پیش بینی اختلالات شناختی مرتبط با سن اولیه در موش ها با تکانشگری در جوانان
|کد مقاله||سال انتشار||مقاله انگلیسی||ترجمه فارسی||تعداد کلمات|
|33442||2004||13 صفحه PDF||سفارش دهید||10295 کلمه|
Publisher : Elsevier - Science Direct (الزویر - ساینس دایرکت)
Journal : Neurobiology of Aging, Volume 25, Issue 4, April 2004, Pages 525–537
Impulsivity is a feature of psychiatric disorders such as mania, addictive behaviors or attention deficit-hyperactivity disorder (ADHD), which has recently been related to complaints of forgetfulness in adults. We investigated whether impulsiveness exerts a long-term influence on cognitive function in rats in a longitudinal study. Impulsivity, assessed by the ability to complete a sequence of presses to obtain food (conditioning box), spatial working memory (8-arm radial maze) assessed with varying degree of attentional load and recognition memory (Y-maze) were tested at different ages. Marked individual differences in impulsivity were observed at youth and remained stable at middle-age despite a general decline in the trait. Working memory scores of impulsive and non-impulsive rats did not differ in youth, whereas by middle-age the impulsive group had impaired working memory and was more sensitive to a higher attentional demand. Thus, impulsiveness in youth predicts cognitive performance in middle-age. These findings may help refine the search for early biological substrates of successful aging and for preventive follow-up of subjects at risk of impaired cognitive aging.
Impulsivity is a dimensional personality trait that has been applied to many different aspects of the behavior of humans and animals. Deficits in behavioral inhibition , waiting capacity , timing  and , behavioral switching  and tolerance of delay of gratification  and  have been proposed to encompass many of these behavioral phenomena  and such disparate behaviors reflect a multifactorial process . Personality theorists have demonstrated that there are individual differences in impulsivity from scales based on self-report questionnaires ,  and . Extroverted adults, compared to introverts, have been characterized as more impulsive, more sensation-seeking, more responsive to rewards and less able to sustain attention in situations of low stimulation . In a pathological context, impulsiveness is an important aspect of several psychiatric disorders  and is a good predictor of both psychopathy and conduct problems . It has been related to drug addiction and to different kinds of mental illness including personality, bipolar, and attention deficit-hyperactivity disorders (ADHD). ADHD is a common behavioral disorder among school-age children, which is mainly characterized by inattentiveness, hyperkinesis and impulsiveness. The latter trait is regarded as the symptom of greatest significance  and . A similarity can be drawn between attention deficits with hyperactivity in children and extreme extroversion in adults: the description of extroverted people is very similar to what is observed in hyperactive children . They are also cognitively characterized by deficits in executive functions with specific impairments in behavioral response inhibition and sustained attention. Longitudinal clinical studies of children with ADHD followed into adult life report that one- to two-thirds continue to manifest appreciable ADHD symptoms ,  and . Forgetfulness or poor memory is among the more frequent complaints of adults with ADHD , ,  and . Thus, impulsiveness may exert a long-term influence on cognitive processes, but to our knowledge, this hypothesis has never been experimentally verified. Animal models of human psychopathologies are increasingly used by biological psychiatrists and psychopharmacologists researching brain systems involved in abnormal behavior and developing drugs to treat such disorders. Evenden and coworkers have devised various experimental paradigms demonstrating the multifactorial nature of impulsivity , , , , , , ,  and . Using psychoactive drugs as dissection tools, they identified three separate and apparently independent ways in which impulsivity may be expressed: the preparation for action, the execution of behavior patterns and the assessment of the consequences of actions. The relationship between impulsivity and cognition has also been reported in animals in several cognitive tasks in which the number of premature responses, which reflect impulsivity, is measured. It has been suggested that this relationship is a possible confounding factor in tests of cognitive function . Negative correlations have been noted between the accuracy of attention performance in the 5-choice serial reaction time task and the number of premature responses in rats , ,  and . Individual differences in animals’ behavior can also exhibit dimensions that parallel certain human personality traits. This was first demonstrated in macaques  and rats . Animal models of psychopathology based on natural individual differences have been rarely exploited. Behavioral traits existing spontaneously in a normal population could be assessed and animals showing extreme behaviors selected from a normal population of outbred subjects might represent a more natural model of certain psychopathologies. Using this approach, we have characterized a behavioral trait in rats which resembles features of high-sensation seekers in humans. We have demonstrated the value of this animal model in identifying some of the biological bases of this trait  and . Individual differences in both attentional processes and impulsiveness in rats have been successfully used to evidence the role of regulatory systems  and . However, impulsivity was assessed in a task designed to measure attentional processes, the 5-choice serial reaction time task  and impulsive rats, responding prematurely, could not be distinguished from rats performing poorly in the attentional task, precluding distinction between the two processes. The present study was designed to investigate the relationships between the impulsive behavioral trait and cognitive processes during aging in a longitudinal study. The first question was whether an impulsive behavioral trait could be characterized in a normal cohort of Sprague–Dawley rats, using a specific impulsive task requiring a low demand on attention processes. This task assessed the ability to carry out a chain of sequential acts in order to achieve a goal, i.e. the executive component of impulsive behavior , ,  and . This schedule requires several important processes contributing to impulsivity: timing, as the animals have to evaluate the passage of time when pressing one of the two levers to avoid premature responding, and behavioral inhibition of switching to the other lever before the required number of presses to obtain food has been reached. The temporal stability of this trait was examined in a longitudinal study. Second, the relationships between impulsiveness and cognitive abilities were studied in youth and during aging. The working memory performance of impulsive and non-impulsive rats was characterized at youth and middle-age using two tasks known to evidence age-related individual differences: spatial recognition memory, assessed in a Y-maze task developed by our group  and  and working memory with varying degrees of attentional demand in an 8-arm radial maze. 2. Methods 2.1. Animals Two groups of 40 male Sprague–Dawley rats (Iffa-Credo, Lyon) were received at 6 weeks of age. They were housed in groups of four in a temperature (22 °C) and humidity controlled room (60%) on a 12:12 h light–dark (8:00–20:00 h) schedule. They had free access to food and water except during the testing periods during which they were under dietary restriction. During these periods, the rats were each fed about 15 g laboratory food everyday (60 g per cage). This ration was adjusted in order to keep the rats’ weight between 80 and 85% below their expected weight at the same age, calculated from the standard weight curves of male Sprague–Dawley rats (Iffa-Credo). All the experiments were carried out during the light phase. The behavioral tests began when the rats were 2 months old. One group (young group or Y group) was tested for impulsivity and then working memory at 2–5 months of age. The second group (longitudinal group or L group) was tested for impulsivity at 2–3 months and was kept in the animal facilities ad libitum before being tested again at 16–18 months of age, for impulsivity and memory (working memory and spatial recognition memory). This protocol avoids a possible effect of the repetition of the learning task on working memory performance. A third measure of impulsivity was made at 24–25 months on group L. 2.2. Apparatus and behavioral testing 2.2.1. Impulsivity 188.8.131.52. Apparatus The apparatus consisted of eight sound-insulated light-tight outer chambers each containing a two lever conditioning box (Imetronic, Pessac). The boxes () were constructed from white plastic panels with a Plexiglas door. They were equipped with a fan providing a background sound. Each box was permanently illuminated by a diffuse 2 lx light source located in the middle of the ceiling. The floor consisted of 5 mm diameter stainless steel bars spaced 1.5 cm apart. Two stainless steel levers protruded horizontally 1 cm from the wall situated at the left of the door, 16 cm apart and 6 cm above the grid floor. A tray was situated centrally on the opposite wall. Food pellets (45 mg, Bioserv, USA) were delivered in the tray by a food dispenser. A program (Imetronic, Pessac) controlled the chambers and collected the data on a microcomputer situated outside the testing room. 184.108.40.206. Procedure Impulsivity was assessed using a fixed consecutive number schedule (FCN8) (adapted from ). Over several days before the beginning of the experiment, the animals were handled a few minutes everyday. The food was removed from the home cage of the rats on the day before the first test. Thereafter they were fed in the evening after testing. Rats were placed 30 min before each session in the experimental room. Each rat was tested in the same chamber throughout the experiment. On the first day, the levers were retracted and the rats were placed for 30 min into the operant chambers with 10 food pellets placed in the food tray. On Day 2, they were tested under a fixed time schedule of reinforcement in which one food pellet was delivered every 60 s in a non-contingent manner for 30 min. On Day 3 of training, the left lever was inserted into the box, and every press resulted in the delivery of a food pellet. On the following day, the right lever was inserted and the same schedule of reinforcement was employed. This alternation procedure was continued until the rats had pressed both levers at least 100 times in less than 20 min. Fixed consecutive number training was then begun. On the first day the rats were required first to press the left lever (FCN lever) and the right lever (reinforced lever) to obtain food (FCN1) during a 45-min session. This session was continued until the rats had obtained at least 60 pellets. Then, the FCN requirement was increased to 3 and according to the same criterion, to 5 and 8 (test condition). To accelerate the learning phase, an additional step (FCN2) was added for group Y. If the chain was shorter than 2, 3, 5 or 8 (respectively), the rat was required to start a new chain. If the chain was longer, it had no consequence and the pellet was delivered when the rat pressed the reinforced lever. Rats that failed to reach the criterion to be tested under a FCN8 schedule after 20 training sessions were excluded. The other rats were tested under the FCN8 schedule during 8 days. The mean scores of each animal obtained during Days 2–8 were recorded. When tested for the second and third measures of impulsivity, rats were tested 3 days with a FCN8 schedule. If they could reach a criterion of 30 pellets obtained during the last session, they were tested for eight additional FCN8 schedule sessions (test phase). Otherwise, a training phase was started according to the previous one, before reaching the FCN8 schedule sessions. 220.127.116.11. Measurements The data from both experiments were analyzed in a similar manner. For each measure (except for learning the task), values were obtained from the mean of the 2–8 test days. The measures were the following: • Response efficiency: The number of responses made on the FCN lever divided by the number of pellets obtained. This shows the average number of lever responses required to obtain a food pellet (minimal (optimal) value=8). An increase in the numerical value of this measure reflects a reduction in efficiency. • Chain length: The average length of the chain of responses made on FCN lever before a response was made on the Reinf. Lever (optimal value is 8). This value was chosen to classify rats into three groups: a first group defining impulsive rats (IMP) contained all the rats with a mean chain length below 6, a second group defining non-impulsive rats (NIMP) with a mean chain length above 8, and the third contained the remainder. A control of the stability of the mean chain length during the 7 days of the test phase was made. Only rats with stable scores were kept. • Proportion of efficient chains: Percentage of at least eight consecutive presses on FCN lever as a proportion of the total number of chains made on this lever. The distribution of chain lengths was also analyzed: the proportion of total number of chains greater than length 1, length 2, length 3 and so on was calculated. • Response rate: The mean total number of both lever responses per session. • Latency to collect food pellets: The mean latency(ies) to visit the food magazine after an efficient response. • Learning of the procedure before reaching test phase: The number of sessions needed to reach the test phase was also noted. 2.2.2. Working memory 18.104.22.168. Apparatus The apparatus consisted of an octagonal central platform communicating through 8 doors with 8 identical arms (70 cm long, 14 cm wide) equally spaced from the platform. The doors were opened and closed automatically under program control from a computer (Imetronic, Pessac) outside the testing room. Vertical walls (20 cm high near the center and 13 cm high at the other end) were made of transparent Plexiglas. Food cups were fixed at the end of each arm. The apparatus was placed in a defined position in a sound-attenuated room under dim illumination. A white noise (70 dB) attenuated noise of the motors controlling the doors. Numerous visual cues were placed on the walls. All the cues were kept constant throughout the experiments. 22.214.171.124. Procedure During the first day of habituation, rats were left for 2 min to explore each closed arm of the maze containing food. During the following days, the rat was placed in the closed central platform for 10 s. Then, all the doors were opened and rat was left to explore the arms. When the rat returned to the center, each visited arm was then closed by a door. The session was terminated when all 8 arms were visited. This procedure was continued daily until the following criterion of habituation was reached: duration of session <5 min and all pellets had to be eaten in two consecutive sessions. This procedure habituated rats to the maze (opening and closing of the doors, eating the pellets). Acquisition: In the acquisition phase, each rat was subjected to one trial per day over 6 days. Food (one 45 mg pellet) was placed at the end of each arm. The rat was placed in the closed central platform for 10 s, all the doors were opened, and the animal was left to explore the arms. Each time the animal returned to the center, the doors were closed again for 6 s, prior to the next exploration. This procedure prevents systematic visits in adjacent arms. An entry into a non-baited arm was considered as an error. The trial ended when the rat had visited each of the 8 arms. The trial was discontinued when more than 16 visits had been made, or after 20 min. Effect of the duration of confinement before a choice on working memory: After the acquisition phase, the effect of the duration of confinement in the central platform was assessed. This duration was reduced to 1 s (4 sessions), reestablished to 6 s (2 sessions) and increased to 12 s (1 session). Interferences: After two final sessions using a 6-s confinement duration in the central platform, the effect of interferences on working memory was assessed with two different protocols. Interferences were introduced during two daily sessions using a 6-s confinement duration, separated by a session without interference. The first interference consisted of four 2-s interruptions of the white noise separated by a 2-s interval when the rats were at the end of an arm during choices 2, 3, 5 and 7. The second interference consisted of a 5-min interruption between the fourth and fifth choices in which rats were removed from the central platform and placed in a similar chamber to the one where they had been trained for impulsivity. The chamber was dimly illuminated and only contained the two levers. After 5 min the animal was again placed on the central platform and allowed to complete the trial. The following parameters were noted: total number of errors, number of errors during the eight first choices and number of visits made before the first error. The program collected these data and enabled visual control of the doors and the position of the rat in the maze. Young and middle-aged rats were tested with the same protocol. 2.2.3. Spatial recognition 126.96.36.199. Apparatus A gray plastic Y-maze (Imetronic, Pessac) was used to assess spatial recognition. Each arm was 50 cm long, 16 cm wide and 32 cm high and was equipped with two infrared light beams 22 cm apart crossing each arm 3 cm above the floor. One beam was situated 3 cm from the center, while the other was placed 25 cm from the end of the arm. A visit to an arm was recorded only when the proximal and distal beams were interrupted in succession. Interruption of these infrared beams was recorded on a micro-computer situated outside the testing room. In order to suppress olfactory cues, the floor of the maze was covered with odor-saturated sawdust, which was mixed after each trial. The maze was placed in a sound-attenuated room under dim illumination. Numerous visual cues were placed on the walls of the testing room and were kept constant throughout the behavioral testing (see  and ). The number and the duration of explorations of each arm were recorded every minute for the retrieval trials. The results were expressed as percentages of visits and time spent in the novel arm with respect to the total number of visits and the total duration of visits in the three arms, respectively. 188.8.131.52. Procedure This task consisted of two trials separated by a 4- and 6-h inter-trial interval. In the first trial, one arm of the Y-maze was closed with a guillotine door. During the acquisition phase (trial 1), one arm of the Y-maze was closed. The animals were placed in an arm, their head pointing away from the center of the maze, and were allowed to visit the two arms of the maze for 5 min. During the inter-trial interval (ITI), rats were replaced in their home cages, outside the testing room. In the retrieval phase (trial 2), animals had free access to the three arms for 5 min. The animals were placed in the same arm of the maze at the beginning of each trial, but the position of the novel arm was at the left for half of each animal group and at the right of the starting arm for the other half (in a random order). The time spent in each arm of the maze as well as the number of visits to the three arms were measured during the first 2 min of the second trial (see ). The results were expressed as percentage of time spent in the novel arm with respect to the total duration of visits in the three arms and percentage of visits in the novel arm with respect to the total number of visits in the three arms. Rats which did not reach a criterion of 40% of duration or number of visits in the novel arm compared to the other two arms (a random exploration being 33%) were considered as unable to recognize the novel arm. When rats failed to recognize the novel arm with the 4-h ITI, response to novelty and visual or motivational capacities were controlled using a short ITI (2-min). All the rats failing to reach a criterion of 40% of duration or number of visits in the novel arm compared to the other two arms with a short ITI were excluded from all the cognitive tasks. 2.3. Statistical analysis The IMP, NIMP and INT group survival rates were compared using the Log-rank test . Comparisons of impulsivity and working memory scores of the three groups were made using analysis of variance (ANOVA), followed by analyses of simple main effects and by post-hoc comparisons using the Newman–Keuls (NK) test when appropriate. Longitudinal analysis of impulsivity scores were performed using factorial ANOVA with repeated measures with age (3, 15, 25 months) as a within-subjects factor and group (IMP, NIMP, INT) as a between-subjects factor, for age/group interactions analysis. Student’s t-tests were used to compare scores of impulsivity of the different groups and to evaluate the difference between performance in the Y-maze and random choice. Correlations between scores of impulsivity obtained during aging and between impulsivity and working memory scores were evaluated using Bravais–Pearson’s correlation test. Inter-individual variability between performances of young and old rats in the impulsive task were compared with the Bartlett test. 3. Results 3.1. Individual differences in impulsivity in youth The Y and L groups were tested during youth in the impulsivity task. In group L, six rats were excluded from the analysis because they did not reach the criterion to be tested under the FCN8 schedule. One did not learn to press on the lever, and five needed an average of 14±1.4 sessions to reach the criterion at the FCN3 schedule, whereas the others only required 6.9±0.5 sessions (t=5.56, d.f.=5.7, P<0.001). In group Y, four rats were excluded from this analysis because they did not reach the criterion for the test phase. They also needed significantly more sessions to reach the criterion at the FCN3 schedule (10.7±1.0) compared to the others (4.6±0.3) (t=6.06, d.f.=38, P<0.001). Y group benefited from an additional step (FCN2) in the learning of the task compared to L group: the number of sessions to reach the criterion for being tested under a FCN8 schedule (6.9±0.4) was significantly less than that of the L group (11.9±0.5) (t=8.24, d.f.=68, P<0.001). No significant difference was observed between the scores reflecting impulsivity or activity in the Y and L groups, and so only the data obtained with group L will be detailed below. Important individual differences were observed: the mean chain length over the last 7 days of the test phase ranged from 3.6 to 10.6. Rats were split in three groups according to their mean length of chains: a first group defining impulsive rats (IMP, n=11) contained all the rats with a mean chain length below 6, a second group defining non-impulsive rats (NIMP, n=8) with a mean chain length above 8, and the third contained the remainder defined as intermediate (INT, n=15) rats. Individual differences in mean length of chains are represented on Fig. 1A. The mean length of chains of IMP rats was 4.7±0.2, INT rats, 6.8±0.1 and NIMP rats, 9.3±0.3. The distribution of the mean chain lengths (proportion of total number of chains greater than length 1, length 2, length 3, etc.) comparing the behavior of the three groups is represented in Fig. 1B. Full-size image (20 K) Fig. 1. Inter-individual differences in impulsivity performances of a group of young rats. (A) Distribution of individual scores of rats responding under a FCN8 schedule of reinforcement and selection of non-impulsive rats (NIMP, score of mean length of chains above 8) impulsive rats (IMP, score below 6) and the remainder with an intermediate score (INT). (B) Distribution (%) of mean chain lengths of efficient (≥8) or inefficient chains (<8) of the three groups. Optimal performance (8) is indicated by the vertical line. Short chains of presses characterize an impulsive response whereas long chains of presses characterize a non-impulsive response. Figure options As expected, the three groups differed significantly in the parameters reflecting impulsivity: percentage of efficient chains (chains≥8) was significantly lower in IMP rats compared to both INT and NIMP rats, F(2,31)=114.4, P<0.001; NK, P<0.001 ( Fig. 2A) as well as the response efficiency, F(2,31)=6.38, P<0.01; NK, P<0.01 ( Fig. 2B). Full-size image (43 K) Fig. 2. Comparisons of performances of IMP, INT and NIMP groups of young rats under a FCN8 schedule of reinforcement. Impulsive scores of IMP rats reflected by efficient chain rate (A) and response efficiency (B) significantly differed from both INT and NIMP groups. Conversely, IMP group had a lower total activity compared to the other two groups as shown by the total number of lever presses during the test (C). Learning of the task reflected by the number of training sessions before test did not differ between the three groups (D). ANOVA: ∗∗∗P<0.001 and ∗∗P<0.01 for comparisons between IMP and NIMP rats; °°°P<0.001 and °°P<0.01 for comparisons between IMP and INT rats. Figure options The rate of responding was significantly lower in IMP rats compared to both INT and NIMP rats, F(2,31)=15.3, P<0.001; NK, P<0.001 ( Fig. 2C). Positive correlations were observed between the rate of responding and percentage of efficient chains (r=0.65, d.f.=32, P<0.001) as well as the mean length of chains (r=0.7, d.f.=32, P<0.001), and a negative correlation was observed with response efficiency (r=−0.62, d.f.=32, P<0.001). The mean latency to collect earned food pellets did not differ between the three groups (F(2,31)=1.03, ns). Learning performances reflected by the number of sessions needed to reach the FCN8 schedule did not differ significantly between the three groups (F(2,31)=2.86, ns) ( Fig. 2D). The number of sessions needed to reach the criterion at the FCN3 schedule was also similar for IMP and NIMP rats (8.1±0.9 and 5.9±1.1, respectively, t=1.57, d.f.=17, ns). Similarly, the number of sessions required to reach the test phase in the Y group did not significantly differ between IMP (n=8) and NIMP rats (n=9). In addition, there were no differences between the two in reaching the FCN8 or the FCN3 schedules (FCN8: IMP=8.0±0.7; NIMP=6.3±0.8, t=1.5, d.f.=15, ns; FCN3: IMP=4.7±0.6; NIMP=4.3±0.9, t=0.39, d.f.=15, ns). 3.2. Longitudinal study of impulsivity Lifetime data analysis revealed no significant differences between survival rates of the IMP, INT and NIMP groups the last measurement (χ2=0.63, d.f.=2, ns). 3.2.1. Progression of impulsivity with age 184.108.40.206. From youth to middle-age Rats from group L tested for impulsivity during youth were retested 1 year later, at 15 months of age. At 15 months, three rats died (IMP rats). The six rats which were previously unable to reach the criterion at 3 months were retested at 15 months, but they still could not reach the criterion to be tested under the FCN8 schedule. They were definitively excluded from the experiment. Scores reflecting impulsivity fell significantly with age. Mean length of chains increased from 6.9±0.3 at 3 months to 7.6±0.3 at 15 months (F(1,30)=6.13, P<0.05). Percentage of efficient chains also increased with age (F(1,30)=6.35, P<0.05) and middle-aged rats made more efficient responses (F(1,30)=5.43, P<0.05) ( Fig. 3A and B). Full-size image (13 K) Fig. 3. Longitudinal study of impulsivity. Impulsivity was measured three time in rats under a FCN8 schedule of reinforcement: at youth, middle-age and when old. Impulsive scores reflected by efficient chain rate (A) and response efficiency (B) significantly decreased with age from youth to middle-age and did not change significantly from middle age to old age. Conversely, total activity significantly increased as shown by the total number of lever presses during the test (C). Learning of the task reflected by the number of training sessions before test was facilitated at middle-age by previous experience in this task when young and this improvement remained when old (D). ANOVA: ∗∗∗P<0.001 and ∗P<0.05 for comparisons between scores obtained at youth and middle-age. Figure options The total number of responses significantly increased (F(1,30)=6.08, P<0.05) and the number of training sessions required to reach the test phase was highly facilitated by their previous experience (F(1,30)=143.57, P<0.001) ( Fig. 3C and D). 220.127.116.11. From middle age to old age Rats from group L were tested for the third time at 25 months of age. At 25 months, 22 rats survived to the last measurement (55%). Among the surviving rats, 3 were previously excluded from the analysis and 6 (4 IMP and 2 INT rats) failed to reach the criterion for being tested under a FCN8 schedule. In contrast to the young or middle-aged rats, most of them alternated short periods of activity and long periods of rest. However, the 13 remaining rats performed the task without obvious impairment of motor or motivational abilities. These 13 remaining rats were representative of the entire starting population as shown by the fact that their first impulsivity scores did not differ from those of the non-surviving rats (efficient chain rate: F(1,33)=1.09, ns; response efficiency: F(1,33)=0.92, ns; total response: F(1,33)=2.50, ns; learning: F(1,33)=2.33, ns). At 25 months, scores reflecting impulsivity did not significantly differ from those obtained at 15 months: mean length of chains (F(1,12)=0.51, ns; percentage of efficient chains (F(1,12)=0.75, ns); response efficiency (F(1,12)=0.35, ns) ( Fig. 3A and B). The total number of responses was also stable from 15 to 25 months (F(1,12)=2.0, ns) and the number of training sessions required to reach the test phase did not differ (F(1,12)=0.75, ns) ( Fig. 3C and D). 3.2.2. Aging of the impulsivity trait defined in youth Scores measured in the impulsivity task of IMP, INT and NIMP groups defined during youth were compared at 15 and 25 months. 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