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Research report

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Acute restraint stress and corticosterone transiently disrupts novelty preference in an object recognition task

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Viviana Vargas-López a,c , Angélica Torres-Berrio a,b , Lina González-Martínez a,b , Alejandro Múnera a,c , Marisol R. Lamprea a,b,∗ a

Behavioral Neurophysiology Laboratory, Universidad Nacional de Colombia, Bogotá, Colombia Psychology Department, School of Human Sciences, Universidad Nacional de Colombia, Bogotá, Colombia c Physiological Sciences Department, School of Medicine, Universidad Nacional de Colombia, Bogotá, Colombia b

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Rats underwent movement restraint before training in an object recognition task. Pretraining stress impaired novel object preference at short- but not at long-term. Other rats were given corticosterone before being tested in object recognition task. Pretest corticosterone impaired novel object preference at short- and long-term test. Acute stress- or corticosterone-induced novelty aversion may explain such findings.

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Article history: Received 11 February 2015 Received in revised form 4 May 2015 Accepted 8 May 2015 Available online xxx

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Keywords: Acute stress Corticosterone Object recognition task Memory retrieval Novelty Rat

The object recognition task is a procedure based on rodents’ natural tendency to explore novel objects which is frequently used for memory testing. However, in some instances novelty preference is replaced by familiarity preference, raising questions regarding the validity of novelty preference as a pure recognition memory index. Acute stress- and corticosterone administration-induced novel object preference disruption has been frequently interpreted as memory impairment; however, it is still not clear whether such effect can be actually attributed to either mnemonic disruption or altered novelty seeking. Seventyfive adult male Wistar rats were trained in an object recognition task and subjected to either acute stress or corticosterone administration to evaluate the effect of stress or corticosterone on an object recognition task. Acute stress was induced by restraining movement for 1 or 4 h, ending 30 min before the sample trial. Corticosterone was injected intraperitoneally 10 min before the test trial which was performed either 1 or 24 h after the sample trial. Four-hour, but not 1-h, stress induced familiar object preference during the test trial performed 1 h after the sample trial; however, acute stress had no effects on the test when performed 24 h after sample trial. Systemic administration of corticosterone before the test trial performed either 1 or 24 h after the sample trial also resulted in familiar object preference. However, neither acute stress nor corticosterone induced changes in locomotor behaviour. Taken together, such results suggested that acute stress probably does not induce memory retrieval impairment but, instead, induces an emotional arousing state which motivates novelty avoidance. © 2015 Published by Elsevier B.V.

1. Introduction Abbreviations: cf, confer; DI, discrimination index; FO, familiar object; NO, novel object; ORT, object recognition task; ORM, object recognition memory. ∗ Corresponding author. Current address: Laboratorio de Neurociencias, Departamento de Psicología, Facultad de Ciencias Humanas, Universidad Nacional de Colombia, Edificio 212, Oficina 218, Carrera 30 No 45-03, Ciudad Universitaria, 111321 Bogotá, D.C., Colombia. Tel.: +57 1 3165000x16373; fax: +57 1 3165000x15114. E-mail addresses: [email protected], [email protected] (M.R. Lamprea).

Stress response encompasses a series of physiological reactions Q2 directly or indirectly eliciting behavioural, emotional and cognitive modifications (Lupien and McEwen, 1997; Roozendaal, 2002; Joëls et al., 2006). It has been reported that the effect of stress on memory varies regarding source, duration and intensity of the stressor, the timing of the stressor regarding memory phase and the type of task used (Sandi and Pinelo-Nava, 2007). Stress induced either shortly before or immediately after training generally enhances memory

http://dx.doi.org/10.1016/j.bbr.2015.05.006 0166-4328/© 2015 Published by Elsevier B.V.

Please cite this article in press as: Vargas-López V, et al. Acute restraint stress and corticosterone transiently disrupts novelty preference in an object recognition task. Behav Brain Res (2015), http://dx.doi.org/10.1016/j.bbr.2015.05.006

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consolidation; however, when stress is induced before retrieval it usually produces a harmful effect on memory (de Quervain et al., 1998; Roozendaal, 2002, 2003). Several studies have described an inverted-U pattern for stress effects on memory, i.e. either low or high levels of stress or corticoids impair memory, whereas intermediate levels enhance memory (Sandi and Pinelo-Nava, 2007; Lupien et al., 2009). The object recognition task (ORT; Ennaceur and Delacour, 1988) is a procedure in which rodents show their ability to discriminate familiar from novel objects, based on their natural tendency to explore novel features in their environment (Aggleton, 1985; Mumby, 2001; Mumby et al., 2007; Dere et al., 2007). Some experiments involving ORT have demonstrated that either acute stress or corticosterone administration disrupt novel object preference during a test trial and have stated that this effect is caused by memory retrieval impairment (Morrow et al., 2000; Baker and Kim, 2002; Okuda et al., 2004; Howland and Cazakoff, 2010; Li et al., 2012). However, it is still not clear whether such effects can be attributed to memory impairment exclusively (Cazakoff et al., 2010), emotional changes-induced memory derailment (Rosellini and Widman, 1989; Okuda et al., 2004; Urani et al., 2011), or perturbed novelty seeking (Eagle et al., 2013). Frequently novelty preference and object recognition concepts are used as interchangeable but, since in some instances novelty preference is substituted by familiarity preference, it is questionable whether novelty preference provides a valid index of recognition memory. Furthermore, objects’ features, emotional state, or delay between sessions in the ORT can alter object exploration without implying lack of novelty recognition or memory impairment (Ennaceur, 2010). It has been described in rodents that novel object exploration is reduced by either acute stress (Rosellini and Widman, 1989) or pathogen-induced increased glucocorticoid levels (Kawashima and Kusnecov, 2002). In spite of the aforementioned findings, deleterious effects of stress on ORT has usually been interpreted as memory retrieval impairment. In the present study, we evaluated acute stress and systemic corticosterone administration effects on ORT and, based on the results, we pose the hypothesis that altered object exploration during test trial is due to stress-induced transient novelty avoidance, rather than memory retrieval impairment.

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Seventy-five, 66 ± 4 day old (mean ± standard error of the mean), naïve, male Wistar rats, weighing 275 ± 4 g at the beginning of the experiments, and supplied by the Instituto Nacional de Salud (Bogotá, Colombia) were used as subjects. The animals were housed in a sound-attenuated room (vivarium) in polycarbonate cages (32 cm × 38 cm × 18 cm) in groups of four with free access to water and food during the whole experiment and kept in controlled environmental conditions: 12-h light/dark cycle (lights on from 07:00 to 19:00), 20 ± 1 ◦ C room temperature and 50 ± 10% relative humidity. The subjects were kept in the vivarium for one week before any experimental procedure to allow them to become acclimatised to their new housing conditions. Behavioural procedures were conducted between 08:00 and 13:00 to avoid the circadian rise in corticosterone secretion. All experimental procedures were performed according to local and international guidelines (NIH Guide for the Use and Care of Laboratory Animals) and were approved by the local Ethics Committee (School of Medicine, Universidad Nacional de Colombia). All efforts were made to minimise the number of animals and avoid experimental subjects’ unnecessary suffering.

2.2. Procedures 2.2.1. Object recognition task The ORT was evaluated using a black acrylic open field (60 cm × 60 cm × 60 cm) placed in a sound-attenuated experimental room provided with a white-noise generator. Two overhead, 100-W, white-light bulbs were orientated so as to obtain uniform illumination of the whole open field. The objects used during ORT sample and test trials were black acrylic rectangular prisms (14 cm high × 6 cm deep × 14 cm wide) or pyramids (14 cm high × 14 cm wide) which were heavy enough to ensure that they could not easily be displaced by a rat and had different textures (smooth or rough). The use of texture as novelty cue was based on a previous study in our laboratory (Moreno et al., 2010). Olfactive clues were removed after every trial by thoroughly cleansing the objects and the open field with 10% ethanol solution. Subjects were handled gently every day for 5 min during acclimatisation to minimise manipulation-related stress. ORT consisted of three 10-min trials on either two or three days (Fig. 1). Each animal was placed in the open field during the first trial (habituation trial) and allowed to freely explore it for 10 min. The habituation trial was aimed at reducing novelty responses to the open field and to rule out any idiosyncratic place preference. During the second trial (sample trial), 24 h after the habituation trial, each animal was placed in the open field containing two objects which were identical in shape and texture (either two smooth rectangular prisms or two rough rectangular prisms, named familiar objects (FO)), located near two randomly chosen opposite corners (12 cm away from the walls). During the third trial (test trial), performed either one or 24 h after the sample trial, each animal was placed in the open field containing two objects: a FO and a novel object (NO) which were identical in shape but different in texture to FO, located in the same corners used during the sample trial. The subjects’ locomotor behaviour, object texture during sample trial and NO position during test trial was counterbalanced between animals in each group to reduce potential bias due either to non-specific locomotor behaviour differences or idiosyncratic place and/or texture preferences. In spite of it having been frequently reported that object recognition memory (ORM) lasts for a few hours, our group has previously demonstrated that ORM may last for up to 24 h when acquired and tested using trials lasting 10 min (Moreno et al., 2010; Nava-Mesa et al., 2013). 2.2.2. Acute stress induction Acute stress was induced by movement restraint for 1 or 4 h (Pacák and Palkovitz, 2001; Buynitsky and Mostofsky, 2009). Subjects randomly assigned to be submitted to stress were gently placed in polycarbonate cylinders (20 cm long, 6.5 cm in diameter) for either 1 or 4 h; these were designed to restrain major head and limb movement. The subjects were allowed to get out of the restrainers 30 min before sample trial and to move freely around their home cages to avoid non-specific motor effects due to movement restriction. Control subjects stayed in their home cage before sample trial. 2.2.3. Drugs Corticosterone-2-hydroxypropyl-b-cyclodextrin complex (Sigma, St Louis, MO, USA) was dissolved in saline to reach a final 0.125 mg/ml corticosterone concentration (Haller et al., 2001). A 1 ml/kg dose of this solution was injected intraperitoneally into subjects designated to receive corticosterone. The final dose (0.125 mg/kg) was chosen on the basis of previous pilot experiments demonstrating the harmful effects of this dose on spatial memory retrieval (unpublished data) and, in previous studies, demonstrating that such dose induces corticosterone levels similar

Please cite this article in press as: Vargas-López V, et al. Acute restraint stress and corticosterone transiently disrupts novelty preference in an object recognition task. Behav Brain Res (2015), http://dx.doi.org/10.1016/j.bbr.2015.05.006

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Fig. 1. Timeline for the experimental procedures. (A) To evaluate how acute stress administered before training modified subjects’ performance on ORT, one third of the animals remained in their cages without stress and the remaining two thirds of the subjects were subjected to movement restriction for either 1 or 4 h just before sample trial. Trained subjects were randomly assigned to be evaluated either one or 24 h after sample trial. (B) To evaluate how corticosterone modified subjects’ performance on ORT when administered before the test trial, subjects underwent a sample trial. Trained subjects were randomly assigned to be evaluated either one or 24 h after sample trial. Half of the subjects assigned to be evaluated at a given time were randomly assigned to receive intraperitoneal injection of vehicle whilst the remainder received an intraperitoneal corticosterone injection.

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to those obtained with restraint-induced stress (Haller et al., 2001). A 1 ml/kg dose of 0.9% saline was injected intraperitoneally into subjects designated to receive vehicle. Corticosterone or saline was injected intraperitoneally 10 min before the test trial. 2.3. Experimental design Subjects were randomly assigned to one of the following groups to evaluate the effect of acute stress on short-term or long-term performance on the ORT (Fig. 1A): (1) control, no stress was induced before sample trial (n = 17); (2) 1-h stress, subjects were subjected to movement restraint for 1 h before sample trial (n = 17) and (3) 4-h stress, subjects were subjected to movement restraint for 4 h before sample trial (n = 17). The subjects in each group were then randomly assigned to be tested either 1 (n = 8) or 24 (n = 9) h after sample trial. Subjects having experienced sample trial were randomly assigned to one of the following groups to evaluate corticosterone effect on short- and long-term ORT performance (Fig. 1B): (1) vehicle-injected, subjects received an intraperitoneal injection of saline before test trial (n = 12); or (2) corticosterone-injected, subjects received an intraperitoneal injection of corticosterone before test trial (n = 12). The subjects in each group were then randomly assigned to be tested either 1 (n = 6) or 24 (n = 6) h after the sample trial. 2.4. Data recording and analysis Each subject’s behaviour during the experimental trials was observed and recorded by a video camera linked to a video recorder and a video monitor located in an adjacent room. All behavioural measurements were made off-line by a researcher blind to the experimental treatments using X-Plo-Rat 2005 software developed by Exploratory Behavior Laboratory at the Sao Paulo University in Ribeirao Preto, Brazil. The open field was virtually divided into nine squares (20 cm × 20 cm each) and the number of complete crossings from one square to another was counted to evaluate locomotive activity. Each trial was divided into five, 2-min intervals and relative number of crossings per interval was used to evaluate open field habituation. Object exploration was defined as sniffing, touching the object with the nose, or pointing the nose towards the object from a distance shorter than 2 cm. Accordingly, the number (frequency) and

duration (time) of explorations of each object were recorded for each sample or test trial and expressed as a percentage of total exploration (relative exploration frequency and time) to evaluate object preference. One rat spending less than 20 s exploring the objects on sample trial was excluded from analysis since pilot experiments indicated that such rats do not adequately acquire the task (unpublished data). The missing animal was replaced with a new one. Additionally, discrimination indexes (DI) were calculated based on the difference in exploration frequency and time for each object during a given trial (a similar index has been used by Okuda et al., 2004). DI for the sample trial were calculated as the difference in exploration frequency or time between each familiar object (FO1 and FO2, respectively) divided by the total number of explorations or time for both objects: 100*(FO1 − FO2)/(FO1 + FO2). For test trials, DI were calculated as the difference in exploration frequency or time between novel object and familiar object (NO and FO, respectively) divided by total number of explorations or time for both objects: 100*(NO − FO)/(NO + FO). Such DI allowed intergroup comparison of the subjects’ preference for the NO in a given trial. The subjects’ behavioural measurements were grouped for intergroup comparison. Changes in locomotor activity or in DI for each group were characterised during each ORT trial using either one-way ANOVA followed by post-hoc comparison using the Holm-Sidak method (to evaluate acute stress effect) or Student’s t-test (to evaluate corticosterone effect). Object preference was evaluated by comparing each group’s DI with the DI displayed by all non-stressed subjects (n = 41) during the sample trial (empirical zero) using Student’s t-test. Significance level was set at p < 0.05.

3. Results 3.1. Neither stress nor corticosterone changed locomotor activity in the open field The number of crossings in the open field decreased during successive time intervals in habituation trial (F(4, 200) = 32.643; p < 0.0001; interval 1 cf interval 2: t = 4.206, p < 0.0001; interval 1 cf interval 3: t = 6.132, p < 0.0001; interval 1 cf interval 4: t = 8.270, p < 0.0001; interval 1 cf interval 5: t = 8.270, p < 0.0001). Furthermore, there were no statistical differences regarding crossings between stressed and non-stressed animals during sample and test trials in the experiments designed to evaluate the effect

Please cite this article in press as: Vargas-López V, et al. Acute restraint stress and corticosterone transiently disrupts novelty preference in an object recognition task. Behav Brain Res (2015), http://dx.doi.org/10.1016/j.bbr.2015.05.006

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Fig. 2. Acute stress induced before sample trial did not affect locomotive activity but impaired performance on short-term memory test. (A) Bar plot illustrating the total number of crossings through open-field zone borders. (B and C) Bar plots illustrating exploration frequency (B) and exploration time (C) DI. Left-hand bars illustrate subjects’ performance during sample trial; right-hand side bars illustrate subjects’ performance during short-term memory test. Each bar represents the group’s mean + standard deviation (white bars, control; grey bars, 1-h stress; black bars, 4-h stress). Dotted lines represent upper and lower limits of the empirical zero’s 99.9% confidence interval. Locomotive activity was not significantly different between groups during sample trial and short-term memory test. Animals from all groups displayed indistinct exploration of both objects during sample trial. While control animals preferentially explored the NO, 4-h stressed animals preferred to explore the FO during short-term memory test. One-hour stressed animals partially displayed a preference for NO. Abbreviations: * indicates a significant difference regarding the performance of control group subjects during the same trial; § indicates a significant difference regarding empirical zero.

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of stress on ORT performance in either the short- (Fig. 2A; sample trial: F(2, 21) = 0.900, p = 0.422; test trial: F(2, 21) = 0.316, p = 0.732) or long-term (Fig. 3A; sample trial: F(2, 24) = 1.970, p = 0.185; test trial: F(2, 24) = 2.920, p = 0.073). Similarly, corticosterone-injected animals’ number of crossings was not significantly different from those displayed by vehicle-injected animals during sample and test

Fig. 3. Neither locomotive activity nor performance on long-term memory test was affected by acute stress induced before sample trial. (A) Bar plot illustrating the total number of crossings through open-field zone borders. (B and C) Bar plots illustrating exploration frequency (B) and exploration time (C) DI. Left-hand side bars illustrate subjects’ performance during sample trial; right-hand side bars illustrate subjects’ performance during long-term memory test. Each bar represents the group’s mean + standard deviation (white bars, control; grey bars, 1-h stress; black bars, 4-h stress). Dotted lines represent upper and lower limits of the empirical zero’s 99.9% confidence interval. Locomotive activity was not significantly different between groups during sample trial and long-term memory test. Animals from all groups displayed indistinct exploration (DI close to zero) of both objects during sample trial; by contrast, subjects from all groups significantly explored more the NO during long-term memory test (positive DI). Abbreviations: § indicates a significant difference regarding empirical zero.

trials in the experiments designed to evaluate corticosterone effect on ORT performance in either the short- (Fig. 4A; sample trial: t(10) = 0.832, p = 0.425; test trial: t(10) = 1.381, p = 0.197) or long-term (Fig. 5A; sample trial: t(8) = 0.514, p = 0.621; test trial: t(8) = 0.376, p = 0.716).

Please cite this article in press as: Vargas-López V, et al. Acute restraint stress and corticosterone transiently disrupts novelty preference in an object recognition task. Behav Brain Res (2015), http://dx.doi.org/10.1016/j.bbr.2015.05.006

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Fig. 4. Systemic corticosterone injected before test trial did not affect locomotive activity but impaired performance during short-term memory test. (A) Bar plot illustrating the total number of crossings through open-field zone borders. (B and C) Bar plots illustrating exploration frequency (B) and exploration time (C) DI. Left-hand side bars illustrate subjects’ performance during sample trial; right-hand side bars illustrate subjects’ performance during short-term memory test. Each bar represents the group’s mean + standard deviation (vertical lined bars, vehicle; horizontal lined bars, corticosterone). Dotted lines represent upper and lower limits of the empirical zero’s 99.9% confidence interval. Locomotive activity was not significantly different between groups during sample trial and short-term memory test. Subjects from both groups displayed indistinct object exploration during sample trial. While vehicleinjected animals preferentially explored the NO, corticosterone-injected animals preferred to explore the FO during short-term memory test. Abbreviations: * indicates a significant difference regarding the performance of vehicle-injected group subjects during the same trial; § indicates a significant difference regarding empirical zero.

Fig. 5. Systemic corticosterone injected before test trial did not affect locomotive activity but impaired performance during long-term memory test. (A) Bar plot illustrating the total number of crossings through open-field zone borders. (B and C) Bar plots illustrating exploration frequency (B) and exploration time (C) DI. Left-hand side bars illustrate subjects’ performance during sample trial; right-hand side bars illustrate subjects’ performance during long-term memory test. Each bar represents the group’s mean + standard deviation (vertical lined bars, vehicle; horizontal lined bars, corticosterone). Dotted lines represent upper and lower limits of the empirical zero’s 99.9% confidence interval. Locomotive activity was not significantly different between groups during sample trial and long-term memory test. Animals from both groups displayed indistinct object exploration during sample trial. While vehicleinjected animals preferentially explored the NO, corticosterone-injected animals did not prefer it during long-term memory test. Abbreviations: * indicates a significant difference regarding the performance of vehicle-injected group subjects during the same trial; § indicates a significant difference regarding empirical zero.

3.2. Acute stress did not modify object exploration during sample trial

(Short-term ORT: frequency DI: F(2, 21) = 1.547, p = 0.21; time DI: F(2, 21) = 1.306, p = 0.279; Fig. 2B and C, left-hand. Long-term ORT: frequency DI: F(2, 24) = 0.475, p = 0.701; time DI: F(2, 24) = 1.714, p = 0.171; Fig. 3B and C, left-hand side). This indicated that stress did not induce idiosyncratic object preference when objects were presented for the first time.

Stressed and non-stressed animals displayed no significant exploration preference during sample trial, as indicated by the absence of significant differences concerning empirical zero

Please cite this article in press as: Vargas-López V, et al. Acute restraint stress and corticosterone transiently disrupts novelty preference in an object recognition task. Behav Brain Res (2015), http://dx.doi.org/10.1016/j.bbr.2015.05.006

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3.3. Acute stress before sample trial impaired short-term novel object preference There were significant differences between groups regarding object preference during short-term test trial (frequency DI: F(2, 21) = 7.338, p < 0.001; time DI: F(2, 21) = 11.872, p < 0.001; Fig. 2B and C, right-hand side). Post hoc analysis demonstrated that while 1-h stressed subjects performed like control subjects (frequency DI: t = 0.481, p = 0.635; time DI: t = 0.443, p = 0.662), there was a significant difference between control and 4-h stress subjects’ performance (frequency DI: t = 3.115; p = 0.010; time DI: t = 2.737, p = 0.025). Control subjects displayed a significant NO preference during short-term memory test (frequency DI cf empirical zero: t(47) = 2.632, p = 0.011; time DI cf empirical zero: t(47) = 4.785, p < 0.001). By contrast, object preference was perturbed in 4-h stressed subjects during short-term test trial since they preferred to explore the FO (frequency DI cf empirical zero: t(47) = 3.051, p = 0.004; time DI cf empirical zero: t(47) = 0.035, p = 0.972). Onehour stressed subjects’ NO preference was impaired regarding frequency but not time (frequency DI cf empirical zero: t(47) = 1.754, p = 0.086; time DI cf empirical zero: t(47) = 4.333, p < 0.001). These results indicated that acute stress induced before sample trial impaired short-term NO preference and that the degree of such impairment was directly proportional to stress duration. 3.4. Acute stress before sample trial did not impair long-term novel object preference There were no significant differences between groups respecting object preference during short-term test trial (frequency DI: F(2, 24) = 0.0595, p = 0.942; time DI: F(2, 24) = 0.745, p = 0.485; Fig. 3B and C, right-hand side). Control (frequency DI cf empirical zero: t(48) = 3.201, p = 0.002; time DI cf empirical zero: t(48) = 6.387, p < 0.001), 1-h stressed (frequency DI cf empirical zero: t(48) = 2.860, p = 0.006; time DI cf empirical zero: t(48) = 4.333, p < 0.001), and 4h stressed subjects (frequency DI cf empirical zero: t(48) = 3.461, p = 0.001; time DI cf empirical zero: t(48) = 5.658, p < 0.001) displayed a significant NO preference. These results indicated that acute stress induced before sample trial did not impair NO preference tested 24 h later. 3.5. Corticosterone before test trial impaired short-term novel object preference Object exploration was significantly different in subjects receiving vehicle than in subjects receiving corticosterone before short-term memory test (frequency DI: t(10) = 4.336, p < 0.001; time DI: t(10) = 2.678, p = 0.023; Fig. 4B and C, right-hand side). While vehicle-injected subjects preferred to explore the NO (frequency DI cf empirical zero: t(45) = 2.461, p = 0.018; time DI cf empirical zero: t(45) = 3.401, p = 0.001), corticosterone-injected animals explored more the FO in terms of frequency (frequency DI cf empirical zero: t(45) = 4.433, p < 0.001; time DI cf empirical zero: t(45) = 1.788, p = 0.080). This result indicated that corticosterone injected just before short-term test trial impaired the expression of NO preference. 3.6. Systemic corticosterone injection before test trial impaired long-term novel object preference Object exploration was significantly different in subjects receiving vehicle than in subjects receiving corticosterone before long-term memory test (frequency DI: t(10) = 4.743, p < 0.001; time DI: t(10) = 8.745, p < 0.001; Fig. 5B and C, right-hand side). While vehicle-injected subjects preferred to explore the NO (frequency

DI cf empirical zero: t(45) = 3.128, p = 0.003; time DI cf empirical zero: t(45) = 9.459, p < 0.001), corticosterone-injected animals explored indistinctly both objects (frequency DI cf empirical zero: t(45) = 1.024, p = 0.311; time DI cf empirical zero: t(45) = 1.918, p = 0.061). This result indicated that corticosterone injected just before long-term test trial also impaired the expression of NO preference.

4. Discussion This work found that long (4 h), but not brief (1 h), acute stress administered prior to sample trial impaired the subjects’ performance on an ORT when evaluated 1 h after sample trial. By contrast, subjects’ performance on long-term ORT was not impaired by acute stress, regardless of its duration. Systemic injection of corticosterone 10 min before either short- or long-term test trials also induced poor performance during an ORT. Impairments in ORT performance induced by acute stress or corticosterone injection were not attributable to changes in locomotor activity or to a reduced tendency to explore the objects, since there were no significant differences regarding control subjects in either the number of crossings through different zones of the open-field or in the percentage of explorations of the objects. Few reports have explored the effects of acute stress induced before sample trial regarding ORM. Baker and Kim (2002) showed that combined stress (restraint and tail shocks) impaired ORM when tested 3 h, but not 5 min or 48 h after sample trial. Kart-Teke et al. (2006) showed that a light stressor (intra-peritoneal saline injection) applied 30 min before the sample trial disrupted ORM when tested 50 min later. Li et al. (2012) recently showed that 1-h movement restraint-induced stress before the sample trial had no effect on ORM when tested 4 h later. Some evidence has indicated that either stress or systemic corticosterone injection impairs performance on an ORT. Morrow et al. (2000) described that acute stress induced by exposure to a predator’s odour during the 15-min delay between sample and test trials impaired ORM. Similarly, Okuda et al. (2004) showed that injecting corticosterone after the sample trial impaired ORM when tested 1 h later, but improved it when tested 24 h later. Recently, Cazakoff et al. (2010) showed that acute stress induced by placing animals on an elevated platform 30 min before the test trial impaired ORM. Likewise, Li et al. (2012) found that acute stress induced immediately before test trial induced partial impairment of ORM. Our results agreed with the aforementioned reports since we found that moderated stress induced before sample trial impaired ORT performance when evaluated 1 h later but not when evaluated 24 h later, and that corticosterone injection before test trial impaired both short- and long-term ORT performance. The one-trial ORT is a behavioural test based on the innate tendency of rodents to explore novel features of a well-known environment (Dere et al., 2007; Winters et al., 2008). When ORT performance is evaluated, memory of a familiar object is inferred through an animal’s preference to explore a novel object significantly more than the familiar one when both are presented jointly in a previously known environment. Thus, the stress-induced decrease regarding preference to explore a novel object during short-term ORT evaluation observed in the present work could be interpreted in terms of an inability to retrieve the familiar object memory trace; such interpretation would agree with that given by other authors regarding similar results. A possible cause of such impairment would be an acute stress-induced acquisition impairment; however, this can be ruled out as animals stressed before sample trial performed as well on ORT as control animals did when tested 24 h after sample trial. Although the same fact can be used as empirical evidence to rule out stress-induced

Please cite this article in press as: Vargas-López V, et al. Acute restraint stress and corticosterone transiently disrupts novelty preference in an object recognition task. Behav Brain Res (2015), http://dx.doi.org/10.1016/j.bbr.2015.05.006

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consolidation impairment, additional groups of animals were injected with corticosterone before short- and long-term test trials to check this possibility. An effect on consolidation explaining the lack of preference for the novel object displayed by stressed subjects during the short-term memory test can be rejected since impaired ORT performance was also found in both groups. However, our findings go beyond this, since stressed subjects did not display the expected indifferent object exploration pattern (i.e., the absence of any preference for exploring any of the objects presented during the test trial) associated with impaired ORM during the short-term memory test; instead, they displayed a preference for exploring the familiar object. Another explanation should thus be considered for such unexpected aspect of performance. In this vein, it has been shown that either stress or systemic corticosterone injection can reduce rodents’ preference for novel stimuli. Rosellini and Widman (1989) suggested that acute stress-induced enhancement of defensive behaviour would explain their finding that rats previously exposed to stress explored significantly less novel objects placed in a familiar environment than non-stressed controls did, without displaying significant differences in locomotor activity. More recently, Kawashima and Kusnecov (2002) showed that exposure to staphylococcal enterotoxin A (which induces dosedependent enhancement of corticosterone and adrenocorticotropic hormone levels in mice) also provoked a significant reduction concerning the exploration of novel objects without affecting motor activity. In addition, enterotoxin administration significantly reduces the consumption of a novel solution, but only when such solution is associated with contextual novelty (Kawashima and Kusnecov, 2002). Furthermore, Eagle et al. (2013) suggested that stress-induced ORT impaired performance may be due to novelty seeking disturbance rather than to memory retrieval impairment. Finally, Urani et al. (2011) proposed that since acute stress-induced deleterious effects on ORT were prevent by antidepressant- or anxiolytic-like agents (SSR125543, a corticotropine releasing factor 1 receptor antagonist; SSR149415, a vasopressin receptor antagonist; or fluoxetine, a serotonin reuptake inhibitor) but not by a cognitive enhancer (donepezil, an acetylcholinesterase inhibitor), such stress-induced effects are more likely to be due to impaired subject’s ability to cope with the task than to memory deficit. Taking the aforementioned antecedents into account when interpreting our results, acute stress or systemic corticosterone administration may have induced an aversion to explore novel objects. In fact, animals submitted to 4-h motor restraint before sample trial as well as animals receiving corticosterone before short-term test trial had a significant preference for exploring the familiar object and avoiding the novel one during the test, as indicated by negative DI which were significantly different from the DI displayed by non-stressed subjects. The evidence provided here therefore suggests that the reduced novel object exploration observed during the short-term memory test could be attributed to a transient novelty aversion state induced by either stress or corticosterone, which precluded the behavioural expression of the familiar object memory trace.

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Torres et al. (2007). Acknowledgements This research was financed by a Universidad Nacional de Colombia grant (DIB-7480). We would like to thank Mr. Jason Garry for his help in editing the manuscript.

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Please cite this article in press as: Vargas-López V, et al. Acute restraint stress and corticosterone transiently disrupts novelty preference in an object recognition task. Behav Brain Res (2015), http://dx.doi.org/10.1016/j.bbr.2015.05.006

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Acute restraint stress and corticosterone transiently disrupts novelty preference in an object recognition task.

The object recognition task is a procedure based on rodents' natural tendency to explore novel objects which is frequently used for memory testing. Ho...
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