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A long-term stress exposure impairs maze learning performance in rats
Neuroscience Letters 273 (1999) 125±128 www.elsevier.com/locate/neulet
A long-term stress exposure impairs maze learning performance in rats Jun-Ichi Nishimura, Yutaka Endo, Fukuko Kimura* Department of Physiology, Yokohama City University School of Medicine, 3±9 Fuku-ura, Kanazawa-ku, Yokohama 236±0004, Japan Received 2 July 1999; received in revised form 6 August 1999; accepted 6 August 1999
Abstract To elucidate hippocampal dysfunctions following chronic stress exposure, we evaluated the effect of chronic stress on maze learning performance, as assessed by a radial eight-arm maze task. In the 12-week stress sessions, male rats in the stress group were exposed to the stress of a 15-min immersion in cold water once a day and, rats in the control group were slightly handled. Rats in the stress group performed signi®cantly poorly during the acquisition period (P , 0:01) and required more trials to attain at least seven correct choices in the ®rst eight choices for ®ve consecutive trials (P , 0:05). Together with our previous ®ndings that chronic stress exposure damages the hippocampus histologically, we concluded that chronic stress exposure resulted in an impairment of maze learning performance, probably due to hippocampal damages. q 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Hippocampus; Chronic stress; Glucocorticoid; Radial arm maze; Memory; Rats
It has been elucidated that a prolonged elevation in the plasma level of glucocorticoids (GCs) damages neurons of the hippocampus [8,16,19], a principal neural target site of the steroid [13]. In addition, these authors and also others as described below have been aware that the hippocampal changes due to chronic stress or GC exposure are similar to those found in the aged hippocampus. For example, exposures to an excess of endogenous GCs through repeated stress caused a reduction of hippocampal neurons [19] and GC caused aging-like changes in the electrophysiological and morphological parameters of the hippocampus [7]. It is known that the hippocampus plays a critical role in certain types of learning and memory, and hippocampal damages cause cognitive impairment [15]. Recently, Lupien et al. [11] reported that prolonged elevation in plasma GC correlated with the degree of hippocampal atrophy and was further related to cognitive de®cits in aged humans. So GC could damage the hippocampus histologically, resulting in impairments of learning and memory functions in aged animals. We have shown that adrenalectomy increases local cerebral blood ¯ow (CBF) in the hippocampus, in a reverse direction against an acceleration of aging [3] and a longterm GC treatment results in an impairment of maze learn* Corresponding author. Tel.: 181-45-787-2579; fax: 181-45787-2580.
ing [4] and a decrease in local CBF in the hippocampus [5], as observed in aged ones [12,20]. We have also reported that a long-term stress or GC exposure causes histological damages of the hippocampus [5,6] and further that chronic stress exposure results in disturbances of daily ¯uctuation of local CBF in the hippocampus, with a signi®cant decrease only during the dark cycle [6]. The results mean that the hippocampal neurons of the chronic stressed rats might be less responsive to environmental stimuli derived from motor activity. These results are likely to be in harmony with the possible impairment of learning abilities. Therefore, the purpose of the present study was to determine whether chronic exposure to such stress as used in that study could cause an impairment of learning function. Adult male Wistar±Imamichi rats obtained from the Animal Reproduction Research Co. (Oomiya, Japan) were used. All animals were housed under standard conditions, with lights on between 05:00 and 19:00 h, room temperature controlled at 248C, and received food and water ad libitum. At 12 weeks of age, rats were divided into two groups, i.e. a control group (n 15) and a chronically stressed group (stress group, n 15). Rats in the stress group were immersed up to the neck in the cold water for 15 min, as previously reported [6]. Rats in the control group were slightly handled for about 1 min as well. Immediately after either procedure, rats were returned to their home
0304-3940/99/$ - see front matter q 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S03 04 - 394 0( 9 9) 00 64 5- X
126
J.-I. Nishimura et al. / Neuroscience Letters 273 (1999) 125±128
Fig. 1. Effects of chronic stress on the number of correct choices in the ®rst eight choices during the ®rst 7 days in rats. Each point and its vertical line indicate the mean and SEM, respectively, based on 15 rats in each group.
cages. These stress exposures were performed once a day, between 13:00 and 15:00 h, over 12 weeks. Following these stress sessions, all 30 rats were allowed a 4-week recovery. Before the maze learning, the mean body weight of rats in the stress group were still lower than those of rats in the control group (control group, 532:8 ^ 6:2 g; stress group, 492:3 ^ 4:0 g), however, body weight gain of rats in the stress group were much higher than those of the control rats (control group, 4:0 ^ 0:6 g/week; stress group, 11:9 ^ 0:6 g/week). Thereafter, a maze learning task was
Fig. 2. Effects of chronic stress on the number of trials to attain the learning criteria in rats. Each bar and its vertical line indicate the mean and SEM, respectively, based on 15 rats in each group.
performed. Brie¯y, it was performed on a radial eight-arm maze apparatus, which had an octagonal center platform, around which were arranged eight arms. The whole apparatus was set in the experimental room, in which there were several visual cues including an experimenter, one door, one un®gured poster and one window with opaque glass. In the apparatus, a guillotine door separated the center platform from each of the arms to prevent the animal from entering directly adjacent arms. In order to insure motivation for maze learning, the rats were subjected to a food deprivation regimen that reduced their body weight to 80±85% of the initial weight. For their familiarization to this apparatus, they were, in a group of ®ve animals, placed in the center platform of the apparatus and allowed to visit the arms freely, where small pellets were scattered. This procedure was done for 10 min, once a day. After a 5-day period of this familiarization, each animal was tested once a day over 21 consecutive days. An arm choice was considered correct if the rat entered an arm with a small pellet as a reward at the end and ate it. An error arm choice was scored if the rat reentered the arm in which it had previously eaten the food. The effects of chronic stress on learning were also evaluated on the basis of the learning criterion, which was de®ned as showing at least seven correct choices in the ®rst eight choices for 5 consecutive days. The rat was left in the maze until all eight pellets were consumed or 10 min had elapsed. Each rat was fed for the day after being returned to its home cage. Differences between means were analyzed by a two-way repeated measures analysis of variance (ANOVA) or Student's t-test, with the signi®cance level being set at P , 0:05. Fig. 1 shows the mean number of correct choices in the ®rst eight choices. There was a clear improvement in performance over the 7-day acquisition period in both the control and stress groups, as indicated by two-way (treatment £ trials) repeated measures ANOVA (P 6; 96 0:002). The ANOVA also revealed that the effect of stress exposure was signi®cant (F 1; 196 0:008) and there was no signi®cant treatment £ trials interaction. As a result, rats in the stress group required more trials to attain the criterion than did rats in the control group (P , 0:05 by Student's t-test) (Fig. 2). Thus, rats in the stress group performed signi®cantly poorly during this acquisition period and were delayed in their acquisition of this spatial learning task, as compared with rats in the control group. The present study demonstrated that chronic stress exposure impaired maze learning performance in rats, as evaluated based on the following two parameters: (1) the number of correct choices in the ®rst eight choices during an improvement of performance over the ®rst 7 days and (2) the number of trials to attain at least seven correct choices in the ®rst eight choices for ®ve consecutive trials. There might be a possibility that somatic status, such as appetite and motor activity, could have in¯uenced their performance. However, we could deny the possibility, because body
J.-I. Nishimura et al. / Neuroscience Letters 273 (1999) 125±128
weight gain of rats in the stress group had been increased to 11.9 g/week, which was much higher than those of rats in the control group, in a 4-week recovery period and we previously reported that motor activity of the rats exposed to the same stress regimen as used in the present study were similar to those of rats in the control group [6]. Although other researchers have also reported on impairments of learning functions caused by chronic stress [1,9,10], the present study is the ®rst to show that an impairment of learning performance could be observed in young rats even following a 4-week recovery period after a longterm stress exposure, not during or immediately after stress exposure. In support of the present results, we have reported that a long-term exposure to the same stress regimen causes hippocampal neurons to be damaged and/or less responsive to environmental stimuli, which are observed a long time after the stress sessions [6]. It is likely that GCs account for the aging-acceleration effect of stress. As mentioned in the introduction, a prolonged elevation in the plasma level of GCs damaged hippocampal neurons [8,16,19]. Sapolsky et al. [17] proposed the glucocorticoid cascade hypothesis for hippocampal aging, that is, hippocampal damages due to an excess exposure to GC could lead to a higher elevation of plasma GC level, which should in turn exacerbate hippocampal damage. Accordingly, hippocampal damages due to an excess exposure to GC through chronic stress could cause an impairment of maze learning performance. However, chronic exposures to stress may decrease the activity of the septo-hippocampal cholinergic system, which itself is involved in spatial learning [2]. This is likely because the stress response of the septo-hippocampal cholinergic neurons was attenuated in aged rats [14]. Also, GC administration for 2 months caused septo-hippocampal cholinergic neurons to degenerate prior to the hippocampal neuronal loss [18], which is likely to lead to a cognitive impairment. Since it has also been reported that the impairment of radial eight-arm maze performance was correlated with a reduction in the number of cholinergic neurons of the septo-hippocampal cholinergic system [2], our ®ndings may be accounted for by such a degeneration of the septo-hippocampal cholinergic system due to an excess of endogenous GC exposure through chronic stress. Together with previous ®ndings that aged rats actually exhibited de®cits in their spatial working memory in radial eight-arm maze [20], our results, at least in part, might support the hypothesis that a long-term exposure to an excess of GCs, endogenous or exogenous, could accelerate hippocampal dysfunctions similar to the aged hippocampus, in physiological aspect. This work was supported, in part, by a Grant-in-Aid for Encouragement of Young Scientists from the Ministry of Education, Science, Sports and Culture, Japan (No. 05770738) to Y.E. and by a grant from the Promotional Foundation for Life Science to F.K.
127
[1] Bodnoff, S.R., Humphreys, A.G., Lehman, J.C., Diamond, D.M., Rose, G.M. and Meaney, M.J., Enduring effects of chronic corticosterone treatment on spatial learning, synaptic plasticity and hippocampal neuropathology in young and mid-aged rats. J. Neurosci., 15 (1995) 61±69. [2] Dipatre, P.L., Oh, J.D., Simmons, J.M. and Butcher, L.L., Intra®mbrial colchicine produces transient impairment of radial-arm maze performance correlated with morphologic abnomalities of septohippocampal neurons expressing cholinergic markers and nerve growth factor receptor. Brain Res., 523 (1990) 316±320. [3] Endo, Y., Nishimura, J.-I. and Kimura, F., Adrenalectomy increases local cerebral blood ¯ow in the rat hippocampus. P¯uÈgers Arch., 426 (1994) 183±188. [4] Endo, Y., Nishimura, J.-I. and Kimura, F., Impairment of maze learning in rats following long-term glucocorticoid treatments. Neurosci. Lett., 203 (1996) 199±202. [5] Endo, Y., Nishimura, J.-I., Kobayashi, S. and Kimura, F., Long-term glucocorticoid treatments decrease local cerebral blood ¯ow in the rat hippocampus, in association with histological damage. Neuroscience, 79 (1997) 745±752. [6] Endo, Y., Nishimura, J.-I., Kobayashi, S. and Kimura, F., Chronic stress exposure in¯uences local cerebral blood ¯ow in the rat hippocampus. Neuroscience, 93 (1999) 551±555. [7] Kerr, D.S., Campbell, L.W., Applegate, M.D., Brodish, A. and Land®eld, P.W., Chronic stress-induced acceleration of electrophysiologic and morphometric biomarkers of hippocampal aging. J. Neurosci., 11 (1991) 1316±1324. [8] Land®eld, P.W., Baskin, R.K. and Pitler, T.A., Brain aging correlates: retardation by hormonal-pharmacological treatments. Science, 214 (1981) 581±584. [9] Luine, V., Martinez, C., Villegas, M., Magarinos, A.M. and McEwen, B.S., Restraint stress reversibly enhances spatial memory performance. Physiol. Behav., 59 (1996) 27±32. [10] Luine, V., Villegas, M., Martinez, C. and McEwen, B.S., Repeated stress causes reversible impairments of spatial memory performance. Brain Res., 639 (1994) 167±170. [11] Lupien, S.J., de Leon, M., de Santi, S., Convit, A., Tarshish, C., Nair, N.P.V., Thakur, M., McEwen, B.S., Hauger, R.L. and Meaney, M.J., Cortisol levels during human aging predict hippocampal atrophy and memory de®cits. Nat. Neurosci., 1 (1998) 69±73. [12] Martin, A.J., Friston, K.J., Colebatch, J.G. and Frackowiak, R.S.J., Decreases in regional cerebral blood ¯ow with normal aging. J. Cereb. Blood Flow Metab., 11 (1991) 684±689. [13] McEwen, B.S., de Kloet, E. and Rostene, W., Adrenal steroid receptors and actions in the nervous system. Physiol. Rev., 66 (1986) 1121±1188. [14] Mizuno, T. and Kimura, F., Attenuated stress response of hippocampal acetylcholine release and adrenocortical secretion in aged rats. Neurosci. Lett., 222 (1997) 49±52. [15] Olton, D.C., Becker, J.T. and Handleman, G.E., Hippocampus, space and memory. Behav. Brain Sci., 2 (1979) 313± 365. [16] Sapolsky, R.M., Krey, L.C. and McEwen, B.S., Prolonged glucocorticoid exposure reduces hippocampal neuron number: implication for aging. J. Neurosci., 5 (1985) 1222±1227. [17] Sapolsky, R.M., Krey, L.C. and McEwen, B.S., The neuroendocrinology of stress and aging: the glucocorticoid cascade hypothesis. Endocrine Rev., 7 (1986) 284±301. [18] Tizabi, Y., Gilad, V.H. and Gilad, G.M., Effects of chronic stressors or corticosterone treatment on the septohippocampal cholinergic system of the rat. Neurosci. Lett., 105 (1989) 177±182.
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J.-I. Nishimura et al. / Neuroscience Letters 273 (1999) 125±128
[19] Uno, H., Tarara, R., Else, J., Suleman, M. and Sapolsky, R.M., Hippocampal damage associated with prolonged and fatal stress in primates. J. Neurosci., 9 (1989) 1705± 1711.
[20] Wallace, J.E., Krauter, E.E. and Campbell, B.A., Animal models of decline memory in the aged: short-term and spatial memory in the aged rat. J. Gerontol., 35 (1980) 355±363.
A long-term stress exposure impairs maze learning performance in rats Jun-Ichi Nishimura, Yutaka Endo, Fukuko Kimura* Department of Physiology, Yokohama City University School of Medicine, 3±9 Fuku-ura, Kanazawa-ku, Yokohama 236±0004, Japan Received 2 July 1999; received in revised form 6 August 1999; accepted 6 August 1999
Abstract To elucidate hippocampal dysfunctions following chronic stress exposure, we evaluated the effect of chronic stress on maze learning performance, as assessed by a radial eight-arm maze task. In the 12-week stress sessions, male rats in the stress group were exposed to the stress of a 15-min immersion in cold water once a day and, rats in the control group were slightly handled. Rats in the stress group performed signi®cantly poorly during the acquisition period (P , 0:01) and required more trials to attain at least seven correct choices in the ®rst eight choices for ®ve consecutive trials (P , 0:05). Together with our previous ®ndings that chronic stress exposure damages the hippocampus histologically, we concluded that chronic stress exposure resulted in an impairment of maze learning performance, probably due to hippocampal damages. q 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Hippocampus; Chronic stress; Glucocorticoid; Radial arm maze; Memory; Rats
It has been elucidated that a prolonged elevation in the plasma level of glucocorticoids (GCs) damages neurons of the hippocampus [8,16,19], a principal neural target site of the steroid [13]. In addition, these authors and also others as described below have been aware that the hippocampal changes due to chronic stress or GC exposure are similar to those found in the aged hippocampus. For example, exposures to an excess of endogenous GCs through repeated stress caused a reduction of hippocampal neurons [19] and GC caused aging-like changes in the electrophysiological and morphological parameters of the hippocampus [7]. It is known that the hippocampus plays a critical role in certain types of learning and memory, and hippocampal damages cause cognitive impairment [15]. Recently, Lupien et al. [11] reported that prolonged elevation in plasma GC correlated with the degree of hippocampal atrophy and was further related to cognitive de®cits in aged humans. So GC could damage the hippocampus histologically, resulting in impairments of learning and memory functions in aged animals. We have shown that adrenalectomy increases local cerebral blood ¯ow (CBF) in the hippocampus, in a reverse direction against an acceleration of aging [3] and a longterm GC treatment results in an impairment of maze learn* Corresponding author. Tel.: 181-45-787-2579; fax: 181-45787-2580.
ing [4] and a decrease in local CBF in the hippocampus [5], as observed in aged ones [12,20]. We have also reported that a long-term stress or GC exposure causes histological damages of the hippocampus [5,6] and further that chronic stress exposure results in disturbances of daily ¯uctuation of local CBF in the hippocampus, with a signi®cant decrease only during the dark cycle [6]. The results mean that the hippocampal neurons of the chronic stressed rats might be less responsive to environmental stimuli derived from motor activity. These results are likely to be in harmony with the possible impairment of learning abilities. Therefore, the purpose of the present study was to determine whether chronic exposure to such stress as used in that study could cause an impairment of learning function. Adult male Wistar±Imamichi rats obtained from the Animal Reproduction Research Co. (Oomiya, Japan) were used. All animals were housed under standard conditions, with lights on between 05:00 and 19:00 h, room temperature controlled at 248C, and received food and water ad libitum. At 12 weeks of age, rats were divided into two groups, i.e. a control group (n 15) and a chronically stressed group (stress group, n 15). Rats in the stress group were immersed up to the neck in the cold water for 15 min, as previously reported [6]. Rats in the control group were slightly handled for about 1 min as well. Immediately after either procedure, rats were returned to their home
0304-3940/99/$ - see front matter q 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S03 04 - 394 0( 9 9) 00 64 5- X
126
J.-I. Nishimura et al. / Neuroscience Letters 273 (1999) 125±128
Fig. 1. Effects of chronic stress on the number of correct choices in the ®rst eight choices during the ®rst 7 days in rats. Each point and its vertical line indicate the mean and SEM, respectively, based on 15 rats in each group.
cages. These stress exposures were performed once a day, between 13:00 and 15:00 h, over 12 weeks. Following these stress sessions, all 30 rats were allowed a 4-week recovery. Before the maze learning, the mean body weight of rats in the stress group were still lower than those of rats in the control group (control group, 532:8 ^ 6:2 g; stress group, 492:3 ^ 4:0 g), however, body weight gain of rats in the stress group were much higher than those of the control rats (control group, 4:0 ^ 0:6 g/week; stress group, 11:9 ^ 0:6 g/week). Thereafter, a maze learning task was
Fig. 2. Effects of chronic stress on the number of trials to attain the learning criteria in rats. Each bar and its vertical line indicate the mean and SEM, respectively, based on 15 rats in each group.
performed. Brie¯y, it was performed on a radial eight-arm maze apparatus, which had an octagonal center platform, around which were arranged eight arms. The whole apparatus was set in the experimental room, in which there were several visual cues including an experimenter, one door, one un®gured poster and one window with opaque glass. In the apparatus, a guillotine door separated the center platform from each of the arms to prevent the animal from entering directly adjacent arms. In order to insure motivation for maze learning, the rats were subjected to a food deprivation regimen that reduced their body weight to 80±85% of the initial weight. For their familiarization to this apparatus, they were, in a group of ®ve animals, placed in the center platform of the apparatus and allowed to visit the arms freely, where small pellets were scattered. This procedure was done for 10 min, once a day. After a 5-day period of this familiarization, each animal was tested once a day over 21 consecutive days. An arm choice was considered correct if the rat entered an arm with a small pellet as a reward at the end and ate it. An error arm choice was scored if the rat reentered the arm in which it had previously eaten the food. The effects of chronic stress on learning were also evaluated on the basis of the learning criterion, which was de®ned as showing at least seven correct choices in the ®rst eight choices for 5 consecutive days. The rat was left in the maze until all eight pellets were consumed or 10 min had elapsed. Each rat was fed for the day after being returned to its home cage. Differences between means were analyzed by a two-way repeated measures analysis of variance (ANOVA) or Student's t-test, with the signi®cance level being set at P , 0:05. Fig. 1 shows the mean number of correct choices in the ®rst eight choices. There was a clear improvement in performance over the 7-day acquisition period in both the control and stress groups, as indicated by two-way (treatment £ trials) repeated measures ANOVA (P 6; 96 0:002). The ANOVA also revealed that the effect of stress exposure was signi®cant (F 1; 196 0:008) and there was no signi®cant treatment £ trials interaction. As a result, rats in the stress group required more trials to attain the criterion than did rats in the control group (P , 0:05 by Student's t-test) (Fig. 2). Thus, rats in the stress group performed signi®cantly poorly during this acquisition period and were delayed in their acquisition of this spatial learning task, as compared with rats in the control group. The present study demonstrated that chronic stress exposure impaired maze learning performance in rats, as evaluated based on the following two parameters: (1) the number of correct choices in the ®rst eight choices during an improvement of performance over the ®rst 7 days and (2) the number of trials to attain at least seven correct choices in the ®rst eight choices for ®ve consecutive trials. There might be a possibility that somatic status, such as appetite and motor activity, could have in¯uenced their performance. However, we could deny the possibility, because body
J.-I. Nishimura et al. / Neuroscience Letters 273 (1999) 125±128
weight gain of rats in the stress group had been increased to 11.9 g/week, which was much higher than those of rats in the control group, in a 4-week recovery period and we previously reported that motor activity of the rats exposed to the same stress regimen as used in the present study were similar to those of rats in the control group [6]. Although other researchers have also reported on impairments of learning functions caused by chronic stress [1,9,10], the present study is the ®rst to show that an impairment of learning performance could be observed in young rats even following a 4-week recovery period after a longterm stress exposure, not during or immediately after stress exposure. In support of the present results, we have reported that a long-term exposure to the same stress regimen causes hippocampal neurons to be damaged and/or less responsive to environmental stimuli, which are observed a long time after the stress sessions [6]. It is likely that GCs account for the aging-acceleration effect of stress. As mentioned in the introduction, a prolonged elevation in the plasma level of GCs damaged hippocampal neurons [8,16,19]. Sapolsky et al. [17] proposed the glucocorticoid cascade hypothesis for hippocampal aging, that is, hippocampal damages due to an excess exposure to GC could lead to a higher elevation of plasma GC level, which should in turn exacerbate hippocampal damage. Accordingly, hippocampal damages due to an excess exposure to GC through chronic stress could cause an impairment of maze learning performance. However, chronic exposures to stress may decrease the activity of the septo-hippocampal cholinergic system, which itself is involved in spatial learning [2]. This is likely because the stress response of the septo-hippocampal cholinergic neurons was attenuated in aged rats [14]. Also, GC administration for 2 months caused septo-hippocampal cholinergic neurons to degenerate prior to the hippocampal neuronal loss [18], which is likely to lead to a cognitive impairment. Since it has also been reported that the impairment of radial eight-arm maze performance was correlated with a reduction in the number of cholinergic neurons of the septo-hippocampal cholinergic system [2], our ®ndings may be accounted for by such a degeneration of the septo-hippocampal cholinergic system due to an excess of endogenous GC exposure through chronic stress. Together with previous ®ndings that aged rats actually exhibited de®cits in their spatial working memory in radial eight-arm maze [20], our results, at least in part, might support the hypothesis that a long-term exposure to an excess of GCs, endogenous or exogenous, could accelerate hippocampal dysfunctions similar to the aged hippocampus, in physiological aspect. This work was supported, in part, by a Grant-in-Aid for Encouragement of Young Scientists from the Ministry of Education, Science, Sports and Culture, Japan (No. 05770738) to Y.E. and by a grant from the Promotional Foundation for Life Science to F.K.
127
[1] Bodnoff, S.R., Humphreys, A.G., Lehman, J.C., Diamond, D.M., Rose, G.M. and Meaney, M.J., Enduring effects of chronic corticosterone treatment on spatial learning, synaptic plasticity and hippocampal neuropathology in young and mid-aged rats. J. Neurosci., 15 (1995) 61±69. [2] Dipatre, P.L., Oh, J.D., Simmons, J.M. and Butcher, L.L., Intra®mbrial colchicine produces transient impairment of radial-arm maze performance correlated with morphologic abnomalities of septohippocampal neurons expressing cholinergic markers and nerve growth factor receptor. Brain Res., 523 (1990) 316±320. [3] Endo, Y., Nishimura, J.-I. and Kimura, F., Adrenalectomy increases local cerebral blood ¯ow in the rat hippocampus. P¯uÈgers Arch., 426 (1994) 183±188. [4] Endo, Y., Nishimura, J.-I. and Kimura, F., Impairment of maze learning in rats following long-term glucocorticoid treatments. Neurosci. Lett., 203 (1996) 199±202. [5] Endo, Y., Nishimura, J.-I., Kobayashi, S. and Kimura, F., Long-term glucocorticoid treatments decrease local cerebral blood ¯ow in the rat hippocampus, in association with histological damage. Neuroscience, 79 (1997) 745±752. [6] Endo, Y., Nishimura, J.-I., Kobayashi, S. and Kimura, F., Chronic stress exposure in¯uences local cerebral blood ¯ow in the rat hippocampus. Neuroscience, 93 (1999) 551±555. [7] Kerr, D.S., Campbell, L.W., Applegate, M.D., Brodish, A. and Land®eld, P.W., Chronic stress-induced acceleration of electrophysiologic and morphometric biomarkers of hippocampal aging. J. Neurosci., 11 (1991) 1316±1324. [8] Land®eld, P.W., Baskin, R.K. and Pitler, T.A., Brain aging correlates: retardation by hormonal-pharmacological treatments. Science, 214 (1981) 581±584. [9] Luine, V., Martinez, C., Villegas, M., Magarinos, A.M. and McEwen, B.S., Restraint stress reversibly enhances spatial memory performance. Physiol. Behav., 59 (1996) 27±32. [10] Luine, V., Villegas, M., Martinez, C. and McEwen, B.S., Repeated stress causes reversible impairments of spatial memory performance. Brain Res., 639 (1994) 167±170. [11] Lupien, S.J., de Leon, M., de Santi, S., Convit, A., Tarshish, C., Nair, N.P.V., Thakur, M., McEwen, B.S., Hauger, R.L. and Meaney, M.J., Cortisol levels during human aging predict hippocampal atrophy and memory de®cits. Nat. Neurosci., 1 (1998) 69±73. [12] Martin, A.J., Friston, K.J., Colebatch, J.G. and Frackowiak, R.S.J., Decreases in regional cerebral blood ¯ow with normal aging. J. Cereb. Blood Flow Metab., 11 (1991) 684±689. [13] McEwen, B.S., de Kloet, E. and Rostene, W., Adrenal steroid receptors and actions in the nervous system. Physiol. Rev., 66 (1986) 1121±1188. [14] Mizuno, T. and Kimura, F., Attenuated stress response of hippocampal acetylcholine release and adrenocortical secretion in aged rats. Neurosci. Lett., 222 (1997) 49±52. [15] Olton, D.C., Becker, J.T. and Handleman, G.E., Hippocampus, space and memory. Behav. Brain Sci., 2 (1979) 313± 365. [16] Sapolsky, R.M., Krey, L.C. and McEwen, B.S., Prolonged glucocorticoid exposure reduces hippocampal neuron number: implication for aging. J. Neurosci., 5 (1985) 1222±1227. [17] Sapolsky, R.M., Krey, L.C. and McEwen, B.S., The neuroendocrinology of stress and aging: the glucocorticoid cascade hypothesis. Endocrine Rev., 7 (1986) 284±301. [18] Tizabi, Y., Gilad, V.H. and Gilad, G.M., Effects of chronic stressors or corticosterone treatment on the septohippocampal cholinergic system of the rat. Neurosci. Lett., 105 (1989) 177±182.
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J.-I. Nishimura et al. / Neuroscience Letters 273 (1999) 125±128
[19] Uno, H., Tarara, R., Else, J., Suleman, M. and Sapolsky, R.M., Hippocampal damage associated with prolonged and fatal stress in primates. J. Neurosci., 9 (1989) 1705± 1711.
[20] Wallace, J.E., Krauter, E.E. and Campbell, B.A., Animal models of decline memory in the aged: short-term and spatial memory in the aged rat. J. Gerontol., 35 (1980) 355±363.