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Interleukin-1β induces anorexia but not spatial learning and memory deficits in the rat
Behavioural Brain Research 170 (2006) 302–307
Research report
Interleukin-1 induces anorexia but not spatial learning and memory deficits in the rat Lisa M. Thomson ∗ , Robert J. Sutherland Canadian Centre for Behavioural Neuroscience, University of Lethbridge, 4401 University Dr., Lethbridge, Alta., Canada T1K 3M4 Received 5 December 2005; received in revised form 27 February 2006; accepted 7 March 2006 Available online 18 April 2006
Abstract Sickness behaviors are a set of adaptive responses to infection that include lethargy, anorexia, and, of direct relevance to this work, learning and memory impairments. The proinflammatory cytokine, interleukin-1 beta (IL-1) has been proposed as the primary peripheral mediator of these sickness behaviors, though few studies have investigated the effects of peripheral IL-1 on learning and memory. We used three different versions of the Morris water task (Morris water task), a spatial learning and memory task, to separately assess the effects of peripheral IL-1 on acquisition, consolidation, and retention of spatial location information. Using a dose that induced anorexia, assessed as a significant reduction in body weight, we observed no performance impairments in the IL-1-treated rats across the different versions of the task, suggesting that peripheral IL-1 alone is insufficient to induce spatial learning and memory impairments in the rat. The observed dissociation of anorexia and cognitive dysfunction suggests that, either spatial learning and memory are not principal components of the sickness response, or cognitive dysfunction requires different or additional peripheral mediator(s). © 2006 Elsevier B.V. All rights reserved. Keywords: Interleukin-1; Morris water task; Spatial learning and memory; Rat
1. Introduction Lethargy, anorexia, and social isolation are a constellation of symptoms, collectively referred to as sickness behavior, that represent a highly energy-conserving mechanism employed by the host to fight infection [13]. Proinflammatory cytokines that are released in the periphery by activated immune cells are responsible for creating signals that trigger these sickness behaviors [4,23]. For example, intraperitoneal (i.p.) administration of the potent proinflammatory cytokine interleukin-1 beta (IL-1) and its antagonist, IL-1ra, have been demonstrated to induce and attenuate, respectively, lethargy [4,23], anorexia [4,23], and social isolation [4]. Cognitive dysfunction has also been proposed to be a key component of sickness behavior that is centrally mediated, but triggered peripherally, by IL-1 [6,15,16]. This hypothesis is based largely upon reports of IL-1’s ability to disrupt perfor∗ Corresponding author. Present address: Department of Anesthesiology, University of Washington, Box 356540, Seattle, WA 98195, USA. Tel.: +1 206 616 2357 (O)/206 729 2215 (R); fax: +1 206 543 2958. E-mail address: [email protected] (L.M. Thomson).
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mance in the Morris water task (Morris water task) [11,18], a task that assesses spatial learning and memory [17]. Oitzl et al. showed that an intracerebroventricular (i.c.v.) injection of IL1 1 h prior to training in a fixed-platform version of the Morris water task produced longer latencies in rats to reach the hidden platform the following day [18]. Though this study demonstrates a role for IL-1 in disrupting spatial learning and memory in the central nervous system, it does not address whether peripheral IL-1 is sufficient to induce such impairments. In the only experiments to investigate the effects of peripheral IL-1 on spatial learning and memory, Gibertini et al. tested the effects of intraperitoneal IL-1 administration on Morris water task performance in mice [11]. Using a fixed-platform version of the task, Gibertini et al. administered IL-1 prior to training on two consecutive days. One week later, the IL-1-injected animals were slower to reach the hidden platform [11], suggesting that IL-1 interfered with the mice’s ability to either learn or remember the location of the platform. Given the suggestive, albeit limited, data supporting a role for peripheral IL-1 in triggering cognitive dysfunction, we sought to systematically examine whether peripheral administration of IL-1 can induce a spatial learning and memory impairment in
L.M. Thomson, R.J. Sutherland / Behavioural Brain Research 170 (2006) 302–307
the rat at doses that are able to trigger other elements of sickness behavior. Because differences have been documented in how mice and rats solve and perform in the Morris water task, with rats described as using a strategy more rooted in available spatial information [8], it is necessary to test whether the IL-1-induced spatial learning and memory impairment observed by Gibertini et al. [11] generalizes to a similar impairment in rats. Therefore, the primary objective of these experiments is to determine whether the peripheral administration of IL-1 disrupts spatial learning and memory in the Morris water task in the rat. Secondly, because IL-1 was injected prior to training in the previous experiments [11,18] it is impossible to determine – if IL-1 does induce a reliable spatial impairment – if it does so by interfering with the learning, consolidation and/or retrieval processes. Therefore, our second objective is to use three different behavioral variants of the Morris water task in order to separately assess the effects of i.p. IL-1 on spatial learning, consolidation, and retention. Finally, we ask whether our dose of IL-1 will induce anorexia, assessed by a loss of body weight. If cognitive dysfunction represents a component of the sickness response that – similar to lethargy, anorexia, and social isolation – is triggered peripherally by IL-1, then rats rendered sick by IL-1 should also show learning memory deficits in the Morris water task.
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experiments was the average latency (i.e., escape latency) of each group to navigate to the hidden platform. Prior to testing for escape latency in the consolidation version of the Morris water task, a probe trial was conducted during which the platform was removed from the pool and each animal was allowed to swim for 30 s before being removed from the pool. The percentage of time the animal spent in the quadrant in which the platform had been previously located was calculated for each animal.
2.4. Interleukin-1 beta Human recombinant interleukin-1 beta (hrIL-1) was purchased from Research Diagnostics Inc. (RDI; catalog no. RDI-201b) for use in the consolidation version of the Morris water task, whereas the cytokine was generously donated by the National Institutes of Health National Cancer Institute Biological Resources Branch (NIH NCI BRB) Preclinical Repository for the acquisition and retention versions of the Morris water task. Both compounds conformed to international standards for in vivo biological activity as previously described [20]. All vehicle controls received i.p. injections of an equivalent volume of pyrogen-free saline (Abbot Laboratories, Lot no. 79-613-DM-01). IL-1 was injected i.p. at 2 g/kg for all experiments. This dose was chosen based on its ability to reliably produce a febrile response (i.e., illness) in the rat [23].
2.5. Anorexia To assess the effects of a 2 g/kg dose of IL-1 on body weight, animals (N = 14, seven animals per group) were weighed before and 24 h following an i.p. injection of 2 g/kg of IL-1 or an equivalent volume of pyrogen-free saline. The change in body weight (expressed as ±(g)) over the 24 h period was used as the dependent variable.
2. Materials and methods 2.6. Morris water task: acquisition 2.1. Animals Male adult (90 days) Long-Evans rats, supplied by Charles Rivers Laboratories (Montr`eal, Qu`ebec) were used in all experiments. Rats were housed in pairs and maintained on a constant light and dark schedule (light on 07:30–19:30 h) in the animal housing facilities at the University of Lethbridge. Animals were allowed free access to both food and water throughout the experiments. Blood samples taken from sentinel animals at the end of the experiments verified that the animals were pathogen-free.
2.2. Apparatus The Morris water task apparatus consisted of a pool (1.5 m diameter) filled to within 20 cm of the top of the wall with water (20 ± 1 ◦ C) that was rendered opaque by skim milk powder. The wall of the pool was uniformly white. In addition, the pool was located in a room rich with distal cues, which remained intact and unobstructed throughout the duration of the experiment. During all hidden platform trials, a hidden platform, constructed of clear plexi-glass (13 cm × 13 cm), was submerged 1.5 cm under the surface of the water. Each trial began with the rat being placed in the pool at one of the four cardinal compass positions around the perimeter of the pool according to a pseudo-random sequence, such that each starting location was used once per block of four trials. The maximum duration of each swim trial was 60 s. If the rat found the platform within this 60 s period, it was allowed to remain on the platform for eight additional seconds. If it did not find the platform during the allotted time, then it was manually placed onto the platform for 8 s before being placed back into its holding cage. Following each swim trial, each rat was placed back into a holding cage where it was allowed to rest for at least 5 min before the start of the next swim trial.
2.3. Data analysis Data were collected using a video camera + Windows-based microcomputer automated system, which included a HVS Image Analysis system with video monitoring and storage capabilities. The main outcome measure used for all
To determine whether IL-1 interferes specifically with the learning of new spatial information, animals were injected with IL-1 prior to having to learn the location of a new platform location. A within-subjects design was used (N = 9) and the order of injections (saline or IL-1) was counterbalanced between groups so that approximately half of the animals received saline the first week (week 1: saline—5 rats and IL-1—4 rats; week 2: saline—4 rats and IL-1—5 rats). One week passed between injections to allow sufficient time for any behavioral effects induced by the cytokine to dissipate. Animals were trained to navigate to a hidden platform that was moved daily to a different location in the pool. Each animal received one block (four trials) of training per day. Before receiving any injections, animals were trained until their average escape latencies reached asymptote. On testing day, animals were injected with 2 g/kg of IL-1, or an equivalent volume of pyrogen-free saline. At 1 and 24 h, animals were required to navigate to a recently moved hidden platform. A block of four trials was conducted in which the difference between the average escape latencies for trials 1 and 2 was calculated for each animal and averaged across treatment groups. This difference was interpreted as the primary outcome measure for acquisition of the task.
2.7. Morris water task: consolidation To test the effects of systemic IL-1 on memory consolidation of spatial information, we used a moving platform version of the Morris water task. In this experiment, animals (N = 14, seven animals per group) were initially trained for five days, with one block of trials a day (four trials per rat), to locate a hidden platform that was moved every other day to a new location within the pool. So, the sequence was: Day 1 (new), Day 2 (same), Day 3 (new), Day 4 (same), and Day 5 (new). Immediately following the completion of the fourth trial on the fifth day, animals were injected with 2 g/kg of IL-1 or pyrogen-free saline. On testing day (Day 6), all animals were first subjected to a probe trial in which the percentage of time spent in the quadrant in which the platform was located on Day 5 was calculated. Following the completion of the probe trial, all animals received an additional block of trials (four trials per rat) during which they had to locate the platform, hidden in the same location as Day 5. Following the completion of the fourth trial, swimming speed was assessed as
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the animals’ latency to swim to and mount a visible platform (pool drained so that approximately 3 in. of the platform were visible above the water surface).
2.8. Morris water task: retention A fixed-platform version of the Morris water task was used in this experiment to test the effects of peripherally administered IL-1 on the retention of a well-learned spatial location. A within-subjects design was used (N = 9) and the order of injections (saline or IL-1) was counterbalanced between groups so that approximately half of the animals received saline the first week (week 1: saline—5 rats and IL-1—4 rats; week 2: saline—4 rats and IL-1—5 rats). One week passed between injections to allow sufficient time for any behavioral effects induced by the cytokine to dissipate. Before receiving any injections, animals were trained to find the location of a fixed hidden platform until their average escape latencies reached asymptote. On testing day, animals were injected with 2 g/kg of IL-1 or an equivalent volume of pyrogen-free saline. At 1 and 24 h after injections, animals were tested over the course of four trials (one block) to locate the hidden platform. The escape latency for each of the four trials was averaged and used as the dependent variable.
Fig. 2. IL-1 effects on swimming speed. Values represent means ± S.E.M. of swimming speed (m/s) 24 h following an injection of 2 g/kg of IL-1 (N = 7) or saline (N = 7). No differences exist between groups (P > .05).
3. Results 3.1. Effects of IL-1β on body weight Rats injected with IL-1 lost significantly more weight than saline-injected rats (Fig. 1). An independent samples t-test on the change in weight over 24 h between the IL-1 and salinetreated animals revealed a significant difference between groups, with the saline-treated animals having gained weight, and the IL-1-treated animals having lost weight (t(12) = 2.48, P < .05; M(saline) = 6.43; M(IL-1) = −15.29). 3.2. IL-1β and Morris water task No differences were observed in swimming speed between rats injected with saline or 2 g/kg IL-1 (t(12) = −1.09, P > .05; Fig. 2). 3.2.1. Acquisition Rats readily learned the location of a recently moved platform irrespective of whether they received an injection of IL-1 1 or 24 h prior to the task. As depicted in Figs. 3 and 4, IL-1 and saline-treated animals performed equally well in locating
Fig. 1. IL-1 effects on body weight. Values represent means ± S.E.M. of the change in body weight in grams 24 h following an injection of 2 g/kg of IL-1 (N = 7) or saline (N = 7). IL-1-injected rats lost significantly more weight than saline-injected rats. * P < .05.
Fig. 3. IL-1 effects on acquisition of new platform location 1 h following injection. Values represent means ± S.E.M. of average escape latency in seconds for animals injected with 2 g/kg of IL-1 (N = 9) or an equi-volume amount of pyrogen-free saline (N = 9). No significant differences observed between groups (P > .05).
the new location of a hidden platform. A paired-samples t-test revealed no significant differences in the difference in escape latencies for trials 1 and 2 between groups, neither 1 h following (t(8) = .62, P > .05), nor 24 h following (t(8) = .85, P > .05) injections. A repeated-measures analysis of variance (ANOVA) with both condition and trial as within-subject factors revealed that, though the two groups performed equally well over the
Fig. 4. IL-1 effects on acquisition of a new platform location 24 h following injection. Values represent means ± S.E.M. of average escape latency in seconds for animals injected with 2 g/kg of IL-1 (N = 9) or an equi-volume amount of pyrogen-free saline (N = 9). No significant differences observed between groups (P > .05).
L.M. Thomson, R.J. Sutherland / Behavioural Brain Research 170 (2006) 302–307
Fig. 5. IL-1 effects on memory consolidation. Values represent means ± S.E.M. of average escape latency in seconds for animals injected with 2 g/kg IL1 (N = 7) or saline (N = 7). No significant differences between groups (P > .05).
four trials, as evidenced by the absence of a condition by trial interaction 1 h (F(3,24) = .56, P > .05) and 24 h (F(3,24) = 2.03, P > .05) following injection, the two groups showed significant improvement over the four trials 1 h (F(3,24) = 11.02, P < .01), but not 24 h (F(3,24) = 2.43, P > .05) following injection. 3.2.2. Consolidation Both saline and IL-1-treated animals were able to remember the location of a hidden platform 24 h after it had been moved. A one-way ANOVA on the percentage of time spent in the quadrant in which the platform had been located the previous day revealed both groups averaged approximately the same amount of time of the 30 s probe trial in the correct quadrant (F(1,12) = .03, P > .05; M(saline) = 35%; M(IL-1) = 40%). Additionally, as Fig. 5 depicts, no significant differences were observed between groups in their ability to successfully navigate to the platform during the four trials following the initial probe trial. Using trial as a within-subjects factor and condition as a between-subjects factor, a repeated-measures ANOVA revealed no differences between groups in escape latency as revealed by the absence of an effect of condition (F(1,12) = .74, P > .05) and the absence of a trial by condition interaction (F(3,36) = .28, P > .05). 3.2.3. Retention Both saline and IL-1-treated animals were able to remember the location of a fixed, hidden platform 1 and 24 h after injection (Figs. 6 and 7). A repeated-measures ANOVA with both condition and trial as within-subjects factors revealed no effect of condition (F(1, 8) = .30, P > .05), nor a trial by condition interaction (F(3,24) = .28, P > .05; Fig. 6). The two groups also produced similar escape latencies 24 h following injections, as evidenced by the absence of an effect of condition (F(1,8) = .47, P > .05), or of a trial by condition interaction (F(3,24) = 2.02, P > .05; Fig. 7).
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Fig. 6. IL-1 effects on retention for a fixed platform 1 h following injection. Values represent means ± S.E.M. of average escape latency in seconds for animals injected with 2 g/kg of IL-1 (N = 9) or an equi-volume amount of pyrogen-free saline (N = 9). No significant differences observed between groups (P > .05).
ing and memory impairments have been based largely upon one report by Gibertini et al. [11] who demonstrated an apparent IL1-induced spatial learning and memory impairment in mice. The primary objective of the present study was to determine whether a spatial learning and/or memory impairment could be observed in rats after peripheral IL-1 administration. In all versions of the Morris water task – those measuring acquisition, consolidation, or retention – IL-1-treated animals performed as well as controls in navigating to the hidden platform. All animals were able to successfully learn each task, demonstrated by consistently low (i.e., <15 s) escape latencies and no significant differences in escape latencies were observed between saline and IL-1-treated rats. Importantly, the dose that was used in all learning and memory experiments (2 g/kg) was a dose that induced significant weight loss, one of the cardinal signs of sickness, over a 24 h period. Similar doses have previously been observed to induce fever in rats [14,23]. Thus, this dose was sufficient to render the rats sick, but insufficient to induce spatial learning and memory deficits as assessed by the Morris water task. To our knowledge, this is the first clear demonstration of normal learning and memory in the presence of other sickness behaviors. This dissociation suggests that learning and memory impairments may not represent an obligatory component of the behavioral response to sickness, as has been previously suggested [6,15,16].
4. Discussion Others have hypothesized that, similar to sickness behaviors that include lethargy and anorexia, peripheral IL-1 is sufficient to trigger cognitive dysfunction [6,15,16]. Though suggestive, the reports that peripheral IL-1 is sufficient to induce learn-
Fig. 7. Effects of IL-1 on retention for fixed platform 24 h following injection. Values represent means ± S.E.M. of the average escape latency in seconds for animals injected with 2 g/kg of IL-1 (N = 9) or pyrogen-free saline (N = 9). No significant differences observed between groups (P > .05).
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The difference between our results and the data reported by Gibertini et al. [11] could be attributed to differences between mice and rats in the strategies they use to learn and remember the location of a hidden platform. Frick et al. [8] have documented one such difference, using their observation that rats out-perform mice in learning the hidden platform location, a test of spatial memory [17], but perform similarly to mice in learning the cued (i.e., visible) platform location, a non-spatial task, to conclude that rats use more spatial information to solve the task [8]. It is conceivable, therefore, that different task-solving strategies between species are also differentially sensitive to the effects of peripheral IL-1. It is also conceivable that the difference in our results is due to the different doses used. Whereas Gibertini et al. [11] gave mice two daily injections of 100 ng/mouse of IL-1 i.p., we gave rats one acute i.p. injection of 2 g/kg. We have previously tested peripheral IL-1 on a conditioned fear response to context and observed a trend for a “U”-shaped dose–response, in which rats treated with 2 g/kg of IL-1 exhibited less (nonsignificant) freezing behavior to the original context than did rats treated with lower or higher doses [22]. Such a “U”-shaped dose–response relationship has been described for IL-1 and cognition with both basal and high doses of IL-1 actually improving some measures of learning and memory [5,10,24], a full dose–response curve would need to be conducted to conclude that peripheral administration of IL-1 does not impair spatial navigation in the rat. Finally, the effects of IL-1 on spatial learning and memory should be investigated using non-aversive tasks, such as the Y-maze [7]. It is possible that peripheral IL-1 is sufficient to induce learning and memory impairments in the rat, but the physiological stress response to the noxious stimulus (i.e., cold water) in the Morris water task occludes these deficits. Indeed, this possibility is made more conceivable by Gibertini’s observation [10] that colder water temperatures and higher doses of IL-1 – two variations that could induce a cortisol response high enough to suppress IL-1 effects – abolished previously documented [11] IL-1-induced spatial learning and memory deficits. Therefore, it is necessary to test the effects of peripheral IL-1 on nonaversive learning and memory tasks before the role of IL-1 in learning and memory can be stated with any certainty. Though our results suggest peripheral IL-1 may not mediate the learning and memory impairments that accompany sickness behavior, the cytokine does appear to have an important role in cognition, at least centrally. Reports show that basal IL-1 levels may be important to learning and memory, as central antagonism of the IL-1 receptor impairs spatial learning and memory [24]. Additionally, mice lacking the IL-1 receptor are impaired in the Morris water task and do not show hippocampal longterm potentiation [2]. Several reports also suggest that central administration of IL-1 impairs memory in tasks requiring the hippocampus, such as contextual conditioning tasks [3] and the Morris water task [18]. Converging evidence appears to suggest, then, that both basal and exogenous IL-1 mediate learning and memory within the central nervous system. This may be a direct result of IL-1 on hippocampal IL-1 receptors, or an indirect result of IL-1’s effects on the HPA axis. Song et al. [21] have,
for example, shown that glucocorticoid antagonism blocks the effects of centrally administered IL-1 working memory. Unlike centrally active IL-1, peripheral IL-1 may not induce learning and memory impairments. Certainly, our results suggest that IL-1 is not sufficient to induce impairments in a spatial learning and memory task that requires the hippocampus. We have previously reported a lack of an effect of peripheral IL1 on a conditioned fear response to a context [22] suggesting that the lack of an effect of peripheral IL-1 may extend to other hippocampal-dependent learning and memory tasks. Importantly, if our observation that peripheral IL-1 is not sufficient to induce hippocampal-dependent learning and memory is confirmed with non-aversive tasks and a full dose–response curve, it does not preclude a role for peripheral IL-1 hippocampal-dependent learning and memory. It may be the case, for instance, that other proinflammatory cytokines are required in the periphery to initiate the central response that induces observable impairments. For example, tumor necrosis factor is an additional proinflammatory cytokine that has been linked to spatial learning and memory impairments [1,9,12]. It is possible that peripheral signaling by this molecule is required – either alone or in concert with IL-1 – to trigger spatial learning and memory impairments. Additionally, peripheral IL-1 may act alone, or in concert with other peripheral proinflammatory cytokines to initiate learning and memory impairments if central inflammation is already present. Certainly, Perry’s work [19] suggests that interactions between systemic inflammation (tissue injury, infection) and conditions characterized by central inflammation (e.g., Alzheimer’s disease) cause more severe learning and memory impairments than would typically result from either condition alone. In summary, our data do not support peripheral IL-1 as being sufficient to induce spatial learning and memory impairments in rats. Our observation that a dose (2 g/kg) of IL-1 which was sufficient to induce anorexia did not also induce a selective cognitive impairment suggests that the current recognition of cognitive dysfunction as a principal component of the behavioral response to sickness that is peripherally triggered by IL-1 may need to be re-evaluated. Acknowledgement The authors wish to thank the Natural Sciences and Engineering Research Council of Canada (NSERC) for financial support (grant awarded to R.J.S.). References [1] Aloe L, Properzi F, Probert L, Akassoglou K, Kassiotis G, Micera A, et al. Learning abilities, NGF and BDNF brain levels in two lines of TNF-alpha transgenic mice, one characterized by neurolgical disorders, the other phenotypically normal. Brain Res 1999;840:125–37. [2] Avital A, Goshen I, Kamsler A, Segal M, Iverfeldt K, Richter-Levin G, et al. Impaired interleukin-1 signaling is associated with deficits in hippocampal memory processes and neural plasticity. Hippocampus 2003;13:826–34.
L.M. Thomson, R.J. Sutherland / Behavioural Brain Research 170 (2006) 302–307 [3] Barrientos RM, Higgins EA, Sprunger DB, Watkins LR, Rudy JW, Maier SF. Memory for context is impaired by a post context exposure injection of interleukin-1 beta into dorsal hippocampus. Behav Brain Res 2002;134:291–8. [4] Bluth´e RM, Dantzer R, Kelley KW. Effects of interleukin-1 receptor antagonist on the behavioral effects of lipopolysaccharide in rat. Brain Res 1992;573:318–20. [5] Brennan FX, Beck KD, Servatius RJ. Low doses of interleukin-1beta improve the leverpress avoidance performance of Sprague–Dawley rats. Neurobiol Learn Mem 2003;80:168–71. [6] Dantzer R. Cytokine-induced sickness behavior: where do we stand? Brain Behav Immun 2001;15:7–24. [7] Dellu F, Mayo W, Cherkaoui J, Le Moal M, Simon H. A two-trial memory task with automated recording: study in young and aged rats. Brain Res 1992;588:132–9. [8] Frick KM, Stillner ET, Berger-Sweeney J. Mice are not little rats: species differences in a one-day water maze task. Neuroreport 2000;11:3461–5. [9] Gerber J, Bottcher T, Hahn M, Siemar A, Bunkowski S, Nau R. Increased mortality and spatial memory deficits in TNF-alpha-deficient mice in ceftriaxone-treated experimental pneumococcal meningitis. Neurobiol Dis 2004;16:133–8. [10] Gibertini M. Cytokines and cognitive behavior. Neuroimmunomodulation 1998;5:160–5. [11] Gibertini M, Newton C, Friedman H, Klein TW. Spatial learning impairment in mice infected with Legionella pneumophila or administered exogenous interleukin-1-. Brain Behav Immun 1995;9:113–28. [12] Golan H, Levav T, Mendelsohn A, Huleihel M. Involvement of tumor necrosis factor alpha in hippocampal development and function. Cereb Cortex 2004;14:97–105. [13] Hart BL. Biological basis of the behavior of sick animals. Neurosci Biobehav Rev 1988;12:123–37. [14] Luheshi GN, Bluthe RM, Rushforth D, Mulcahy N, Konsman JP, Goldbach M, et al. Vagotomy attenuates the behavioural but not the
[15]
[16]
[17] [18]
[19]
[20]
[21]
[22]
[23]
[24]
307
pyrogenic effects of interleukin-1 in rats. Auton Neurosci 2000;85:127– 32. Maier SF. Bi-directional immune-brain communication: implications for understanding stress, pain, and cognition. Brain Behav Immun 2003;17:69–85. Maier SF, Watkins LR. Immune-to-central nervous system communication and its role in modulating pain and cognition: implications for cancer and cancer treatment. Brain Behav Immun 2003;17:S125–31. Morris RGM. Spatial localization does not depend on the presence of local cues. Learn Motiv 1981;12:239–60. Oitzl MS, van Oers H, Sch¨obitz B, de Kloet ER. Interleukin-1 beta, but not interleukin-6, impairs spatial navigation learning. Brain Res 1993;4:160–3. Perry VH. The influence of systemic inflammation on inflammation in the brain: implications for chronic neurodegenerative disease. Brain Behav Immun 2004;18:407–13. Poole S, Gaines Das RE. The international standards for interleukin-1 alpha and interleukin-1 beta. Evaluation in an international collaborative study. J Immunol Methods 1991;142:1–13. Song C, Phillips AG, Leonard BE, Horrobin DF. Ethyl-eicosapentaenoic acid ingestion prevents corticosterone-mediated memory impairment induced by central administration of interleukin-1beta in rats. Mol Psychiatry 2004;9:630–8. Thomson LM, Sutherland RJ. Systemic administration of lipopolysaccharide and interleukin-1beta have different effects on memory consolidation. Brain Res Bull 2005;67:24–9. Yirmiya R, Tio DL, Taylor AN. Effects of fetal alcohol exposure on fever, sickness behavior, and pituitary-adrenal activation induced by interleukin-1 beta in young adult rats. Brain Behav Immun 1996;10:205–20. Yirmiya R, Winocur G, Goshen I. Brain interleukin-1 is involved in spatial memory and passive avoidance conditioning. Neurobiol Learn Mem 2002;78:379–89.
Research report
Interleukin-1 induces anorexia but not spatial learning and memory deficits in the rat Lisa M. Thomson ∗ , Robert J. Sutherland Canadian Centre for Behavioural Neuroscience, University of Lethbridge, 4401 University Dr., Lethbridge, Alta., Canada T1K 3M4 Received 5 December 2005; received in revised form 27 February 2006; accepted 7 March 2006 Available online 18 April 2006
Abstract Sickness behaviors are a set of adaptive responses to infection that include lethargy, anorexia, and, of direct relevance to this work, learning and memory impairments. The proinflammatory cytokine, interleukin-1 beta (IL-1) has been proposed as the primary peripheral mediator of these sickness behaviors, though few studies have investigated the effects of peripheral IL-1 on learning and memory. We used three different versions of the Morris water task (Morris water task), a spatial learning and memory task, to separately assess the effects of peripheral IL-1 on acquisition, consolidation, and retention of spatial location information. Using a dose that induced anorexia, assessed as a significant reduction in body weight, we observed no performance impairments in the IL-1-treated rats across the different versions of the task, suggesting that peripheral IL-1 alone is insufficient to induce spatial learning and memory impairments in the rat. The observed dissociation of anorexia and cognitive dysfunction suggests that, either spatial learning and memory are not principal components of the sickness response, or cognitive dysfunction requires different or additional peripheral mediator(s). © 2006 Elsevier B.V. All rights reserved. Keywords: Interleukin-1; Morris water task; Spatial learning and memory; Rat
1. Introduction Lethargy, anorexia, and social isolation are a constellation of symptoms, collectively referred to as sickness behavior, that represent a highly energy-conserving mechanism employed by the host to fight infection [13]. Proinflammatory cytokines that are released in the periphery by activated immune cells are responsible for creating signals that trigger these sickness behaviors [4,23]. For example, intraperitoneal (i.p.) administration of the potent proinflammatory cytokine interleukin-1 beta (IL-1) and its antagonist, IL-1ra, have been demonstrated to induce and attenuate, respectively, lethargy [4,23], anorexia [4,23], and social isolation [4]. Cognitive dysfunction has also been proposed to be a key component of sickness behavior that is centrally mediated, but triggered peripherally, by IL-1 [6,15,16]. This hypothesis is based largely upon reports of IL-1’s ability to disrupt perfor∗ Corresponding author. Present address: Department of Anesthesiology, University of Washington, Box 356540, Seattle, WA 98195, USA. Tel.: +1 206 616 2357 (O)/206 729 2215 (R); fax: +1 206 543 2958. E-mail address: [email protected] (L.M. Thomson).
0166-4328/$ – see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.bbr.2006.03.004
mance in the Morris water task (Morris water task) [11,18], a task that assesses spatial learning and memory [17]. Oitzl et al. showed that an intracerebroventricular (i.c.v.) injection of IL1 1 h prior to training in a fixed-platform version of the Morris water task produced longer latencies in rats to reach the hidden platform the following day [18]. Though this study demonstrates a role for IL-1 in disrupting spatial learning and memory in the central nervous system, it does not address whether peripheral IL-1 is sufficient to induce such impairments. In the only experiments to investigate the effects of peripheral IL-1 on spatial learning and memory, Gibertini et al. tested the effects of intraperitoneal IL-1 administration on Morris water task performance in mice [11]. Using a fixed-platform version of the task, Gibertini et al. administered IL-1 prior to training on two consecutive days. One week later, the IL-1-injected animals were slower to reach the hidden platform [11], suggesting that IL-1 interfered with the mice’s ability to either learn or remember the location of the platform. Given the suggestive, albeit limited, data supporting a role for peripheral IL-1 in triggering cognitive dysfunction, we sought to systematically examine whether peripheral administration of IL-1 can induce a spatial learning and memory impairment in
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the rat at doses that are able to trigger other elements of sickness behavior. Because differences have been documented in how mice and rats solve and perform in the Morris water task, with rats described as using a strategy more rooted in available spatial information [8], it is necessary to test whether the IL-1-induced spatial learning and memory impairment observed by Gibertini et al. [11] generalizes to a similar impairment in rats. Therefore, the primary objective of these experiments is to determine whether the peripheral administration of IL-1 disrupts spatial learning and memory in the Morris water task in the rat. Secondly, because IL-1 was injected prior to training in the previous experiments [11,18] it is impossible to determine – if IL-1 does induce a reliable spatial impairment – if it does so by interfering with the learning, consolidation and/or retrieval processes. Therefore, our second objective is to use three different behavioral variants of the Morris water task in order to separately assess the effects of i.p. IL-1 on spatial learning, consolidation, and retention. Finally, we ask whether our dose of IL-1 will induce anorexia, assessed by a loss of body weight. If cognitive dysfunction represents a component of the sickness response that – similar to lethargy, anorexia, and social isolation – is triggered peripherally by IL-1, then rats rendered sick by IL-1 should also show learning memory deficits in the Morris water task.
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experiments was the average latency (i.e., escape latency) of each group to navigate to the hidden platform. Prior to testing for escape latency in the consolidation version of the Morris water task, a probe trial was conducted during which the platform was removed from the pool and each animal was allowed to swim for 30 s before being removed from the pool. The percentage of time the animal spent in the quadrant in which the platform had been previously located was calculated for each animal.
2.4. Interleukin-1 beta Human recombinant interleukin-1 beta (hrIL-1) was purchased from Research Diagnostics Inc. (RDI; catalog no. RDI-201b) for use in the consolidation version of the Morris water task, whereas the cytokine was generously donated by the National Institutes of Health National Cancer Institute Biological Resources Branch (NIH NCI BRB) Preclinical Repository for the acquisition and retention versions of the Morris water task. Both compounds conformed to international standards for in vivo biological activity as previously described [20]. All vehicle controls received i.p. injections of an equivalent volume of pyrogen-free saline (Abbot Laboratories, Lot no. 79-613-DM-01). IL-1 was injected i.p. at 2 g/kg for all experiments. This dose was chosen based on its ability to reliably produce a febrile response (i.e., illness) in the rat [23].
2.5. Anorexia To assess the effects of a 2 g/kg dose of IL-1 on body weight, animals (N = 14, seven animals per group) were weighed before and 24 h following an i.p. injection of 2 g/kg of IL-1 or an equivalent volume of pyrogen-free saline. The change in body weight (expressed as ±(g)) over the 24 h period was used as the dependent variable.
2. Materials and methods 2.6. Morris water task: acquisition 2.1. Animals Male adult (90 days) Long-Evans rats, supplied by Charles Rivers Laboratories (Montr`eal, Qu`ebec) were used in all experiments. Rats were housed in pairs and maintained on a constant light and dark schedule (light on 07:30–19:30 h) in the animal housing facilities at the University of Lethbridge. Animals were allowed free access to both food and water throughout the experiments. Blood samples taken from sentinel animals at the end of the experiments verified that the animals were pathogen-free.
2.2. Apparatus The Morris water task apparatus consisted of a pool (1.5 m diameter) filled to within 20 cm of the top of the wall with water (20 ± 1 ◦ C) that was rendered opaque by skim milk powder. The wall of the pool was uniformly white. In addition, the pool was located in a room rich with distal cues, which remained intact and unobstructed throughout the duration of the experiment. During all hidden platform trials, a hidden platform, constructed of clear plexi-glass (13 cm × 13 cm), was submerged 1.5 cm under the surface of the water. Each trial began with the rat being placed in the pool at one of the four cardinal compass positions around the perimeter of the pool according to a pseudo-random sequence, such that each starting location was used once per block of four trials. The maximum duration of each swim trial was 60 s. If the rat found the platform within this 60 s period, it was allowed to remain on the platform for eight additional seconds. If it did not find the platform during the allotted time, then it was manually placed onto the platform for 8 s before being placed back into its holding cage. Following each swim trial, each rat was placed back into a holding cage where it was allowed to rest for at least 5 min before the start of the next swim trial.
2.3. Data analysis Data were collected using a video camera + Windows-based microcomputer automated system, which included a HVS Image Analysis system with video monitoring and storage capabilities. The main outcome measure used for all
To determine whether IL-1 interferes specifically with the learning of new spatial information, animals were injected with IL-1 prior to having to learn the location of a new platform location. A within-subjects design was used (N = 9) and the order of injections (saline or IL-1) was counterbalanced between groups so that approximately half of the animals received saline the first week (week 1: saline—5 rats and IL-1—4 rats; week 2: saline—4 rats and IL-1—5 rats). One week passed between injections to allow sufficient time for any behavioral effects induced by the cytokine to dissipate. Animals were trained to navigate to a hidden platform that was moved daily to a different location in the pool. Each animal received one block (four trials) of training per day. Before receiving any injections, animals were trained until their average escape latencies reached asymptote. On testing day, animals were injected with 2 g/kg of IL-1, or an equivalent volume of pyrogen-free saline. At 1 and 24 h, animals were required to navigate to a recently moved hidden platform. A block of four trials was conducted in which the difference between the average escape latencies for trials 1 and 2 was calculated for each animal and averaged across treatment groups. This difference was interpreted as the primary outcome measure for acquisition of the task.
2.7. Morris water task: consolidation To test the effects of systemic IL-1 on memory consolidation of spatial information, we used a moving platform version of the Morris water task. In this experiment, animals (N = 14, seven animals per group) were initially trained for five days, with one block of trials a day (four trials per rat), to locate a hidden platform that was moved every other day to a new location within the pool. So, the sequence was: Day 1 (new), Day 2 (same), Day 3 (new), Day 4 (same), and Day 5 (new). Immediately following the completion of the fourth trial on the fifth day, animals were injected with 2 g/kg of IL-1 or pyrogen-free saline. On testing day (Day 6), all animals were first subjected to a probe trial in which the percentage of time spent in the quadrant in which the platform was located on Day 5 was calculated. Following the completion of the probe trial, all animals received an additional block of trials (four trials per rat) during which they had to locate the platform, hidden in the same location as Day 5. Following the completion of the fourth trial, swimming speed was assessed as
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the animals’ latency to swim to and mount a visible platform (pool drained so that approximately 3 in. of the platform were visible above the water surface).
2.8. Morris water task: retention A fixed-platform version of the Morris water task was used in this experiment to test the effects of peripherally administered IL-1 on the retention of a well-learned spatial location. A within-subjects design was used (N = 9) and the order of injections (saline or IL-1) was counterbalanced between groups so that approximately half of the animals received saline the first week (week 1: saline—5 rats and IL-1—4 rats; week 2: saline—4 rats and IL-1—5 rats). One week passed between injections to allow sufficient time for any behavioral effects induced by the cytokine to dissipate. Before receiving any injections, animals were trained to find the location of a fixed hidden platform until their average escape latencies reached asymptote. On testing day, animals were injected with 2 g/kg of IL-1 or an equivalent volume of pyrogen-free saline. At 1 and 24 h after injections, animals were tested over the course of four trials (one block) to locate the hidden platform. The escape latency for each of the four trials was averaged and used as the dependent variable.
Fig. 2. IL-1 effects on swimming speed. Values represent means ± S.E.M. of swimming speed (m/s) 24 h following an injection of 2 g/kg of IL-1 (N = 7) or saline (N = 7). No differences exist between groups (P > .05).
3. Results 3.1. Effects of IL-1β on body weight Rats injected with IL-1 lost significantly more weight than saline-injected rats (Fig. 1). An independent samples t-test on the change in weight over 24 h between the IL-1 and salinetreated animals revealed a significant difference between groups, with the saline-treated animals having gained weight, and the IL-1-treated animals having lost weight (t(12) = 2.48, P < .05; M(saline) = 6.43; M(IL-1) = −15.29). 3.2. IL-1β and Morris water task No differences were observed in swimming speed between rats injected with saline or 2 g/kg IL-1 (t(12) = −1.09, P > .05; Fig. 2). 3.2.1. Acquisition Rats readily learned the location of a recently moved platform irrespective of whether they received an injection of IL-1 1 or 24 h prior to the task. As depicted in Figs. 3 and 4, IL-1 and saline-treated animals performed equally well in locating
Fig. 1. IL-1 effects on body weight. Values represent means ± S.E.M. of the change in body weight in grams 24 h following an injection of 2 g/kg of IL-1 (N = 7) or saline (N = 7). IL-1-injected rats lost significantly more weight than saline-injected rats. * P < .05.
Fig. 3. IL-1 effects on acquisition of new platform location 1 h following injection. Values represent means ± S.E.M. of average escape latency in seconds for animals injected with 2 g/kg of IL-1 (N = 9) or an equi-volume amount of pyrogen-free saline (N = 9). No significant differences observed between groups (P > .05).
the new location of a hidden platform. A paired-samples t-test revealed no significant differences in the difference in escape latencies for trials 1 and 2 between groups, neither 1 h following (t(8) = .62, P > .05), nor 24 h following (t(8) = .85, P > .05) injections. A repeated-measures analysis of variance (ANOVA) with both condition and trial as within-subject factors revealed that, though the two groups performed equally well over the
Fig. 4. IL-1 effects on acquisition of a new platform location 24 h following injection. Values represent means ± S.E.M. of average escape latency in seconds for animals injected with 2 g/kg of IL-1 (N = 9) or an equi-volume amount of pyrogen-free saline (N = 9). No significant differences observed between groups (P > .05).
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Fig. 5. IL-1 effects on memory consolidation. Values represent means ± S.E.M. of average escape latency in seconds for animals injected with 2 g/kg IL1 (N = 7) or saline (N = 7). No significant differences between groups (P > .05).
four trials, as evidenced by the absence of a condition by trial interaction 1 h (F(3,24) = .56, P > .05) and 24 h (F(3,24) = 2.03, P > .05) following injection, the two groups showed significant improvement over the four trials 1 h (F(3,24) = 11.02, P < .01), but not 24 h (F(3,24) = 2.43, P > .05) following injection. 3.2.2. Consolidation Both saline and IL-1-treated animals were able to remember the location of a hidden platform 24 h after it had been moved. A one-way ANOVA on the percentage of time spent in the quadrant in which the platform had been located the previous day revealed both groups averaged approximately the same amount of time of the 30 s probe trial in the correct quadrant (F(1,12) = .03, P > .05; M(saline) = 35%; M(IL-1) = 40%). Additionally, as Fig. 5 depicts, no significant differences were observed between groups in their ability to successfully navigate to the platform during the four trials following the initial probe trial. Using trial as a within-subjects factor and condition as a between-subjects factor, a repeated-measures ANOVA revealed no differences between groups in escape latency as revealed by the absence of an effect of condition (F(1,12) = .74, P > .05) and the absence of a trial by condition interaction (F(3,36) = .28, P > .05). 3.2.3. Retention Both saline and IL-1-treated animals were able to remember the location of a fixed, hidden platform 1 and 24 h after injection (Figs. 6 and 7). A repeated-measures ANOVA with both condition and trial as within-subjects factors revealed no effect of condition (F(1, 8) = .30, P > .05), nor a trial by condition interaction (F(3,24) = .28, P > .05; Fig. 6). The two groups also produced similar escape latencies 24 h following injections, as evidenced by the absence of an effect of condition (F(1,8) = .47, P > .05), or of a trial by condition interaction (F(3,24) = 2.02, P > .05; Fig. 7).
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Fig. 6. IL-1 effects on retention for a fixed platform 1 h following injection. Values represent means ± S.E.M. of average escape latency in seconds for animals injected with 2 g/kg of IL-1 (N = 9) or an equi-volume amount of pyrogen-free saline (N = 9). No significant differences observed between groups (P > .05).
ing and memory impairments have been based largely upon one report by Gibertini et al. [11] who demonstrated an apparent IL1-induced spatial learning and memory impairment in mice. The primary objective of the present study was to determine whether a spatial learning and/or memory impairment could be observed in rats after peripheral IL-1 administration. In all versions of the Morris water task – those measuring acquisition, consolidation, or retention – IL-1-treated animals performed as well as controls in navigating to the hidden platform. All animals were able to successfully learn each task, demonstrated by consistently low (i.e., <15 s) escape latencies and no significant differences in escape latencies were observed between saline and IL-1-treated rats. Importantly, the dose that was used in all learning and memory experiments (2 g/kg) was a dose that induced significant weight loss, one of the cardinal signs of sickness, over a 24 h period. Similar doses have previously been observed to induce fever in rats [14,23]. Thus, this dose was sufficient to render the rats sick, but insufficient to induce spatial learning and memory deficits as assessed by the Morris water task. To our knowledge, this is the first clear demonstration of normal learning and memory in the presence of other sickness behaviors. This dissociation suggests that learning and memory impairments may not represent an obligatory component of the behavioral response to sickness, as has been previously suggested [6,15,16].
4. Discussion Others have hypothesized that, similar to sickness behaviors that include lethargy and anorexia, peripheral IL-1 is sufficient to trigger cognitive dysfunction [6,15,16]. Though suggestive, the reports that peripheral IL-1 is sufficient to induce learn-
Fig. 7. Effects of IL-1 on retention for fixed platform 24 h following injection. Values represent means ± S.E.M. of the average escape latency in seconds for animals injected with 2 g/kg of IL-1 (N = 9) or pyrogen-free saline (N = 9). No significant differences observed between groups (P > .05).
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The difference between our results and the data reported by Gibertini et al. [11] could be attributed to differences between mice and rats in the strategies they use to learn and remember the location of a hidden platform. Frick et al. [8] have documented one such difference, using their observation that rats out-perform mice in learning the hidden platform location, a test of spatial memory [17], but perform similarly to mice in learning the cued (i.e., visible) platform location, a non-spatial task, to conclude that rats use more spatial information to solve the task [8]. It is conceivable, therefore, that different task-solving strategies between species are also differentially sensitive to the effects of peripheral IL-1. It is also conceivable that the difference in our results is due to the different doses used. Whereas Gibertini et al. [11] gave mice two daily injections of 100 ng/mouse of IL-1 i.p., we gave rats one acute i.p. injection of 2 g/kg. We have previously tested peripheral IL-1 on a conditioned fear response to context and observed a trend for a “U”-shaped dose–response, in which rats treated with 2 g/kg of IL-1 exhibited less (nonsignificant) freezing behavior to the original context than did rats treated with lower or higher doses [22]. Such a “U”-shaped dose–response relationship has been described for IL-1 and cognition with both basal and high doses of IL-1 actually improving some measures of learning and memory [5,10,24], a full dose–response curve would need to be conducted to conclude that peripheral administration of IL-1 does not impair spatial navigation in the rat. Finally, the effects of IL-1 on spatial learning and memory should be investigated using non-aversive tasks, such as the Y-maze [7]. It is possible that peripheral IL-1 is sufficient to induce learning and memory impairments in the rat, but the physiological stress response to the noxious stimulus (i.e., cold water) in the Morris water task occludes these deficits. Indeed, this possibility is made more conceivable by Gibertini’s observation [10] that colder water temperatures and higher doses of IL-1 – two variations that could induce a cortisol response high enough to suppress IL-1 effects – abolished previously documented [11] IL-1-induced spatial learning and memory deficits. Therefore, it is necessary to test the effects of peripheral IL-1 on nonaversive learning and memory tasks before the role of IL-1 in learning and memory can be stated with any certainty. Though our results suggest peripheral IL-1 may not mediate the learning and memory impairments that accompany sickness behavior, the cytokine does appear to have an important role in cognition, at least centrally. Reports show that basal IL-1 levels may be important to learning and memory, as central antagonism of the IL-1 receptor impairs spatial learning and memory [24]. Additionally, mice lacking the IL-1 receptor are impaired in the Morris water task and do not show hippocampal longterm potentiation [2]. Several reports also suggest that central administration of IL-1 impairs memory in tasks requiring the hippocampus, such as contextual conditioning tasks [3] and the Morris water task [18]. Converging evidence appears to suggest, then, that both basal and exogenous IL-1 mediate learning and memory within the central nervous system. This may be a direct result of IL-1 on hippocampal IL-1 receptors, or an indirect result of IL-1’s effects on the HPA axis. Song et al. [21] have,
for example, shown that glucocorticoid antagonism blocks the effects of centrally administered IL-1 working memory. Unlike centrally active IL-1, peripheral IL-1 may not induce learning and memory impairments. Certainly, our results suggest that IL-1 is not sufficient to induce impairments in a spatial learning and memory task that requires the hippocampus. We have previously reported a lack of an effect of peripheral IL1 on a conditioned fear response to a context [22] suggesting that the lack of an effect of peripheral IL-1 may extend to other hippocampal-dependent learning and memory tasks. Importantly, if our observation that peripheral IL-1 is not sufficient to induce hippocampal-dependent learning and memory is confirmed with non-aversive tasks and a full dose–response curve, it does not preclude a role for peripheral IL-1 hippocampal-dependent learning and memory. It may be the case, for instance, that other proinflammatory cytokines are required in the periphery to initiate the central response that induces observable impairments. For example, tumor necrosis factor is an additional proinflammatory cytokine that has been linked to spatial learning and memory impairments [1,9,12]. It is possible that peripheral signaling by this molecule is required – either alone or in concert with IL-1 – to trigger spatial learning and memory impairments. Additionally, peripheral IL-1 may act alone, or in concert with other peripheral proinflammatory cytokines to initiate learning and memory impairments if central inflammation is already present. Certainly, Perry’s work [19] suggests that interactions between systemic inflammation (tissue injury, infection) and conditions characterized by central inflammation (e.g., Alzheimer’s disease) cause more severe learning and memory impairments than would typically result from either condition alone. In summary, our data do not support peripheral IL-1 as being sufficient to induce spatial learning and memory impairments in rats. Our observation that a dose (2 g/kg) of IL-1 which was sufficient to induce anorexia did not also induce a selective cognitive impairment suggests that the current recognition of cognitive dysfunction as a principal component of the behavioral response to sickness that is peripherally triggered by IL-1 may need to be re-evaluated. Acknowledgement The authors wish to thank the Natural Sciences and Engineering Research Council of Canada (NSERC) for financial support (grant awarded to R.J.S.). References [1] Aloe L, Properzi F, Probert L, Akassoglou K, Kassiotis G, Micera A, et al. Learning abilities, NGF and BDNF brain levels in two lines of TNF-alpha transgenic mice, one characterized by neurolgical disorders, the other phenotypically normal. Brain Res 1999;840:125–37. [2] Avital A, Goshen I, Kamsler A, Segal M, Iverfeldt K, Richter-Levin G, et al. Impaired interleukin-1 signaling is associated with deficits in hippocampal memory processes and neural plasticity. Hippocampus 2003;13:826–34.
L.M. Thomson, R.J. Sutherland / Behavioural Brain Research 170 (2006) 302–307 [3] Barrientos RM, Higgins EA, Sprunger DB, Watkins LR, Rudy JW, Maier SF. Memory for context is impaired by a post context exposure injection of interleukin-1 beta into dorsal hippocampus. Behav Brain Res 2002;134:291–8. [4] Bluth´e RM, Dantzer R, Kelley KW. Effects of interleukin-1 receptor antagonist on the behavioral effects of lipopolysaccharide in rat. Brain Res 1992;573:318–20. [5] Brennan FX, Beck KD, Servatius RJ. Low doses of interleukin-1beta improve the leverpress avoidance performance of Sprague–Dawley rats. Neurobiol Learn Mem 2003;80:168–71. [6] Dantzer R. Cytokine-induced sickness behavior: where do we stand? Brain Behav Immun 2001;15:7–24. [7] Dellu F, Mayo W, Cherkaoui J, Le Moal M, Simon H. A two-trial memory task with automated recording: study in young and aged rats. Brain Res 1992;588:132–9. [8] Frick KM, Stillner ET, Berger-Sweeney J. Mice are not little rats: species differences in a one-day water maze task. Neuroreport 2000;11:3461–5. [9] Gerber J, Bottcher T, Hahn M, Siemar A, Bunkowski S, Nau R. Increased mortality and spatial memory deficits in TNF-alpha-deficient mice in ceftriaxone-treated experimental pneumococcal meningitis. Neurobiol Dis 2004;16:133–8. [10] Gibertini M. Cytokines and cognitive behavior. Neuroimmunomodulation 1998;5:160–5. [11] Gibertini M, Newton C, Friedman H, Klein TW. Spatial learning impairment in mice infected with Legionella pneumophila or administered exogenous interleukin-1-. Brain Behav Immun 1995;9:113–28. [12] Golan H, Levav T, Mendelsohn A, Huleihel M. Involvement of tumor necrosis factor alpha in hippocampal development and function. Cereb Cortex 2004;14:97–105. [13] Hart BL. Biological basis of the behavior of sick animals. Neurosci Biobehav Rev 1988;12:123–37. [14] Luheshi GN, Bluthe RM, Rushforth D, Mulcahy N, Konsman JP, Goldbach M, et al. Vagotomy attenuates the behavioural but not the
[15]
[16]
[17] [18]
[19]
[20]
[21]
[22]
[23]
[24]
307
pyrogenic effects of interleukin-1 in rats. Auton Neurosci 2000;85:127– 32. Maier SF. Bi-directional immune-brain communication: implications for understanding stress, pain, and cognition. Brain Behav Immun 2003;17:69–85. Maier SF, Watkins LR. Immune-to-central nervous system communication and its role in modulating pain and cognition: implications for cancer and cancer treatment. Brain Behav Immun 2003;17:S125–31. Morris RGM. Spatial localization does not depend on the presence of local cues. Learn Motiv 1981;12:239–60. Oitzl MS, van Oers H, Sch¨obitz B, de Kloet ER. Interleukin-1 beta, but not interleukin-6, impairs spatial navigation learning. Brain Res 1993;4:160–3. Perry VH. The influence of systemic inflammation on inflammation in the brain: implications for chronic neurodegenerative disease. Brain Behav Immun 2004;18:407–13. Poole S, Gaines Das RE. The international standards for interleukin-1 alpha and interleukin-1 beta. Evaluation in an international collaborative study. J Immunol Methods 1991;142:1–13. Song C, Phillips AG, Leonard BE, Horrobin DF. Ethyl-eicosapentaenoic acid ingestion prevents corticosterone-mediated memory impairment induced by central administration of interleukin-1beta in rats. Mol Psychiatry 2004;9:630–8. Thomson LM, Sutherland RJ. Systemic administration of lipopolysaccharide and interleukin-1beta have different effects on memory consolidation. Brain Res Bull 2005;67:24–9. Yirmiya R, Tio DL, Taylor AN. Effects of fetal alcohol exposure on fever, sickness behavior, and pituitary-adrenal activation induced by interleukin-1 beta in young adult rats. Brain Behav Immun 1996;10:205–20. Yirmiya R, Winocur G, Goshen I. Brain interleukin-1 is involved in spatial memory and passive avoidance conditioning. Neurobiol Learn Mem 2002;78:379–89.