotine is involved in learning and memory. However, there are only few studies that have evaluated the relationship between nicotine and memory reconsolidation. In this study, we investigated the effects of nicotine on the reconsolidation of novel object recognition memory in rats. Behavior procedure involved four training phases: habituation (Days 1 and 2), sample (Day 3), reactivation (Day 4) and test (Day 6). Rats were injected with saline or nicotine (0.1, 0.2 and 0.4 mg/kg) immediately or 6 h after reactivation. The discrimination index was used to assess memory performance and calculated as the difference in time exploring on the novel and familiar objects. Results showed that nicotine administration immediately but not 6 h after reactivation significantly enhanced memory performance of rats. Further results showed that the enhancing effect of nicotine on memory performance was dependent on memory reactivation, and was not attributed to the changes of the nonspecific responses (locomotor activity and anxiety level) 48 h after nicotine administration. The results suggest that post-reactivation nicotine administration enhances the reconsolidation of novel object recognition memory. Our present finding extends previous research on the nicotinic effects on learning and memory. © 2014 Elsevier Inc. All rights reserved.
1. Introduction According to the traditional memory consolidation hypothesis, newly acquired memory is initially present in a transient unstable state in which the memory trace can be disrupted by various treatments, but becomes resistant to disruption over time (Alberini, 2005). This process is called memory consolidation. However, a wellconsolidated memory could be again rendered labile and susceptible to disruption upon its reactivation. Memory reconsolidation refers to the process by which memories that have been destabilized by reactivation are restabilized (Dudai, 2006). It is proposed that memory reconsolidation is a vital mechanism of memory modification by which the memory maintains relevant to present and future behaviors (Lee, 2009). Although the issue of memory reconsolidation remains controversial (Lattal and Abel, 2004; Miller and Matzel, 2000), the reconsolidation of memories has been observed in many species including invertebrates and vertebrates (Reichelt and Lee, 2013). Numerous studies have suggested that consolidation and reconsolidation share brain circuits and molecular processes, but the neuronal mechanisms
⁎ Corresponding author. Tel.: +86 13974709033; fax: +86 734 8281389. E-mail address: [email protected] (Y. You). 1 These authors contributed to this paper equally.
http://dx.doi.org/10.1016/j.pbb.2014.11.019 0091-3057/© 2014 Elsevier Inc. All rights reserved.
involved do not completely overlap (Lee et al., 2004; Lee and Hynds, 2012; Taubenfeld et al., 2001). Declarative memory refers to a conscious memory for events and facts and is often subdivided into semantic memory (memory for general information) and episodic memory (memory for personal events) (Squire and Zola, 1996). Declarative memory is usually thought to be acquired with relatively few exposures to the material to be learned. The novel object recognition (NOR) memory task is a simple behavioral assay of memory that relies primarily on the spontaneous tendency of rats to explore a novel object more than a familiar one in the absence of externally applied rules or reinforcement (Antunes and Biala, 2012). Currently the NOR task has become a widely used paradigm for the investigation of the neurobiology of mammalian declarative memory (Winters et al., 2008). Similar to other types of memories, NOR memory can be modified by various pharmacological treatments. For example, microinfusion of a protein synthesis inhibitor anisomycin into the dorsal hippocampus or the ventromedial prefrontal cortex impaired consolidation and reconsolidation of NOR memory (Akirav and Maroun, 2006; Rossato et al., 2007). Recent studies have suggested an important role of nicotinic acetylcholine receptors (nAChRs) in a variety of learning and memory, such as fear conditioning (Tian et al., 2008), spatial learning (Sharifzadeh et al., 2005), trace eyeblink conditioning (Brown et al., 2010), and various forms of recognition memories (Boess et al., 2007; Froeliger et al.,
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2009; Kenney et al., 2011; Puma et al., 1999; Tinsley et al., 2011). Activation of nAChRs typically enhances the NOR memory by promoting stronger memory encoding, consolidation or/and retrieval (Boess et al., 2007; Melichercik et al., 2012; Obinu et al., 2002; Puma et al., 1999). To date, however, whether nicotine affects the reconsolidation of NOR memory remains to be elucidated. In the present study, we explored the effects of post-reactivation nicotine administration on the reconsolidation of NOR memory in rats. 2. Material and methods 2.1. Subject The subjects were adult male Sprague-Dawley rats (230–250 g) obtained from the Laboratory Animal Center of University of South China, Hengyang, China. After arrival, the rats were housed individually in a temperature- and humidity-controlled room with ad libitum access to food and water. Animals were maintained on a 12 h light/dark schedule, with lights on at 7 A.M. After being housed, the rats were handled (3–5 min per rat per day) for 1 week to habituate them to the experimenter. Experiments were conducted according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals, and experimental protocols were approved by the animal care and use committee of University of South China. 2.2. Behavioral apparatus As we have previously described (He et al., 2013), the training apparatus consisted of two similar black Plexiglas boxes (50 × 50 × 40 cm) which were used to test 2 animals at the same time respectively. Each box was placed in a sound-attenuating cabinet which was located in a brightly lit and isolated room. Illumination was provided by a 15 W white house light mounted on the ceiling of cabinet, and a 65 dB background noise was supplied by a ventilation fan in the cabinet. The floor of the box was covered with sawdust. The objects used in the test were made of water-repellant materials such as glass and plastic with differences in shape and color. The sizes of the objects were about 6 × 6 × 8 cm. Objects were fixed to the floor of the training apparatus, 10 cm from the walls. The location and objects were counterbalanced to control for any preferences that the rats might have had for one of the corners or of the objects. The sawdust was stirred and the box and the objects were cleaned with 40% ethanol solution between trials. Exploration of an object was defined as pointing the nose to the object at a distance of b1 cm and/or touching it with the nose.
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The time spent on exploring each object and the total time spent on exploring both objects were recorded. The discrimination index used to assess memory performance was expressed as the difference in time exploring on the novel and familiar objects divided by the total time spent on exploring both objects (Ennaceur and Delacour, 1988). As described below in experiment 1, we observed that rats treated with nicotine at doses of 0.1 and 0.2 mg/kg presented an enhancement of memory performance on Day 6, which implies that nicotine may enhance the reconsolidation of NOR memory. To further strengthen our conclusion, three additional experiments (2, 3 and 4) were added. Experiment 2 was designed to evaluate the effects of nicotine administration 6 h after reactivation on NOR memory reconsolidation. Training procedures were as described in experiment 1, except that rats were injected intraperitoneally with saline or nicotine at a dose of 0.1 mg/kg, 6 h after reactivation on Day 4. According to a previous note (Nader et al., 2000), a valid criterion to consider a potential effect on reconsolidation is that such manipulation must be effective only following memory reactivation rather than when memory is not reactivated. Thus, Experiment 3 was designed to assess whether nicotine enhances NOR memory performance without the reactivation of memory. Training procedures were as described in experiment 1, except that on Day 4 rats were transported from their home cages and only received intraperitoneally saline or nicotine at a dose of 0.1 mg/kg (no reactivation). Experiment 4 was designed to study whether nicotine affects the nonspecific responses (locomotor activity and anxiety level) of rats 48 h after nicotine administration. The rats received intraperitoneally saline or nicotine at a dose of 0.1 mg/kg. Forty-eight hours after injection, rats were taken from their home cages and transported to the open field test chambers (60 × 60 × 50 cm) (Shanghai Jiliang Software Technology Co. Ltd., Shanghai, China) for 5 min and their behaviors were recorded as digital videos. The digital videos were then analyzed offline. The distance of rat traveling (defined as locomotor activity index) and the ratio of the time spent in the central zone to the time spent in the peripheral zone (defined as the anxiety level index) in the open field test chamber were analyzed by the commercial software provided by Shanghai Jiliang Software Technology Co. Ltd., Shanghai, China. 2.4. Statistical analyses Statistical analyses were performed using one-way ANOVA (SigmaStat 3.1). Post-hoc comparisons were performed with the Tukey HSD method. All data were represented as mean ± SEM. Significant level was set at p b 0.05.
2.3. Experiment design and procedure
3. Results
Experiment 1 was designed to evaluate the effects of nicotine administration immediately after reactivation on NOR memory reconsolidation. The behavioral procedure involved four phases: habituation, sample, reactivation and the test phase. On Days 1 and 2 (habituation phase), rats were taken from their home cages and transported to the training box for 5 min with no objects presented to habituate them to the training box. On Day 3 (sample phase), rats were transported from their home cages to the training box, and were exposed to 2 objects (A and B) for 4 min as described above. The total time spent on exploring both objects was recorded. On Day 4 (reactivation phase), rats were exposed to the same 2 sample objects (A and B) for a 2-min period to reactivate the memory trace. The total time spent on exploring both objects was recorded. Immediately after reactivation, rats were injected intraperitoneally with saline or nicotine hydrogen tartrate salt (Sigma Co., St. Louis, USA) at doses of 0.1, 0.2 and 0.4 mg/kg respectively. All nicotine doses are expressed as those of the freebase. On Day 6 (test phase), rats were exposed to a duplicate of an object from the sample/reactivation trial and a novel object for 2 min.
3.1. Experiment 1: effects of nicotine administration immediately after reactivation on NOR memory performance Fig. 1 shows the effects of nicotine administration immediately after reactivation on NOR memory performance in experiment 1. During the sample phase (Fig. 1A), a one-way ANOVA of the total time spent on exploring both objects found no significant differences between groups (F(3, 28) = 0.165, p N 0.05), indicating that the four groups showed equivalent levels of exploring objects. During the reactivation phase (Fig. 1B), a one-way ANOVA of the total time spent on exploring both objects found no significant differences between groups (F(3, 28) = 0.222, p N 0.05). During the test phase (Fig. 1C), a one-way ANOVA revealed a significant group effect (F(3, 28) = 6.199, p b 0.01). Post hoc comparisons showed that compared with saline treated rats, rats injected with nicotine at 0.1 and 0.2 mg presented a significantly higher discrimination index (p b 0.01 and p b 0.05, respectively). There was no significant difference in the discrimination index between saline and nicotine injected at 0.4 mg (p N 0.05).
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Fig. 1. Nicotine administration immediately after reactivation enhances NOR memory performance in experiment 1. (A) The total time spent on exploring both objects is shown for the four groups on the sample phase. (B) The total time spent on exploring both objects is shown for the four groups on the reactivation phase. (C) The discrimination index is shown for the four groups on the test phase. ⁎p b 0.05 and ⁎⁎p b 0.01 versus saline group. N = 8 per treatment. All data are represented as mean ± SEM.
3.2. Experiment 2: effects of nicotine administration 6 h after reactivation on NOR memory performance Fig. 2 shows the effects of nicotine administration 6 h after reactivation on NOR memory performance. During the sample phase (Fig. 2A), a one-way ANOVA of the total time spent on exploring both objects revealed no significant group effect (F(1, 17) = 0.0316, p N 0.05), indicating that the two groups showed equivalent levels of exploration of objects. During the reactivation phase (Fig. 2B), a one-way ANOVA of the total time spent on exploring both objects revealed no significant group effect (F(1, 17) = 0.379, p N 0.05). During the test phase (Fig. 2C), a one-way ANOVA of discrimination index found no significant differences between groups (F(1, 17) = 0.0234, p N 0.05). 3.3. Experiment 3: effects of nicotine administration on NOR memory performance without memory reactivation Fig. 3 shows the effects of nicotine administration on NOR memory performance without memory reactivation in experiment 3. During the sample phase (Fig. 3A), a one-way ANOVA of the total time spent on exploring both objects found no significant differences between groups (F(1, 17) = 0.122, p N 0.05), indicating that the two groups showed equivalent levels of exploring both objects. During the test phase (Fig. 3B), a one-way ANOVA of discrimination index found no significant differences between groups (F(1, 17) = 0.215, p N 0.05). 3.4. Experiment 4: effects of nicotine administration on nonspecific responses Fig. 4 shows the effects of nicotine on nonspecific responses (locomotor activity and anxiety level) 48 h after nicotine administration.
For locomotor activity (Fig. 4A), a one-way ANOVA of the distance of rat traveling revealed no significant differences between groups (F(1, 22) = 0.0921, p N 0.05). For anxiety level (Fig. 4B), a one-way ANOVA of the ratio of time spent in the central zone to time spent in the peripheral zone found no significant differences between groups (F(1, 22) = 0.865, p N 0.05). 4. Discussion The aim of the present study was to explore the effects of postreactivation nicotine administration on the reconsolidation of NOR memory. In experiment 1, rats treated with nicotine at doses of 0.1 and 0.2 mg/kg but not 0.4 mg/kg immediately after reactivation presented a significantly higher discrimination index. The results are consistent with the suggestion that the nicotine administration or nicotinic receptor stimulation produces an inverted “U”-shaped dose– response curve on cognitive performance (Newhouse et al., 2004). It was important to rule out the possibility that nicotine may enhance memory performance without the reactivation of memory. To control for this possible effect (experiment 3), rats received nicotine (0.1 mg/kg) at the same time interval without reexposure to the training boxes (no reactivation) on Day 4. On Day 6, we found that there was no significant difference in the level of discrimination index between saline and nicotine-treated rats, indicating that the behavioral effect of nicotine on memory performance is dependent on memory reactivation. Another possibility is that nicotine may induce change of nonspecific responses (locomotor activity and anxiety level) of rats 48 h after nicotine administration. In order to further evaluate this possibility (experiment 4), nonspecific responses were assessed 48 h after rats received nicotine at a dose of 0.1 mg/kg. We found that saline and nicotine-treated rats showed a comparable level of locomotor activity
Fig. 2. Nicotine administration at a dose of 0.1 mg/kg 6 h after reactivation does not affect NOR memory performance in experiment 2. (A) The total time spent on exploring both objects was shown for the two groups on the sample phase. (B) The total time spent on exploring both objects was shown for the two groups on the reactivation phase. (C) The discrimination index was shown for the two groups on the test phase. N = 9–10 per treatment. All data are represented as mean ± SEM.
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Fig. 3. Nicotine administration at a dose of 0.1 mg/kg does not affect NOR memory performance without memory reactivation in experiment 3. (A) The total time spent on exploring both objects was shown for the two groups on the sample phase. (B) The discrimination index is shown for the two groups on the test phase. N = 9–10 per treatment. All data are represented as mean ± SEM.
and anxiety, indicating that the administration of nicotine at a dose of 0.1 mg does not result in the change of the nonspecific response 48 h after nicotine administration. Taken together, the data suggest that post-reactivation nicotine administration does enhance the reconsolidation of NOR memory. Previous studies have suggested that various agents affect the consolidation of new memories when administered during a specific time window (which varies from minutes to hours) after reactivation (Jobim et al., 2012; Nader et al., 2000). Administration of these drugs after this time window does not affect memory reconsolidation. For example, rapamycin impaired NOR memory reconsolidation when infused immediately but not 6 h after reactivation (Jobim et al., 2012). In the present study we found that nicotine administration immediately after reactivation enhanced NOR memory reconsolidation in experiment 1. We next asked whether a time window also exists for nicotinic effects on reconsolidation by delaying nicotine administration for 6 h after reactivation. In contrast to nicotine administration immediately after reactivation, nicotine administration 6 h after reactivation had no effect on reconsolidation in experiment 2. Thus, there is a specific time window that is critical for the nicotinic effect on the reconsolidation of NOR memory. There are a number of studies examining the effects of nAChR activation on NOR memory performance. The NOR task usually involves two phases: sample and test. The novel α7 nAChR agonists, such as EVP5141, EVP-6124 and ABBF, enhance NOR memory performance when administered before the sample phase in mice (Boess et al., 2007; Boess et al., 2013; Prickaerts et al., 2012). α7pep2, an interfering peptide
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that disrupts the α7 nAchR–NMDAR interaction, impairs NOR memory performance when administered before the test phase in mice (Li et al., 2013). Acute systemic nicotine administration enhances the acquisition, consolidation and retrieval of NOR memory (Puma et al., 1999). The enhancing effect of nicotine on the acquisition of NOR memory was further confirmed by a recent study; acute intra-perirhinal cortex or intrahippocampal infusions of nicotine facilitated NOR memory performance by promoting stronger encoding and/or consolidation of memory in rats (Melichercik et al., 2012). These studies suggest that nAChR activation typically enhances memory performance by affecting the acquisition, consolidation and retrieval of NOR memory. To date, however, there are no studies which explored the roles of nAChR activation in the reconsolidation of NOR memory. Our present results confirm previous findings in which nAChR activation by nicotine enhances NOR memory performance. Moreover, the enhancing effect of nicotine is mediated by affecting the reconsolidation of NOR memory. This is consistent with a previous study showing that nicotine enhanced memory performance when injected immediately after reactivation to rats subjected to a contextual fear conditioning task (Tian et al., 2011). The specific mechanism by which nicotine exerts its enhancing effect on memory reconsolidation remains unclear. It has been suggested that there is a set of brain structures involved in the acquisition, consolidation and retrieval of object recognition memory (Antunes and Biala, 2012; Winters et al., 2008). Early data from animal studies suggest that the hippocampus and/or amygdala are critical for object recognition memory (Melichercik et al., 2012; Murray and Mishkin, 1984; Zola-Morgan et al., 1982). Subsequent studies further suggest a vital role of the medial temporal lobe (especially the perirhinal cortex) in the performance of object recognition tasks (Melichercik et al., 2012; Murray and Mishkin, 1986; Winters et al., 2008). The involvement of nAChRs in cognitive function has been assessed widely in several brain regions such as the hippocampus, perirhinal cortex, amygdala and frontal cortex (Levin et al., 2006; Melichercik et al., 2012). Nicotine promotes the release of several neurotransmitters important for cognitive function including acetylcholine, dopamine, serotonin, gammaaminobutyric acid and glutamate (Wonnacott et al., 1989). Furthermore, a growing number of evidence demonstrates an important role of nAChR activation in synaptic plasticity mechanisms widely believed to underlie long-term memory formation and maintenance (Kenney and Gould, 2008). Possibly, nAChR activation triggers a variety of cellular and molecular processes that may contribute to the nicotinic effects on memory reconsolidation. It is interesting to explore this point in future studies. In conclusion, we demonstrated in this study that nicotine administration immediately but not 6 h after reactivation significantly enhances NOR memory performance. The results suggest that post-reactivation nicotine administration enhances the reconsolidation of NOR memory. Our present finding extends previous studies on the effects of nicotine on learning and memory. Acknowledgments This study was supported by the National Natural Science Foundation of China (81171281), the Science and Technology Project of Hunan Province (2013FJ3133), the Construct Program of the Key Discipline in Hunan Province and the Construct Program of the Key Discipline in University of South China. The authors wish to thank Dr. Moshe Laudon and Dr. Shujun Zhang for their editorial help.
Fig. 4. Nicotine administration at a dose of 0.1 mg/kg does not affect nonspecific responses (locomotor activity and anxiety level) 48 h after nicotine administration in experiment 4. (A) The distance of rat traveling (as locomotor activity index) in the open field test chamber is shown for the two groups. (B) The ratio of time spent in the central zone to time spent in the peripheral zone (defined as anxiety level index) in the open field test chamber is shown for the two groups. N = 12 per treatment. All data are represented as mean ± SEM.
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