Induced depressive behavior impairs learning and memory in rats

Neuroscience 129 (2004) 129 –139

INDUCED DEPRESSIVE BEHAVIOR IMPAIRS LEARNING AND MEMORY IN RATS M.-K. SUN* AND D. L. ALKON

pression in humans has a dramatic impact on cognition (Kuzis et al., 1997; Tröster et al., 1995; Dolan, 2002; Ravnkilde et al., 2002; Uekermann et al., 2003), although it is often difficult to distinguish between early dementia and depression in elderly populations clinically. Memory, especially explicit memory, is consistently impaired in depressed patients (Ellwart et al., 2003). This is an important issue because depressive symptoms occur in 30 – 40% of Alzheimer’s dementia (AD; Mega et al., 1996; Assal and Cummings, 2002; Bassiony et al., 2002; Polidori et al., 2001; Sun and Alkon, 2002b) and are often part of an early AD syndrome (Kaye, 1998; Berger et al., 1999; Espiritu et al., 2001). These limitations on the study of depression in humans have three major consequences. First, detailed molecular and cellular/network analyses cannot be performed in humans. Second, investigations in patients are often contaminated with the influence of medication. It is practically impossible (and probably unethical) to recruit severely depressed patients who have not been treated with antidepressant and other medications. Third, development of new types of effective antidepressants without suitable animal models is much more difficult, if not impossible, so that no new classes of effective antidepressants have been developed despite decades of intensive research. Nevertheless, several animal models of depression have been developed, largely based on the effectiveness of known antidepressants or responses to stress, due to the current lack of known depression-vulnerability genes for development of animal models. These models have been used as research tool to screen effective antidepressant agents. The mostly widely used animal models include the forced swim test, tail suspension test, and olfactory bulbectomy (Cryan et al., 2002; Nestler et al., 2002). The forced swim test exhibits a predictive value in detecting antidepressant action but does not reliably detect selective serotonin reuptake inhibitors, including failed responses to chronic antidepressant treatment (Lucki, 1997; Takamori et al., 2001). It needs a modified scoring for achieving improved detection (Cryan et al., 2002). In a recent study, about half of the rats in the forced swim test were reported to dive under the water surface (Linthorst et al., 2002), a behavior that was rarely observed and not reliably altered by any of the antidepressants tested by other investigators (Detke et al., 1995b). The diving behavior resembles responses to trauma, as in underwater trauma studies (Wang et al., 2000). The tail suspension test induces a state of a lack of struggling (despair), which is reversed by acute antidepressant treatment. However, some animals climb their tails. Olfactory bulbectomy, on

Blanchette Rockefeller Neurosciences Institute, 9601 Medical Center Drive, Johns Hopkins Academic and Research Building, Room 319, Rockville, MD 20850, USA

Abstract—While it is generally accepted that cognitive processes such as learning and memory are affected by emotion, the impact of depression on learning and memory has rarely been directly studied in experimental animals. Effects of induced depressive behavior on learning and memory were determined in rats, using an open space swim test, a novel animal model of depressive behavior that is developed recently in our laboratory. The model indexes searching activity of the animals, with the induced depressive immobility behavior showing specific sensitivity to three major prototypic classes of antidepressants and a selective serotonin reuptake inhibitor. The induced depressive behavior in rats showed a delayed response to chronic antidepressant treatment and had a lasting effect on the ability of rats to learn and recall the learned experience. It impaired the subsequent ability of rats to learn and recall both a spatial water maze task and a multi-trial passive avoidance task. These impairments were all sensitive to antidepressant therapeutics, but not to buspirone, an anxiolytic. By way of contrast, the ability of the rats to sense and move to a visible platform and to escape from an unconditioned shock stimulus was neither impaired by inducing the depressive behavior nor altered by the drug treatment, suggesting that non-specific changes in sensorimotor ability were not involved. These impairments of learning and memory indicate that the depressive behaviorinduced deficits show generalizability and are not contextlimited. This animal model of depressive behavior shows promising potential as a screen for novel antidepressive therapeutics and as a disease model for revealing network/cellular/molecular mechanisms in the pathophysiology of depression and depression-induced cognitive deficits. © 2004 IBRO. Published by Elsevier Ltd. All rights reserved. Key words: antidepressants, depression model, imipramine, passive avoidance, rat, spatial memory.

Depression is one of the most prevalent forms of mental illness in humans (Gainotti et al., 2001; Wong and Licinio, 2001; Nestler et al., 2002). It is not only life threatening but also negatively impacts on functional recovery from other neurological disorders. Unlike many other brain functions, most of our knowledge about depression and its potential effects on cognition is from empirical observations in human patients. De*Corresponding author. Tel: ⫹1-301-294-7181; fax: ⫹1-301-294-7007. E-mail address: [email protected] (M.-K. Sun). Abbreviations: AD, Alzheimer’s dementia; ANOVA, analysis of variance; US, unconditioned stimulus.

0306-4522/04$30.00⫹0.00 © 2004 IBRO. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.neuroscience.2004.07.041

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the other hand, results in a behavioral change correlated with changes in depression. A hyperactive response in a novel, brightly lit open filed apparatus, is reversed chronically by antidepressant treatment. The test is based on behavioral similarity and its mechanism of action is poorly understood. The value of these animal models of depressive behavior in defining the pathophysiology of depression or the impact of depression on cognition remains uncertain. Recently, we have developed and tested a novel animal model of depressive behavior, the open space swim test (Sun and Alkon, 2003). The model uses a large pool, with the induced depressive behavior resulting from a lack of motivation (hopelessness), rather than a lack of “physical space” (Sun and Alkon, 2003). Rats are not forced to swim in the test, which monitors reliably the behavioral changes objectively, without requiring judging and scoring by the investigators, and detects the antidepressive activity of all classes of antidepressants as well as the selective serotonin reuptake inhibitor. In the present study, we directly examine effects of the induced depressive behavior on two types of learning and memory tasks: the spatial water maze task and the multi-trial passive avoidance task. Our results show that the induced depressive behavior mimics the human disease, exhibiting a dramatic impact on the ability of learning and memory. The test may have value as a choice of depressive models in revealing pathophysiological mechanism(s) of depression and depression-cognition interaction and in searching for new classes of antidepressants.

EXPERIMENTAL PROCEDURES Materials Adult male Wistar rats (180 –200 g) were housed two per cage in a temperature-controlled (20 –24 °C) room for at least a week prior to experimentation, allowed free access to food and water, and kept on a 12-h light/dark cycle. In addition to some preliminary tests (see below), 144 rats were used. They were randomly assigned to 18 groups (eight each; 32 into four groups for spatial maze task and visible platform test, 32 into four groups for passive avoidance task, 32 into four groups for testing sensitivity in response to shock only, 32 into four groups for visible platform without water escape-motivated spatial learning, and 16 into two groups for chronic antidepressant treatment study) and were moved to the test room in their home cages at least 1 h before trials. Imipramine (Sigma, St. Louis, MO, USA), a prototypical tricyclic antidepressant, and buspirone (Sigma), an anxiolytic, were solubilized in saline, which was used as vehicle in the control groups. Drugs (10 mg/kg⫻3/day, i.p.) and vehicle were administered between the swimming trial sessions at 23 h, 3 h, and 1 h before the second and the third trial session in the acute open space swim test, respectively. The use of three doses between the three test trials produces more consistent predictive effects than those of a single dose (Porsolt et al., 1978, 1997; Poncelet et al., 1986). In separate groups of rats, chronic effects of imipramine on induced immobility were evaluated when imipramine was administered daily, starting 24 h after the completion of the three open space swim test trials. In these studies, no imipramine was administered between the three open space swim test trials.

Open space swim test: induction of depressive behavior Rats were placed individually in a round pool, which has a diameter of 152 cm and height of 60 cm and was filled with 40 cm H2O (24⫾1 °C). The room and pool are part of the standard setup used for spatial water maze task (Sun et al., 2002). No escape was provided in these trials during the test. Rats were free to swim (or not to swim) for 15 min and then removed and returned to their home cages after drying. The observer(s) were obscured from sight of the rats during the trials, but were able to observe the animals’ behaviors on a video screen monitor (Video Monitor BWM9; Javelin Electronics Inc.) during the trials. The same procedure (15 min session/day) was followed 24 h later for 2 more days. We previously reported that a maximum change in mobility was induced on the third trial (Sun and Alkon, 2003). The swimming/drifting path was recorded with a video-tracking system (Poly-Track Video Tracking System; San Diego Instruments, Inc., San Diego, CA, USA), which was also used for the spatial water maze task in other studies (Sun et al., 2002; Sun and Alkon, 2002). The distance moved (mobility) includes all the distance moved during the entire 15 min, as caused by active swimming/ searching as well as slow drifts. Active swimming is defined as those swimming motions a rat is making to move around in the pool. We have previously reported that the swim activity monitored accurately reflects duration of mobility and that the maximum effect is induced on the third trial (Sun and Alkon, 2003). In the study of impact of induced depressive behavior on learning and memory, the antidepressant drug (or buspirone and vehicle) was administered only during the inter-depressive behavior induction days, not during the subsequent learning and memory tasks. The control groups of rats that were not exposed to the three trials to induce depressive behavior, were also moved into the trial room and stayed in the room for the same period as the other groups.

Spatial water maze learning and memory task Effects of the induced depressive behavior on spatial learning and memory were evaluated with the Morris water maze task (Meiri et al., 1998; Sun et al., 2001, 2002), in a 150 cm-diameter pool (24⫾1 °C). The maze was divided into four quadrants. Control rats were allowed to swim for 2 min in the pool without a hidden platform, the same day when the other groups were on their third day of depressive behavior induction. Twenty-four hours later, all rats were trained for two trials/day for 4 days to find a hidden platform (9 cm diameter). The platform was centered in one of the quadrants and submerged about 2 cm below the water surface. At the start of all trials, rats were placed in the water facing the maze wall, using different starting positions, and allowed to swim until they found the platform, where they remained for 20 s. A rat that failed to find the platform within 2 min was guided there, with the maximum latency of 120 s scored. The swimming path was recorded by a video-tracking system, which computed latency to find the platform, distance swum, heading angle, and percentage of time spent in the quadrants. After the training trials, a probe trial of 60 s was given 24 h after the last trial, with the platform removed, to assess memory for platform location by the distance swum in the quadrants.

Visible platform test After the probe trial of the water maze task, all four groups of the rats were tested on a visible platform task (a non-spatial task; with the platform marked with a pole that protruded 9 inches above the water surface but at a new location) to evaluate their sensorimotor abilities. The latency to reach the visible platform was recorded and compared between different groups.

M.-K. Sun and D. L. Alkon / Neuroscience 129 (2004) 129 –139 In separate groups of rats, the same test was applied to rats 24 h after the third open space swim test trial, i.e. without the water maze spatial learning trials.

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To determine whether the induced depressive behavior has similar effects on learning and memory tested with different context (wet vs. dry), the multi-trial passive avoidance behavioral test was employed for different groups of rats. Twenty-four hours after the last open space swim trial to induce depressive behavior, rats were subject to the multi-trial passive avoidance test. An avoidance apparatus (Gemini II Avoidance System; San Diego Instruments, Inc.) was used for testing the multi-trial passive avoidance performance. Briefly, the apparatus consisted of two compartments (wide⫻depth⫻high: 25 cm⫻21 cm⫻19 cm), both equipped with a grid floor, house and cue lights, and Sonalert sound generators. The two compartments were separated by a guillotine door. The operation of the lights, tone, and door was controlled with its operating system. The multi-trial passive avoidance learning and memory task consisted of two trials: an acquisition trial and a retention trial. In the acquisition trial, the rats were trained to avoid the unconditioned stimulus (US) of foot shock, which was delivered through the grid floor (see below). Each rat was placed in the compartment on the right side (the initial compartment). The inter-compartment door was opened after a 60 s acclimation period. At the same time the house light and tone in the initial compartment were also switched on as the conditioned stimuli. If the rat stepped into the dark compartment on the left side (the dark compartment), the door was closed automatically and an inescapable foot shock (0.25 mA/2 s) was delivered through the grid floor of the dark compartment. After receiving the foot shock, the rat was removed and placed back into the initial compartment. The same acquisition trial procedure was repeated and continued until the rat stayed in the initial compartment for 120 s. The number of training trials was used as the index of learning acquisition. The retention trial started 24 h after the end of the acquisition trial. Each rat was placed in the initial compartment, as in the training trial. The door was opened after a 60 s acclimation period, with house light and tone being switched on at the same time. The step-through latency in the retention trial (with a maximum 300 s cutoff time) was used as the index of retention of the learned experience (Yamada et al., 1996; Hefco et al., 2003). Shock was not administered at the retention trial. Longer retention latencies index better retention of the learned experience.

Responses to US shock as a motivator To determine whether the open space swim test trials would change sensitivity of rats to the US shock, responses of rats to the US shock as a motivator were evaluated in separate rats, tested 24 h after the third open space swim trial to induce the depressive behavior. The same avoidance apparatus (Gemini II Avoidance System) was used for testing the US shock as a motivator. The test consisted of one trial. Each rat was placed in the compartment on the left side (the dark compartment). The house light and tone in the other compartment were switched on after a 60 s acclimation period. At the same time, the inter-compartment door was also opened and an escapable foot shock (0.25 mA) was delivered through the grid floor (the dark compartment). The shock motivates rats to escape into the compartment on the right side (the compartment with light and tone on). If no escape occurred within 20 s of US presentation, the shock was terminated. The escape latency, which indexes sensorimotor abilities (Depoortere et al., 2003), was recorded and compared between groups. All procedures were conducted according to National Institutes of Health Animal Care and Use Committee guidelines, and

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Fig. 1. The distance moved (mobility) and effects of imipramine (Imi) or buspirone (Bus; 10 mg/kg⫻3/day, i.p.; administered between the open space swim test trials) on the mobility in the open space swim test in rats. Each point represents the mean value (⫾S.E.) from 32 rats per group (pooled data from groups of rats that were subsequently used either in the water maze task, in the visible platform test, in the passive avoidance task, or in US as a motivator test). Rats were placed individually in a round pool for 15 min/session/day and the same procedure was followed 24 h later for 2 more days. The Imi treatment significantly decreased the reduction in the distance moved over the trials. Dep, induced depressive behavior.

were approved by the Ethical Committee of the Institute. Care was taken to minimize the number of animals used and their suffering. Statistical analysis was performed using the analysis of variance (ANOVA), followed by Newman-Keuls multiple comparisons test, wherever appropriate. P⬍0.05 was considered significant.

RESULTS Open space swim test induces immobility in rats As no difference was observed between the four groups that received the same treatments (either three open space swim test trials with vehicle, the three trials with imipramine treatment, or the three trials with buspirone treatment) in the open space swim test and were used for subsequently different tests, these data were pooled together here. In the open space swim test, the rats injected with vehicle showed a gradual and significant reduction (Fig. 1) in the distance moved over the trials (F2,95⫽46.792; P⬍0.001), similar to our previous observations (Sun and Alkon, 2003). As the open space swim test trials progressed, the control rats showed progressively fewer and briefer intermittent periods of active swimming. Typically, a control rat did not make any movements other than those just sufficient to keep its head above the water surface (not shown), a characteristic behavior of depression similar to those reported in the forced swimming test. We reported in our previous study that the induced depressive behavior was sensitive to antidepressant treatments, including the three prototypes and a selective serotonin reuptake inhibitor (Sun and Alkon, 2003). Imipramine was used in the present study to determine whether any effects of induced depressive behavior on learning and memory were sensitive to antidepressant treatment, while buspirone, an anxiolytic, was used as a pharmacological

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Open Space Swim Test and Chronic Antidepressant Treatment

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Fig. 2. Effects of chronic imipramine (Imi) antidepressant treatment on the induced depressive behavior in rats. Each point represents the mean value (⫾S.E.) from eight rats per group. Rats were placed individually in a round pool for 15 min/session/day and the same procedure was followed 24 h later for 2 more days. Imi (15 mg/kg/day, i.p.) and vehicle were administered for 3 weeks (marked at daily doses), starting 24 h after the third open space swim test trial. The mobility was further monitored every 7 days during or after the drug treatment or vehicle (15 min/session/week). Dep, induced depressive behavior.

control. Imipramine treatments significantly decreased the reduction in the distance moved over the trials (Fig. 1), compared with that of the control group. Statistical analysis revealed significant effects of groups (F2,95⫽18.822; P⬍0.001), indicating that the mobility in the rats that were injected with imipramine was significantly higher than that in the rats that were injected with either vehicle or buspirone. A post hoc analysis revealed a significant difference from the second trial to the third trial (P⬍0.05), confirming higher mobility in the rat group that received the imipramine treatment. The buspirone treatment, however, did not produce a significant difference in mobility as compared with the depression/vehicle group (F1,63⫽0.032; P⬎0.05; Fig. 1), suggesting that the imipramine effect on the mobility is related to a specific action of antidepression. The induced depressive behavior is lasting and sensitive to chronic antidepressant treatment The difference between an acute experimental test and clinical effectiveness of antidepressants requires further testing to evaluate whether a chronic medication as those administered in humans would reveal difference or similarity between experimental and clinical profiles of the antidepressive action. As shown in Fig. 2, without antidepressant drug (Dep group with vehicle injection), the open space swim test induced a significant immobility, which lasted at least 1 week without further episodes and weeks with separate open space swim test monitoring episodes. The antidepressant treatment, started 24 h after the three open space swim test trials, was not immediately effective. The first week of treatment did not result in a significant improvement in mobility of the rats (F1,15⫽0.037; P⬎0.05 when compared with those controls). The improvement was observed after 2 weeks of continued imipramine treat-

ment (F1,15⫽17.781; P⬍0.001) and achieved its peak after another week of the continued treatment. When the treatment was stopped, the antidepressant effect began to disappear, with a significant decrease in mobility revealed a week later (F1,15⫽18.502; P⬍0.001 as compared with that of last trial) during the monitoring period. Thus, the induced depressive behavior in the open space swim test is sensitive to chronic antidepressant treatment with a delay. The 3 weeks of daily imipramine treatment does not appear to cure the disorder since the immobility returns as the treatment stops. Effects of induced depressive behavior on spatial learning One day after the third open space swim test trial to induce the depressive behavior (Fig. 1), we tested the effects of induced depressive behavior on spatial learning in rats, using the hidden-platform water maze. As shown in Fig. 3A, the latency to escape to the platform in all four groups of rats decreased following the training sessions, indicating that all rats showed some degrees of learning. But the speed and the extent of the learning were significantly different. Statistical analysis revealed significant effects of groups (F3,31⫽9.983; P⬍0.001), indicating that spatial learning in the rats after depressive behavior induction was significantly slower than that of the control and depression/ imipramine groups. Moreover, a post hoc analysis reveals a significant difference from the second trial (P⬍0.05), confirming worse learning in the rats after the depressive behavior induction. The depressive behavior-induced reduction in learning was eliminated by the antidepressant administration between the open space swim test trials. The imipramine group showed a significant improvement in learning (F1,15⫽39.360, P⬍0.001) as compared with

M.-K. Sun and D. L. Alkon / Neuroscience 129 (2004) 129 –139

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Fig. 3. Effects of induced depressive behavior (Dep) on spatial learning and memory in rats. (A) Impairment of spatial learning by Dep. The water maze learning started 1 day after the third open space swim test trial. The learning impairment was sensitive to imipramine (Imi) treatment, but not to buspirone (Bus) treatment, administered between the open space swim test trials. No drug was administered during the days when the rats were performing the learning and memory task. (B–E) Results of the memory probe test, 24 h after the last water maze learning trial. (B) The control groups showed significant preference in searching in the target quadrant (quadrant 4) during the probe trial. (C) The rats after Dep showed no such preference. (D) The retention impairment caused by the Dep was not observed when the rats received Imi treatment during the Dep. (E) The retention impairment caused by the induced depressive behavior was evident in the rats that received buspirone treatment during the Dep. (E) The target quadrant ratio (target quadrant distance over the distance average in the remaining quadrants) revealed a significantly reduced value in the rats after the Dep with vehicle or Bus treatment, when compared with the other groups. Each point represents the mean value (⫾S.E.) from eight rats per group. (Bus 10 mg/kg⫻3/day, i.p., applied during Dep only; Imi 10 mg/kg⫻3/day, i.p., applied during Dep only.)

that of the rats with depressive behavior induction only (Fig. 3A), while buspirone treatment did not improve the learning (F1,15⫽0.143, P⬎0.05). There was no significant difference in learning between the control rats and the imipramine group after the depressive behavior induction (F1,15⫽0.224, P⬎0.05). The same extent of plateau for escape latency was also reached in the groups of control and imipramine treatment after depressive behavior induction (Fig. 3A).

Memory retention was evaluated after the training. Quadrant tests 24 h after the last training trial revealed that the rats after the depressive behavior induction did not show significant preference for the target quadrant (quadrant 4), where the platform was previously placed during the training trials (F3,31⫽2.125, P⬎0.05; Fig. 3C; ANOVA and Newman-Keuls post hoc test), while the control group (F3,31⫽8.987, P⬍0.001; Fig. 3B) and the rats after depressive behavior induction with imipramine treatment between

M.-K. Sun and D. L. Alkon / Neuroscience 129 (2004) 129 –139

Effects of induced depressive behavior on a visible platform test Measurements of mobility and escape activity also depend on basic functions of the tested subjects: their sensorimotor activity. That is, any changes in visibility and/or motor ability would be expected to affect the results. The sensorimotor activity of rats was tested in a visible platform test, in which no learning is involved. Rats were tested both after water maze spatial learning task and, in separately groups, 24 h after the third open space swim test trial to induce the depressive behavior (Fig. 1), i.e. without water maze training trials. The escape latency to a visible platform, however, did not differ between all four groups comparable (after the water maze spatial learning: F3,31⫽0.362; P⬎0.05, Fig. 4A; after the open space swim test trials: F3,31⫽0.0943, P⬎0.05, Fig. 4B), indicating that the depressive behavior induction or imipramine administration did not grossly affect their sensory or motor abilities. Thus, the behavioral changes observed cannot be attributed to changes in non-specific sensory and motor ability. During the experimental periods, no rats showed any apparent sign of discomfort, hypervigilance or easy startle. Effects of induced depressive behavior on the multitrial passive avoidance learning and memory Different groups of rats were used to examine effects of the induced depressive behavior on the multi-trial passive avoidance learning and memory task. In the open space swim test, rats injected with either vehicle or buspirone showed a significant reduction in their mobility over trials (Fig. 1), similar to the group described above and to our previous observation (Sun and Alkon, 2003). The induced depressive behavior was sensitive to imipramine treatment between the open space swim test trials, which significantly decreased the reduction in the distance moved over the trials (Fig. 1), compared with that of the other groups. The depressive behavior was not induced in the rats with imipramine treatment between the open space swim test trials. A post hoc analysis revealed a significant difference from the second trial to the third trial (P⬍0.05), confirming higher mobility in the rat group that received imipramine treatment.

Visible Platform Test

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the open space swim test trials spent more time searching in the target quadrant (F3,31⫽7.124, P⬍0.001; Fig. 3D). Treatment with buspirone, on the other hand, was not effective (Fig. 3E). There were significant effects of groups (F3,12⫽8.173, P⬍0.01), quadrant (F3,127⫽243.860, P⬍0.001), and groups⫻quadrant (F9,127⫽52.581, P⬍0.001), indicating that the induced depressive behavior impaired the spatial memory and that the memory impairment was sensitive to an antidepressant treatment. Thus, the depressive behavior group of rats and the rats with buspirone treatment showed a significantly smaller (P⬍0.05) target quadrant ratio than that of the other groups (Fig. 3F). The ratio was obtained by dividing the target quadrant distance by an averaged value of nontarget quadrant distance in each group,

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Fig. 4. The induced depressive behavior (Dep) and imipramine (Imi), or buspirone (Bus) administration did not affect the ability of the rats to sense and reach the visible platform, a non-spatial test. Each point represents the mean value (⫾S.E.) from eight rats per group, examined either 24 h after the water maze spatial learning and memory task (A) or 24 h after the third open space swim test trial in separate groups (B). (Bus 10 mg/kg⫻3/day, i.p., applied during Dep; Imi 10 mg/kg⫻3/ day, i.p., applied during Dep.) NS, not significantly different.

After inducing the depressive behavior, rats were trained in the multi-trial passive avoidance task. A learning acquisition trial was conducted 24 h after the third trial inducing the depressive behavior. Memory of the learned passive avoidance task was tested 24 h after the end of the learning acquisition trial. The learning acquisition in the multi-trial passive avoidance task was evaluated with the number of training trials needed in each rat until the rat learned to stay in the initial compartment for 120 s. All rats eventually learned to avoid step-through to the other compartment. As shown in Fig. 5A, however, the numbers of training needed in the rats after the depressive behavior induction and in the rats after the depressive behavior induction with buspirone treatment were significantly bigger than the other two groups, the control group and depression/imipramine group. Statistical analysis revealed significant effects of groups (F3,31⫽8.316; P⬍0.001), indicating that multi-trial passive avoidance learning in rats

M.-K. Sun and D. L. Alkon / Neuroscience 129 (2004) 129 –139

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P⬎0.05), indicating that the antidepressant treatment was fully effective. Memory retention was evaluated after the training. Retention tests 24 h after the acquisition training trial revealed that the rats after the depressive behavior induction with vehicle or buspirone treatment showed a poorer retention of the learned experience since their step-through latency was significantly shorter than the other groups (group difference: F3,31⫽4.881, P⬍0.01; vs. control: F1,15⫽6.629, P⬍0.05; vs. depression/imipramine group: F1,15⫽8.043, P⬍0.05; vs. depression/buspirone group: F1,15⫽0.0374, P⬎0.05; Fig. 5B). The imipramine group did not show a significant difference in the step-through latency (F1,15⫽0.159, P⬎0.05; Fig. 5B) as compared with the control group. Thus, the effect of depressive behavior induction on the passive avoidance retention was eliminated by the imipramine treatment between the open space swim test trials. Effects of open space swim trials on responses to US shock as a motivator

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Fig. 5. Induced depressive behavior (Dep) impaired learning and memory on a multi-trial passive avoidance task. (A) Effects of Dep on the learning acquisition. The numbers of training trials are those needed for the rats to stay in the initial compartment (with light and tone on) for 120 s, to avoid a US shock of (0.25 mA, 2 s). (B) Effects of Dep on the retention latency 24 h after the training trials in the multi-trial passive avoidance behavioral test. Each point represents the mean value (⫾S.E.) from eight rats per group. Bus, buspirone (10 mg/kg⫻3/day, i.p., applied during Dep). Imi, imipramine (10 mg/kg⫻3/ day, i.p., applied during Dep). * Significantly different; NS, not significantly different.

after depressive behavior induction was significantly slower than that of the control group and depression/imipramine group, confirming worse learning in the rats after the depressive behavior induction. The depressive behavior-induced reduction in learning was eliminated by the antidepressant administration during the days between the depressive behavior induction trials. The imipramine group showed a significant improvement in learning (F1,15⫽12.100, P⬍0.005) as compared with that of the rats with depressive behavior induction only (Fig. 5A), while buspirone treatment was ineffective (F1,15⫽0.0215, P⬎0.05). There was no significant difference in learning between the control rats and the imipramine group after the depressive behavior induction (F1,15⫽0.0566,

Different groups of rats were used to examine effects of the open space swim test trials on rats’ responses to the US shock as a motivator, 24 h after the third open space swim test trial (Fig. 1). This was tested because results of the multi-trial passive avoidance also depend on sensorimotor ability (motor ability and sensitivity to the US shock) of the rats. It has been reported that 6.5 min of exposure to 2 °C water in a cylinder can induce skeletal activity-dependent escape impairments in rats due to a “motor activity deficit,” determined 30 min after the cold water event (Weiss and Glazer, 1975). The US shock was a powerful motivator in all the rats tested. All the rats tested escaped to the other compartment without reaching the cutoff time of 20 s. Statistical analysis revealed no significant effects of groups (F3,31⫽0.188; P⬎0.05; Fig. 6), indicating that the open space swim test trials did not have a gross non-specific effect on rats’ sensitivity to the US shock and motor ability. Therefore, the impaired learning and memory in the multitrial passive avoidance task by the open space swim test cannot be attributed to a changed sensorimotor ability of the rats.

DISCUSSION The primary objective of this study was to investigate whether the depressive behavior as induced in the open space swim test would significantly impair learning and memory and whether such effects on learning and memory, if observed, exhibit a feature of generalizability. Two different types of learning and memory tasks were therefore used to evaluate the potential impairments. One of them, the multi-trial passive avoidance task, differs entirely in context from spatial water maze task and the depressive behavior induction. Our results show that the induced depressive behavior indeed has a dramatic influence on subsequent learning and memory. These findings provide insight into the suitability of the model as a research tool for

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Escapy latency (s)

US as a Motivator

NS

NS

NS

De pImi

De pBus

10

5

0

De p

Control

Fig. 6. Open space swim test trials did not impair responses of rats to an escapable US shock as a motivator. Each point represents the mean value (⫾S.E.) of escape latency from eight rats per group. The escape latency is the time difference between the start of the US shock (0.25 mA, 20 s cutoff) delivered to the left compartment and escape of the rats to the other compartment (with light and tone on but no shock). All the rats tested escaped within the cutoff time. Bus, buspirone (10 mg/kg⫻3/day, i.p., applied during Dep, depressive behavior induction). Imi, imipramine (10 mg/kg⫻3/day, i.p., applied during Dep). * Significantly different; NS, not significantly different.

detailed investigation of pathophysiology underlying depressive behavior and influence on cognition. Animal models are indispensable in clarifying pathophysiology that underlies depression, depression– cognition interaction, and in searching for new antidepressants. The validity of our model for depression is indicated by emergence of depressive behavior, non-searching immobility, and by the effectiveness of all three major classes of effective antidepressants and of a selective serotonin reuptake inhibitor (Sun and Alkon, 2003), when the antidepressants were applied at the same doses at which they did not induce changes in non-specific locomotor activity in rats (Bai et al., 2001; Kroczka et al., 2001; Takamori et al., 2001; Kitamura et al., 2002). The relationship between stress and depression can be described as that depression is often viewed as a stress-related disorder but stress per se is not sufficient to cause depression (Nestler et al., 2002). Events that induce depressive behavior in animals, such as those in the forced swim test and the open space swim test, and human are often stressful. Stress defines profiles of the events (triggers), while depression describes behavioral consequence induced by the events or experience. When the subjects are removed from the environment that might be stressful, such as during the memory tasks, they are no longer facing the same stressful events. What is evaluated during the learning and memory tasks is not the stressful events per se or stress interference on learning but impact by the induced behavior change. Non-searching immobility is the behavior induced in the open space swim test (Sun and Alkon, 2003) and considered one core symptom of depressive behavior (Porsolt et al., 1997; Cryan et al., 2002). Hypervigilance and easy startle, characteristic be-

haviors of post-traumatic stress disorder, were not observed in the present study. Although, only male rats were used in this study, female rats were also very sensitive, if not more, to the depressive induction (Sun, unpublished observation). The difference between acute antidepressive effects of antidepressants in animal models of depression and delayed antidepressive effects in human patients has been well documented (for review: Cryan et al., 2002; Nestler et al., 2002). To us, the difference is in fact expected, at least not surprising at all, because the drugs are administered in entirely different phases of the disorder. The acute effect is produced when the drug is administered during the disorder induction phase, preventing the disorder from occurring. The delayed effect is observed during the treatment of the human disorder after the disorder is diagnosed. Preventative or early treatments before disorders become evident or even uncontrollable are usually most effective than a late treatment to restore impaired functions, as occurring in many other diseases. Such a difference can in fact be shown in the same species. In the separate study, 2 weeks of daily doses of a classical antidepressant treatment, starting 24 h after the depressive behavior was induced, were needed to produce a significant improvement of mobility in the open space swim test, a response mimicking the time course in human antidepressant therapy. The results indicate that the open space swim test induces a depressive behavior that is not only lasting but also similar in the time course of clinical effectiveness during antidepressant treatment in humans. The results also reveal that the drug treatment is effective in controlling the behavior during the medication but the disease is not cured. These suggest that the open space swim test may be a good model to study/reveal lasting effects of depressive behavior on synaptic/molecular cascades and that the test can be used to determine whether any treatments and therapies can cure the disorder. Chronic effects of the induced depressive behavior on learning and memory are expected but remain to be evaluated. As we discussed previously, the open space swim test appears to better satisfy three of the four requirements (McKinney and Bunney, 1969; Cryan et al., 2002) for an animal model of depression, with one (reliability across laboratories) remaining to be tested. The results of the present study provide additional evidence supporting the value of the model since it mimics the human disease of depression in producing learning and memory impairments (Sun and Alkon, 2002a, 2003). The co-occurrence and association of depression and dementia in humans is a striking feature of the two disorders. Several possible interrelationships may exist between depression and dementia: 1) depression may occur in response to increasing cognitive impairment and frustration due to cognitive deficits; 2) dementia may occur as a sequel to depression; 3) depression and dementia may share similar neuropathological elements; and 4) some forms of depression are considered as “learned helplessness” and may depend on learned emotional responses that are context-specific. Our results provide direct evi-

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dence that impaired learning and memory may occur as a sequel to depression, while it remains to be studied whether depression occurs as consequence of damaged neural/synaptic functions, which also play a vital role in learning and memory. Our observations, however, have ruled out the possibility that the impaired learning and memory are context-specific (see below). The idea that impaired cognition is an element of depression is also consistent with psychotherapeutic treatments directed at changing cognitive processes (Beck et al., 1989; Haaga and Beck, 1995) and is further supported by studies showing that antidepressant therapy improves cognitive function in humans and animal models (Finkel et al., 1999; Fann et al., 2001; Nowakowska et al., 2001; Harmer et al., 2002; Meneses, 2002; Yau et al., 2002; Sun, 2003). Our results show not only that the induced depressive behavior in rats has a lasting impact (at least for days) on learning and memory but also that the impairment is sensitive to antidepressant treatment, but not to anxiolytic treatment. The latter indicates that the impairment observed is behavior-specific, suggesting that the learning and memory difference between the control and depression is unlikely due to non-depression-related profiles. The learning and memory impairments are not associated with alteration in sensorimotor ability of the animals and therefore differ from those caused by an acute cold water (2 °C for 6.5 min in a cylinder)-induced “motor activation deficit,” examined 30 min later (Weiss and Glazer, 1975). In the present study of impact of induced depressive behavior on learning and memory, the antidepressant agent was administered between the open space swim test trials only, days before the learning and memory tasks were performed. The agent itself had no obvious effects on the learning and memory tasks, tested days afterward (Sun, unpublished observation), while imipramine administered during the memory-testing period has been reported to produce memory deficits, including the passive avoidance task (Zarrindast et al., 2003, 2004). Our results do not rule out the possibility that antidepressants might affect learning and memory when administered during learning and memory trials (Sun and Alkon, 2002b; Yau et al., 2002). But this is not a relevant issue evaluated here. The weakness of the observation that the induced depressive behavior impairs the spatial water maze learning and memory is that the same contextual environment may play an unknown role in the observed deficits since the behavior induction and learning and memory task involve the same type of water-immersion context. The involvement of a context-dependent impairment as the major underlying mechanism is ruled out by the effectiveness of the induced depressive behavior in impairing the multi-trial passive learning and memory. The rats after the induced depressive behavior needed significantly more training trials than the controls to learn to avoid the punishment. In addition, they exhibited worse retention of the learned experience than the control, although these rats received more training trials than the controls to achieve the same level of avoidance during the training trials. The impaired learning and memory of the depressed rats in the passive avoidance

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task is not due to a stress-induced reduced sensitivity to the US shock, or an analgesic response, since the US shock powerfully motivated the different groups of rats in the study and that stressful events are more likely to induce hyperalgesia (de Silva Torres et al., 2003; King et al., 2003). The sensitivity of the learning and memory impairment to the imipramine treatment again strongly suggests that the depressive behavior is most likely the underlying pathophysiology involved. Emotions arise when something important to an individual is at stake and call forth a coordinated change in behavior and peripheral physiological responding (Gross, 2002). Water is not the natural environment for the strain of rats to be in, threatening food and other activities for longterm survival. In the present study, the important something is the failure to find an escape, resulting in nonsearching immobility. Interaction between mood and cognition has mainly been studied in humans and is complicated, depending on characteristics of the memory tasks and context (Polidori et al., 2001; Knight et al., 2002; MacQueen et al., 2002). Memory for emotional material is generally enhanced when compared with that for ‘neutral’ material (Cahill et al., 1994). Successful episodic encoding has been found to be differentially modulated by emotional context and subserved by different processing pathways (Packard and Cahill, 2001; Erk et al., 2003). In terms of depression and memory interaction, two memory phenomena in depression have been separately investigated: a general impairment and specific biases. Thus, depressed patients may show equivalent, or even better, memory for depression-related materials than healthy individuals do (Bower, 1981). Our memory tasks, however, do not have an obvious emotional component so that the study cannot be viewed and compared with those investigating emotional content of learning and memory. Nevertheless, the neural mechanisms that underlie interaction of mood and cognition may be involved in the changed learning and memory performance. For instance, emotional experiences initiate the release of noradrenaline and cortisol, which play a critical role in the modulation of memory consolidation (Kirschbaum et al., 1996; McGaugh, 2000; Neylan et al., 2001; Van Honk et al., 2003). Acute tryptophan depletion, for example, has also been found to lower mood in vulnerable subjects (with a family history of unipolar depression) and to impair memory consolidation in all subjects (Capuron et al., 2000; Riedel et al., 2002), suggesting a common mechanism. While many brain regions have been implicated in regulating emotions (Cryan et al., 2002; Nestler et al., 2002), we still have a very rudimentary understanding of the neural circuitry that underlies normal mood regulation and the mood abnormalities. For instance, several generations of research have failed to provide convincing evidence that depression is caused by abnormalities in the brain’s serotonin or norepinephrine systems, although an enormous number of observations suggest that they must somehow be involved (Detke et al., 1995a). Nevertheless, brain regions that are involved in the regulation of mood and affect (Swerdlow et al., 1987; Drevets, 2000; Cook et

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al., 2002), including locus coeruleus, raphe nuclei, mesencephalic tegmentum, hippocampus, amygdala, the striatum, hypothalamus, and prefrontal cortex, are mostly involved in attention and cognition (Dobbins et al., 2002). The underlying neural networks and molecular mechanisms remain to be investigated. In short, the open space swim model, for its improved objectivity in monitoring, closer resemblance to human conditions, and high predictivity of antidepressant activity, may have important potential in searching for novel classes of antidepressants and in facilitating our understanding of the neuropathophysiology of depression that devastates so many human lives. Although several types of antidepressants are currently available, they have some serious clinical limitations, including ineffectiveness in some depressed patients, intolerable side effects such as sexual dysfunction and nausea to some patients (Montgomery et al., 2002), and a delayed onset of their antidepressant activity. This is especially problematic since an immediate relief is usually desired in antidepressant therapy. Thus, the currently available antidepressants remain sub-optimal, and many show only partial responses through a long-term medications, with only about 50% of depressed patients demonstrating complete remission (Nestler et al., 2002). It would also be important to examine in greater detail the precise memory processes (i.e. encoding, storage, or retrieval) that may be influenced by depressive behavior. It is only through investigation of multiple emotional and cognitive factors that we will gain a complete understanding of how mood influences cognition. For that goal, the open space swim model of depressive behavior may represent a promising and important research tool.

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(Accepted 25 July 2004) (Available online 23 September 2004)