NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS

PERGAMON

Neuroscience and Biobehavioral Reviews 25 (2001) 2941

www.elsevier.com/locate/neubiorev

The immune system and memory consolidation: a role for the cytokine IL-1b
C. Rachal Pugh a, Monika Fleshner b, Linda R. Watkins a, Steven F. Maier a, Jerry W. Rudy a,*
b

University of Colorado at Boulder, Department of Psychology, Campus Box 345, Boulder, CO 80310, USA University of Colorado at Boulder, Department of Kinesiology and Applied Physiology, Campus Box 345, Boulder, CO 80310, USA Received 25 July 2000; revised 20 October 2000; accepted 24 October 2000

Abstract Interleukin-1 beta (IL-1b), known to play a role in orchestrating the physiological and behavioral adjustments that occur during sickness, has also been shown to signicantly inuence memory consolidation. To support this assertion we present neurobiological evidence that the substrates for IL-1b to inuence memory processing and neural plasticity exist. We then present behavioral evidence that central IL-1b administration and agents that induce central IL-1b activity impair the consolidation of memories that depend on the hippocampal formation but have no effect on the consolidation of hippocampal-independent memories. Further, we demonstrate that the impairments in hippocampal-dependent memory consolidation produced by agents that induce IL-1b activity are blocked by antagonizing the actions of IL-1b. Finally, we discuss these data in terms of their implications for a physiological role of IL-1b in memory consolidation processes and a potential role of IL-1b in producing memory impairments associated with stress, aging, Alzheimer's disease, and AIDS related dementia complex. q 2001 Elsevier Science Ltd. All rights reserved.
Keywords: Interleukin-1 beta; Memory Consolidation; Fear Conditioning; Stress; Lipopolysaccharide; gp120; AIDS Dementia; Alzheimer's Disease

1. Introduction One of the important recent advances in understanding the biological basis of behavior is the recognition that there is extensive communication between the central nervous system and the immune system. The new eld of Psychoneuroimmunology is based on the fundamental premise that there is bi-directional communication between the central nervous system and the immune system. A major contribution of this eld has been the discovery that many responses to infectious agents, such as fever, increased slow wave sleep, reduced activity, exploration, and sexual behavior (that together produce a `sickness syndrome') are orchestrated by immune products called proinammatory cytokines that are released in response to the detection of foreign substances (antigens). Cytokines are thought to bring about these changes by their actions in the central nervous system (see Ref. [1] for a review). This idea has led to the belief that the `sickness syndrome' does not reect a passive organism debilitated by illness, but rather a change in the motivational state of the organism that is organized by both the central nervous system and the immune system [2].
* Corresponding author. Tel.: 11-303-492-4498; fax: 11-303-492-2967. E-mail address: jrudy@psych.colorado.edu (J.W. Rudy).

The discovery that proinammatory cytokines are released in the brain, however, has implications that extend beyond their role in orchestrating the sickness syndrome. It raises the possibility that the immune system can also inuence brain structures that mediate cognition [1]. The purpose of this review is to summarize a body of evidence that indicates that cytokines released in the CNS have a signicant impact on cognition. Specically, this review indicates that the proinammatory cytokine, IL-1b, known to play a role in orchestrating the `sickness syndrome' [1], also has a signicant inuence on the consolidation of memories that depend on the hippocampus. While the focus of this paper is on the effects of IL-1b on memory consolidation, it is important to note that interleukin-1 comes in both a and b forms. IL-1a and IL-1b exist as two separate gene products that share approximately 20 30% sequence homology. They appear to exert many of the same physiological effects because both bind to the functional Type I IL-1 receptor [3]. However, IL-1b is concentrated on in the studies presented in this discussion because it is the major secreted form [4] while IL-1a remains membrane bound [5]. It is also important to point out that cytokines rarely work in isolation. Specically, IL-1b release is normally associated with the release of the other proinammatory

0149-7634/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved. PII: S 0149-763 4(00)00048-8

30

C. Rachal Pugh et al. / Neuroscience and Biobehavioral Reviews 25 (2001) 2941

cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFa) and these three cytokines have many redundant physiological effects. In fact, unpublished data from our laboratory has suggested a role for TNFa in producing some of the same memory impairments discussed in this paper. However, in order to maintain focus, the discussion in this paper is restricted to the effects of IL-1b on memory consolidation. In addition to restricting this review to the effects of IL1b on memory consolidation, the discussion also remains focused on the idea that IL-1b acts to impair memory consolidation in the hippocampal formation. While we believe the circumstantial evidence supporting this idea is undeniably strong, we feel that it is nonetheless important to point out that central IL-1b also affects the hypothalamus and subsequent neuroendocrine end products as well as other brain stem areas impacting most monoamine systems. While these other central effects of IL-1b may contribute to the observed memory impairments (see Refs. [6,7]) the evidence points most strongly to the involvement of the hippocampus, and thus, we once again restrict our discussion to this structure. To support the assertion that IL-1b inuences hippocampal-dependent memory consolidation, we will present neurobiological evidence that the substrates for IL-1b to inuence memory processing and neural plasticity exist in the hippocampus. We will then present behavioral evidence that memories known to depend on the integrity of the hippocampus are impaired by IL-1b activity. 2. Neurobiological considerations If IL-1b impacts memory processes mediated by the hippocampus then it should be the case that: (a) there are receptors for the protein in this structure, (b) environmental agents or events induce hippocampal IL-1b activity, and (c) IL-1b has a physiological effect on neuronal plasticity within the hippocampus. There is evidence to support all three of these criteria, suggesting that IL-1b could indeed be involved in hippocampal-dependent memory formation. 2.1. Receptor presence Autoradiographic analysis of radiolabeled IL-1 has shown a high density of binding sites for IL-1 in the hippocampus [8]. These sites have also been conrmed by Takao et al. [9] who documented binding of radiolabeled IL-1 to hippocampal membrane preparations. Binding studies demonstrate that the highest density of IL-1b binding sites in brain are in the dentate gyrus of the hippocampus [9]. More recent studies also have conrmed the presence of IL1 receptors in the hippocampus [10,11]. 2.2. Induction of hippocampal IL-1b It is also important to document that environmental

agents or events induce IL-1b activity within the hippocampus. Several investigators [1214] have provided strong evidence that immune system activation produces large increases in IL-1 activity in the hippocampal formation. Specically, they report that peripheral immune activation by gram-negative bacterial cell walls (lipopolysaccharide; LPS) upregulates IL-1b mRNA in the hippocampus. However, increases in IL-1 mRNA do not necessarily mean that increased IL-1 protein will occur (see Ref. [15]). Importantly, Nguyen et al. [16] have demonstrated that immune system activation by peripheral LPS administration upregulates IL-1b protein in the hippocampal formation. 2.3. IL-1b & hippocampal plasticity Many researchers hypothesize that neural plasticity as revealed in long-term potentiation (LTP) provides a mechanism for hippocampal-dependent memory [17,18]. If IL-1b inuences hippocampal-dependent memory, then one would expect it to also inuence LTP. In fact, IL-1b blocks the expression of LTP in the CA1 and CA3 regions of the hippocampus [19,20] as well as in the dentate gyrus [21,22]. This suppression of LTP is believed to be caused by IL-1 because IL-1 receptor antagonist strongly attenuates the inhibitory effect of IL-1 on LTP expression [22]. 2.4. Summary This brief review reveals that the potential for IL-1b to inuence memory that depends on the hippocampus is strong. The hippocampus contains receptors for this protein, IL-1b gene expression and protein production are activated in the hippocampus by infection, and the presence of IL-1b impairs the development of synaptic plasticity. That the hippocampus is a potential site for IL-1b effects on learning and memory is especially interesting because it is well known that damage to the hippocampus is associated with amnesia in humans (see Refs. [23,24]) and no area of the brain has been more intensely investigated in animals for its contribution to memory. Moreover, it is generally recognized that not all forms of memory depend on the hippocampus. This view is represented by a number of so-called multiple memory perspectives that distinguish between memory systems that depend on the hippocampus and memory systems that do not. Examples of such frameworks include the declarative versus nondeclarative memory systems [23,25], the locale versus taxon systems [26], the memory versus performance systems [27] and the congural versus elemental association systems [28]. The above discussion establishes the potential for IL-1b to inuence memory processes mediated by the hippocampus. The key question, however, is does IL-1b impair hippocampal memory processes that inuence behavior? There is now a substantial body of evidence that supports the hypothesis that IL-1b impairs hippocampal-dependent memory processes and, more specically, that this protein exerts

C. Rachal Pugh et al. / Neuroscience and Biobehavioral Reviews 25 (2001) 2941

31

its inuence on post-trial memory consolidation processes that establish such memories. Regarding the concept of memory consolidation, it is generally recognized that a learning experience initiates a set of processes that endure for some period of time beyond the initial learning experience. Importantly, these post-trial processes are essential to the formation of a stable or enduring memory for the experience. This set of post-trial processes is generically referred to as memory consolidation. Evidence for the existence of memory consolidation comes from a large literature indicating that memory for recent events is vulnerable to disruption by a variety of manipulations that occur shortly after the learning experience has ended (see Ref. [29]). Although there is evidence from several behavioral paradigms implicating IL-1b in learning and memory, the best evidence for this hypothesis comes from the study of fear conditioning. For this reason, we will rst review the behavioral paradigm of fear conditioning and the relationship of contextual fear to the hippocampus. We will then describe the generic training paradigm used in the studies indicating the involvement of IL-1b in memory consolidation. 3. Fear conditioning In the fear conditioning paradigm, rats exposed to tonefootshock pairings in a novel environment (or context) later display defensive fear responses (such as freezing, an increase in heart rate, hypoalgesia, and potentiated acoustic startle) when re-exposed to either the environmental context where shock occurred or to the tone that preceded shock. Defensive responding in the presence of the environmental context where shock occurred is referred to as contextual fear conditioning. Defensive responding in a novel context in the presence of the tone is referred to as auditory-cue fear conditioning. Fear conditioning has become a popular task to study learning and memory processes because the neural circuitry underlying conditioned fear is well understood [3032]. Most notably for the present purpose, contextual fear conditioning depends on the integrity of the hippocampal formation while auditory-cue fear conditioning can occur in its absence [3335]. Thus, if IL-1b is selectively involved in hippocampal-dependent memory then one would expect that IL-1b should impair contextual but not auditory-cue fear conditioning. 3.1. Experimental design considerations As noted, the proinammatory cytokine IL-1b contributes to many of the behavioral responses and physiological adjustments associated with the sickness syndrome. These consequences have important implications for the design of studies directed at the impact of IL-1b on learning and memory. Specically, because any treatment designed to increase IL-1b levels produces sickness, it would be very difcult to interpret its effects on memory if the treatment is

given prior to learning. This is because the behavioral and physiological consequences associated with illness would likely alter how the animal encodes the learning experience. For example, a sick animal would not be likely to explore the training context in the same manner as a normal animal. Consequently, if one observed that increased IL-1b impaired performance on the memory test, the result could not be unequivocally attributed to IL-1b's effect on memory consolidation. For this reason, in the work that will be reviewed, treatments designed to increase IL-1b levels were administered immediately after the learning experience (i.e. within a few minutes), and animals were tested several days later. Consequently, regardless of the treatment condition, all animals were similar at both the time of training and testing. Thus, should an effect of IL-1b on test performance be observed, it can be unambiguously interpreted as due to its impact on post-trial memory consolidation processes. Moreover, because each rat was trained and tested for both hippocampal-dependent contextual fear conditioning and hippocampal-independent auditory-cue fear conditioning, the claim that IL-1b might selectively inuence hippocampal-dependent memory consolidation would be supported if IL-1b impaired contextual but not auditory-cue fear conditioning. 4. The effects of IL-1b on memory consolidation With these caveats in mind, we now describe the evidence implicating IL-1b in the consolidation of hippocampaldependent memory. This case will be made in several ways. First, evidence will be presented that post-training central IL-1b administration impairs contextual (hippocampal-dependent) but not auditory-cue (hippocampal-independent) fear conditioning. Second, it will be shown that a variety of manipulations that induce the release of IL-1b in the hippocampus also impair contextual but not auditory-cue fear. Third, evidence will be reviewed that indicates that the impaired contextual fear produced by each manipulation is blocked by inhibiting the actions of IL-1b. 5. Effect of central IL-1b administration on contextual & auditory-cue fear The most direct evidence that IL-1b impairs hippocampal-dependent memory is provided by a recent study by Pugh et al. [7]. Immediately following conditioning, rats were treated intracerebroventricularly (ICV) with either IL-1b or its vehicle. When subsequently tested for fear conditioning, rats treated with IL-1b (either 10 or 20 ng) displayed impaired contextual fear conditioning but normal auditory-cue fear conditioning (see Fig. 1). It is one thing to demonstrate that IL-1b can impair hippocampal-dependent memory consolidation, however, a critical question is, does this protein impair memory when it is induced in the brain by environmental agents or

32

C. Rachal Pugh et al. / Neuroscience and Biobehavioral Reviews 25 (2001) 2941

5.1. Lipopolysaccharide Lipopolysaccharide (LPS), the active component of gram-negative bacterial cell walls, is a potent stimulator of the immune system. Its peripheral administration produces all of the behavioral and physiological changes that occur during sickness, including decreased food and water intake, decreased exploration, decreased social interaction, increased sleep, fever, hyperalgesia, hypothalamopituitary-adrenal activation and increased sympathetic activity. Peripheral LPS administration is thought to produce all of these changes by inducing the release of IL-1b because blocking the actions of IL-1b prevents many of the LPS induced changes. In addition, peripheral LPS administration increases both IL-1b-mRNA [36,37] and increased IL-1b protein levels are observed in the hippocampus, as well as other brain regions including the cortex, and hypothalamus 30 min to 6 h after its administration ([16] see Fig. 2(a)). Therefore, it is clear that LPS produces sickness and induces IL-1b in the hippocampus. There are two lines of evidence that LPS impairs contextual fear conditioning. In one case, rats were given peripheral LPS after the standard conditioning procedure. Like ICV IL-1b, systemic LPS selectively impaired hippocampal-dependent contextual fear conditioning but had no effect on hippocampal independent auditory-cue fear conditioning (see Fig. 2(b) and (c)). The other line of evidence comes from a variation of the fear conditioning paradigm in which the effect of LPS on the benecial effect of context preexposure was examined. Normally, brief context pre-exposure 24 h before conditioning enhances subsequent contextual fear conditioning [3840]. Pre-exposure is thought to facilitate contextual fear conditioning by allowing the rat to construct a memory representation of the context before conditioning occurs, a process thought to depend on the hippocampus [38,40]. Consistent with the hypothesis that LPS impairs hippocampal-dependent context learning, Pugh et al. [6] reported that LPS administered after context pre-exposure eliminated its benecial effect on subsequent contextual fear conditioning (data not shown). These data demonstrate that peripheral LPS administration increases IL-1b protein in the hippocampus and also selectively impairs contextual fear. It is equally important to appreciate that LPS did not reduce the ability of context preexposure to facilitate contextual fear conditioning if IL-1b receptor antagonist (100 mg/kg sub-cutaneously) was administered prior to LPS treatment (see Fig. 2(d)). This nding is signicant because it strongly supports the hypothesis that LPS exerts its effect on contextual fear conditioning by inducing the activity of IL-1b. 5.2. gp120 gp120 is an envelope glycoprotein of Human Immunodeciency Virus-1. gp120 binds to cells expressing CD4 surface molecules including certain T cells and

Fig. 1. Top: mean percent freezing during the contextual fear test. Bottom: mean percent freezing during the auditory-cue fear test. Rats were injected (ICV) with either IL-1b or vehicle. Bars represent standard errors. Note that IL-1b reduced contextual fear conditioning but had no effect on auditory cue fear conditioning.

events? There are 3 sources of data that provide an afrmative answer to this question. The evidence below shows that IL-1b is induced in the hippocampus by LPS, gp120, and social isolation, and that each manipulation selectively impairs contextual fear conditioning. In addition, these studies indicate that the effect of each treatment can be blocked by inhibiting the actions of IL-1, implying that IL-1b is directly involved in producing these memory impairments.

C. Rachal Pugh et al. / Neuroscience and Biobehavioral Reviews 25 (2001) 2941

33

Fig. 2. (a) IL-1b protein levels in the hippocampus 6 hr after intraperitoneal (i.p.) vehicle or LPS administration. (b) Mean percent freezing during the contextual fear test. (c) Mean percent freezing during the auditory-cue fear test of rats given i.p. injections of vehicle or LPS immediately after conditioning. Note that LPS reduced contextual fear conditioning but had no effect on auditory-cue fear conditioning (d) Mean percentage of freezing during the contextual fear test. Following conditioning, rats were injected i.p. with the vehicle or LPS in combination with the vehicle or IL-1ra. Note that IL-1ra blocked the ability of LPS to impair conditioning. Bars in all gures represent standard errors.

macrophages of the immune system as well as microglia and astrocytes within the brain. Importantly, gp120 induces IL1b release from glial cells in vitro [41]. In vivo, gp120 induces IL-1b mRNA in brain [42], and increases pituitary-adrenal activity by inducing central IL-1b activity [43]. Central gp120 administration also causes increases in IL-1b protein 3 and 6 h after its administration in the hippocampus and cortex, however, no changes in IL-1b protein levels are observed in the hypothalamus at either time point ([44] see Fig. 3(a)). Therefore, central gp120 administration provides another method to examine the effect of increased IL-1b activity on memory consolidation. Pugh et al. [44] report that when ICV gp120 (4, 6, or 8 mg) is administered immediately following fear conditioning, it profoundly impairs contextual fear conditioning while having no effect on auditory-cue fear conditioning

(Fig. 3(b) and (c). Furthermore, this effect is blocked by two different antagonists of IL-1: (a) IL-1ra (0.25 mg ICV given after conditioning but before gp120 administration) or (b) alpha-melanocyte stimulating hormone (aMSH; an endogenous hormone and transmitter that inhibits the actions of IL-1b [45] (0.5 mg ICV was given after conditioning but before gp120 administration). These two results (see Fig. 3(d)) are important because they support the idea that gp120 exerts its effect on the consolidation of contextual memory representations by inducing the release of IL-1b. It is important to note that a full dose response of the effects of gp120 was not carried out in the present experiments. A narrow range of doses was chosen based on pilot studies (from an unrelated series of studies) showing increases in IL-1b protein in the spinal cord after intrathecal

34

C. Rachal Pugh et al. / Neuroscience and Biobehavioral Reviews 25 (2001) 2941

Fig. 3. (a) IL-1b protein levels in the hippocampus 3 and 6 h after ICV vehicle or gp120 administration. (b) Mean percent freezing during the contextual fear test as a function of dose of gp120 given ICV immediately after conditioning. (c) Mean percent freezing during the auditory-cue fear test as a function of dose of gp 120 given ICV immediately after conditioning. Note that gp120 reduced contextual fear conditioning but had no effect on auditory cue fear conditioning (d) Mean percentage of freezing during the contextual fear test. Following conditioning, rats were given either with the vehicle or gp120 (ICV) in combination with either the vehicle, aMSH, or IL-1ra. Note that both aMSH and IL-1ra blocked the ability of gp120 to impair conditioning. Bars in all gures represent standard errors.

gp120 administration. Therefore, while the doses chosen for these studies may seem high, the reader should realize that the doses were not meant to characterize a full dose response to gp120, but rather to evaluate doses previously shown to upregulate IL-1b protein expression in the central nervous system. Future studies will examine the effects of a wider range of doses of gp120 on memory consolidation.

5.3. Social isolation stress Recently, IL-1b also has been implicated in the neurochemical and behavioral consequences of stressors. For example, immobilization stress increases IL-1b mRNA [46] and bioactivity [47] in brain. Inescapable tail shock stress also increases IL-1b protein levels in

C. Rachal Pugh et al. / Neuroscience and Biobehavioral Reviews 25 (2001) 2941

35

Fig. 4. (a) IL-1b protein levels in the hippocampus after 1 or 3 h of social isolation. (b) Mean percent freezing during the contextual fear test as a function of post-training treatment. (c) Mean percent freezing during the auditory-cue fear test as a function of post-training treatment. Note that isolation reduced contextual fear conditioning but had no effect on auditory cue fear conditioning. (d) Mean percent freezing during the contextual fear test for rats given vehicle or IL-1ra and either isolated or returned to the home cage immediately after conditioning. Note that IL-1ra blocked the ability of isolation to impair fear conditioning. Bars in all gures represent standard errors.

brain [16]. Increased levels of IL-1b have also been found in both the hippocampus and cortex but not the hypothalamus or pituitary gland following 1 or 3 h of social isolation ([7] see Fig. 4(a)). Social isolation is operationally dened as the individual housing of rats who are normally group-housed. Thus, social isolation also provides a way to study the effects of IL-1b activity on hippocampal-dependent memory consolidation in the absence of endotoxin or infection. Importantly, postconditioning social isolation also selectively impairs contextual fear conditioning ([7,48,49] see Fig. 4(b) and (c)). In addition, central IL-1ra (0.25 mg ICV)

given immediately after conditioning prevents the impairment in contextual fear conditioning caused by social isolation ([7] see Fig. 4(d)). In summary, the data indicate that the neural substrates for IL-1b to inuence neural processing are present in the hippocampus and that treatments that activate IL-1b (LPS, gp120, and social isolation) selectively impair contextual fear conditioning, which depends on the hippocampus. Moreover, these effects are blocked by inhibiting the actions of IL-1b. Thus these results strongly implicate a role for IL-1b in cognitive processes.

36

C. Rachal Pugh et al. / Neuroscience and Biobehavioral Reviews 25 (2001) 2941

Because these treatments which induce IL-1b activity were not given until after the learning experience, we conclude that they inuence memory consolidation. It should be noted, however, that although LPS, gp120, and social isolation were given within several minutes after training, the activation of IL-1b in brain by these events does not occur until roughly an hour later. This implies that the consolidation period for contextual fear conditioning is either quite long or that IL-1b exerts its effects on contextual fear in some other way. There is in fact strong evidence for the rst explanation that contextual fear conditioning has a lengthy consolidation period. Bourtchouladze et al. [29] have reported that protein synthesis inhibitors administered either immediately or 3 h after training significantly impair contextual fear conditioning. Thus, the activation of IL-1b by the treatments described in this review is well within the time frame of contextual memory consolidation. Strengthening the argument that IL-1b impairs memory consolidation per se (rather than impairing contextual fear conditioning in another non-specic way), pre-exposure to the conditioning context 24 h prior to conditioning and IL-1b activity prevents IL-1b induced impairments in contextual fear (unpublished data and see Ref. [6]). Thus, if an animal goes into the learning experience already having acquired a contextual memory representation, then post-conditioning IL-1b activity does not affect the amount of fear that is conditioned to the context. That is to say that IL-1b activity impairs the formation of contextual memory representations, but, if the representation has already been formed, then IL-1b activity does not affect the manner in which the pre-existing contextual memory representation is associated with shock. 6. Additional evidence for a role of IL-1b in learning & memory Complimenting results obtained with the fear conditioning paradigm are other ndings that indicate IL-1b inuences on hippocampal-dependent memory. Oitzl et al. [50] have reported that ICV IL-1b administration impairs rat's performance on another memory task which depends on the hippocampus, the spatial version of the Morris water escape task. Specically, IL-1b treatment does not interfere with the acquisition of escape behavior, however, it does impair the retention of this learning. This result is consistent with our view that IL-1b impairs memory consolidation. Similar results have been reported by Gibertini et al. [51]. They reported that both IL-1b (ICV) and gram negative Legionella pneunophila (which produces sickness) impair performance on the Morris water escape task. They also showed that the cognitive effects of these treatments were blocked by antibodies directed against IL-1b, suggesting that it is the action of IL-1b that produces the observed impairments. Aubert et al. [52] have found evidence that Bakers Yeast

(another immune activator), LPS, and IL-1b impair the acquisition of another learned behavior that is thought to depend on the hippocampus, autoshaping [5254]. None of these treatments, however, interfere with the expression of the learned behavior once it is acquired. 7. General discussion & implications This review indicates that the effects of the proinammatory cytokine IL-1b extend beyond its role in organizing the behavioral adaptations to infection (the sickness syndrome). Its activation signicantly impairs the consolidation of memories. We have also suggested that IL-1b specically impairs the consolidation of memories that dependent on the hippocampus. This is because performance of the tasks used in the reviewed work depends on the integrity of the hippocampus and because the neural substrates for IL-1b to inuence neural processing are present in the hippocampus. We recognize, however, that the evidence for this conclusion is circumstantial. There is no evidence that: (a) direct infusion of IL-1b into the hippocampus impairs contextual fear conditioning or, (b) delivering agents that block the actions of IL-1b directly in the hippocampus prevent it from impairing memory consolidation. So, the case for a direct effect on neural processing in the hippocampus is not complete. Nevertheless, this should not detract from the general conclusion that IL-1b activity in the brain not only organizes sickness related behaviors, but also inuences cognition. It is accepted that infectious agents activate the immune system and the release of its cytokine products. What needs to be reiterated, however, is that cytokines are also released in brain following exposure to psychological experiences termed stress. Moreover, we have shown that at least one stressful experience (social isolation) that activates IL-1b activity in brain impairs memory consolidation. This is important because it implies that the occasions for IL-1b to impact cognition extend well beyond those that involve infection. Indeed, we think that the exploration of this link between stress, the immune system, brain, and cognition will prove to be an extremely fertile research opportunity. We think that there are many important questions and research opportunities generated by the research just reviewed. We will end our review by discussing some of the future research directions implied by this work. Thus far, we have provided evidence for a role of IL-1b in memory consolidation processes. We now relate these data to a larger literature suggesting that IL-1b could play a role in both normal, physiological as well as pathophysiological learning and memory processes. The proinammatory cytokine, IL-1b has long been recognized as a key mediator of immune and inammatory responses during infection. Research conducted during the past 15 years has provided compelling evidence that low physiological levels of IL-1b are involved in regulating normal neural plasticity (LTP) while increased or pathophysiological levels are involved

C. Rachal Pugh et al. / Neuroscience and Biobehavioral Reviews 25 (2001) 2941

37

in creating memory impairments associated with stress and aging and neurodegenerative disorders such as Alzheimer's Disease and AIDS Related Dementia Complex. While we provide a discussion of the potential role of IL-1b in this wide range of phenomena and disease states, we are not suggesting that IL-1b is the only mediator of these events. We are merely pointing out its potential involvement in the complex neurotransmitter, hormone, and cytokine networks that interact to produce these phenomena. 7.1. Long-term potentiation Long-term potentiation (LTP) is a form of neural plasticity which involves a long-lasting increase in synaptic efcacy following high-frequency stimulation of that synapse. Because the increase in synaptic responsiveness is conned to synapses active at the time of stimulation, many believe that LTP could be a mechanism of biological information storage. Evidence supporting the idea that LTP is related to learning and memory processes comes from a number of different learning and memory paradigms. For example, blocking the induction of NMDA-dependent LTP impairs spatial learning in the Morris water maze [55,56]. Increasing synaptic potentiation in the CA1 region of the hippocampus by deleting the nociceptin receptor results in faster water maze learning and increased retention of a passive avoidance task [57]. Finally, Maren, De Oca, and Fanselow [58] reported a positive correlation between LTP and contextual learning, while Kiyama et al. [59] demonstrated that mice lacking the NR2A subunit of the NMDA receptor show increased thresholds for hippocampal LTP induction and concurrent decits in contextual fear conditioning. Suggesting a role for low levels of IL-1b in modulating the physiological processes underlying LTP, increases in IL-1b gene transcription during LTP have been documented in the hippocampus both in vitro and in vivo during nonpathological conditions. Importantly, this increase in IL-1b gene transcription is specic to potentiation. For example, IL-1b mRNA is only induced in the hippocampus ipsilateral to stimulation, and animals pre-treated with AP-5 (an NMDA receptor antagonist that blocks the induction of LTP) do not show increases in IL-1b mRNA. Suggesting that the increased IL-1b mRNA is translated into protein and that this protein has a physiological effect, blocking IL1 receptors (with IL-1ra) results in a reversible impairment of the maintenance of LTP [60]. These results demonstrate that low physiological levels of IL-1b play a role in synaptic plasticity as demonstrated by LTP. Conversely, a number of research groups have shown that high levels of IL-1b impair LTP. For example, as noted previously, elevated levels of IL-1b block the expression of LTP in the CA1 and CA3 regions of the hippocampus [19,20] as well as in the dentate gyrus [21,22]. This suppression of LTP is believed to be caused by IL-1 because IL-1ra strongly attenuates the inhibitory effect of IL-1 on LTP expression. While the mechanism through which IL-1b impairs LTP

is not yet fully understood, there are several mechanisms through which it could be acting. LTP induction is dependent on glutamate release from the presynaptic cell, strong post-synaptic depolarization, and Ca 21 inux into the postsynaptic cell. Importantly, IL-1b decreases glutamate transmission through its actions on adenosine A1 receptors [61]. IL-1b also impedes the development of post-synaptic depolarization by strongly enhancing the inhibitory actions of GABA through increasing chloride conductance [62]. IL1b also impairs LTP induction by inhibiting calcium currents through protein kinase C [21,63]. IL-1b could negatively affect LTP expression and or learning and memory processes through any or all of these mechanisms. 7.2. Stress As stated earlier, in addition to its role in mediating inammation and sickness behaviors, IL-1b has also been implicated in producing many of the behavioral and neurochemical changes associated with stress. Indeed, the similarity of behavioral and neurochemical sequalae to stress and infection has often been described [64,65], and several different stress paradigms (including immobilization, inescapable tailshock, and isolation) have been shown to induce central IL-1b activity [7,16,46,47]. IL-1b is thought to play a role in affecting consequences of stressors because blocking its actions prevents many stress-induced changes including the increase in norepinephrine, dopamine, serotonin, and adrenocorticotropin hormone (ACTH) following immobilization stress [47]. Stress often results in memory impairments [6671]. Stress also impairs hippocampal LTP [12,72] and primed burst potentiation (a low threshold form of LTP, [73]). It has been hypothesized that increased levels of IL-1b could be related to stress induced impairments in learning and LTP [7,12]. Evidence for this comes from the work of Murray and Lynch [74] who have shown that stressed (isolated) and IL-1b treated rats show impaired expression of LTP. In stressed rats, analysis of hippocampal tissue showed that IL-1b levels were only elevated in those animals that showed impaired LTP [12]. Further evidence for the idea that IL-1b is involved in producing stress-induced learning impairments comes from the ndings that IL-1ra prevents the escape learning failure following inescapable tailshock [75] and the impairment in contextual fear conditioning caused by social isolation [7]. Finally, the learning impairment reported by McEwen et al. [68] was blocked by tianeptine, an agent that increases serotonin re-uptake. This is interesting to note because stressors are known induce central IL-1b activity, and central IL-1b induces increased serotonin release [76,77]. Therefore, while not directly tested, it is possible that the learning impairments observed by McEwen et al. [68] were due initially to increases in IL1b. These data suggest that increases in IL-1b could indeed be involved in producing memory impairments associated with stress.

38

C. Rachal Pugh et al. / Neuroscience and Biobehavioral Reviews 25 (2001) 2941

7.3. Aging Atrophy of the human hippocampus and dementia are features of aging in many individuals [68,78]. Aging is also associated with impaired synaptic plasticity and LTP [74]. Impaired LTP in the hippocampus of the aged brain is correlated with a decrease in membrane arachidonic acid [79], and dietary supplements to restore arachidonic acid levels lead to normal LTP induction [80]. Lynch [12] has recently hypothesized that increases in IL-1b that occur during aging are involved in producing the decrease in membrane arachidonic acid concentration that leads to impaired LTP during aging. Support for this hypothesis comes from the nding that in vitro IL-1b induces lipid peroxidation [81]. In addition, analysis of tissue revealed: (a) a negative correlation between IL-1b and LTP, (b) a positive correlation between IL-1b and lipid peroxidation and (c) an inverse relationship between lipid peroxidation and membrane arachidonic acid concentration. Therefore, IL-1b may induce lipid peroxidation and lipid peroxidation leads to the decrease in membrane arachidonic acid concentration associated with aging and impaired LTP [12]. These data provide evidence that IL-1b may be involved in producing changes in brain function associated with normal aging. 7.4. Alzheimer's disease Alzheimer's disease (AD) is a progressive neurodegenerative disorder that results in loss of cognitive function. Pathologic changes in the brains of AD patients include cortical atrophy and the presence of amyloid plaques (extraneuronal structures found within the cortex and hippocampus) and neurobrillary tangles (intraneuronal lesions found in entorhinal, hippocampal, and neocortical areas). A role for the proinammatory cytokine IL-1b in AD is provided by a number of ndings. First, IL-1b is found in areas surrounding amyloid plaques [82,83], and there is evidence that IL-1 is involved in the progression of plaque formation. For example, IL-1 immunoreactive microglia are abundant in neuritic plaques, but sparse in those that are non-neuritic [84]. IL-1 levels are also signicantly higher in the temporal lobe [82], frontal cortex [85], hippocampus [86,87] and CSF [87] of AD patients when compared to age-matched controls. The decoy receptor IL-1RII, which serves as an endogenous IL-1 antagonist is also elevated in the CSF of AD patients [88] suggesting that compensatory mechanisms to neutralize elevated IL-1b levels may be occurring in AD patients. Besides being present in higher levels in AD patients, IL1b also appears to be involved in the potential physiological processes underlying the development of AD. b-Amyloid (b-A) is a peptide derived from a ubiquitous membranebound protein known as b-amyloid precursor protein (bAPP) that is involved in the pathophysiology of AD. Normally, b-APP is cleaved by a-secretase within the bA sequence preventing the formation of b-A [89]. IL-1b, however, has several effects on the expression and proces-

sing of b-APP. IL-1b stimulates the b-APP protein promoter [90] increasing the expression of b-APP mRNA [91,92]. IL-1b also stimulates protein kinase C to process b-APP into b-A and other amyloid fragments [93]. Indeed, LPS increases IL-1b leading to subsequent increases in the production of amyloidogenic fragments of b-APP [94,95]. Also, the b-A peptide itself stimulates IL-1b production [96] and potentiates the proinammatory cytokine response of astrocytes to LPS [97]. Interestingly, IL-1 is also highly expressed by microglia within hours of head trauma [98] which is a signicant risk factor for the development of AD [99,100]. In addition, there is an inverse relationship between treatment with anti-inammatory agents and the prevalence of AD [101103]. 7.5. AIDS related dementia complex Approximately 80% of AIDS patients have neurological abnormalities, and roughly half of these patients suffer from symptoms related to AIDS Related Dementia Complex (ADC; a variety of neurologic, neuropsychologic, and neuropathologic impairments that include cognitive decits, as well as motor and behavioral dysfunction). While some neurological abnormalities, such as diffuse demyelination or the presence of multinucleated giant cells, are observed in almost all ADC patients [104], these abnormalities do not correlate with the presence or severity of neuropsychological decits associated with ADC [105]. In addition, while some HIV-1 patients do not develop symptoms of ADC until late stage AIDS occurs, others present with symptoms of ADC before any systemic abnormalities are detected [106,107]. Based on these discrepancies, it has been suggested that a single mechanism underlying the clinical features of ADC is unlikely and that a variety of disturbances may underlie the disorder [108]. One potential contributor to the learning impairments associated with ADC is central IL-1b activity. This hypothesis is plausible because there is evidence for elevated IL-1b levels in the cerebrospinal uid of AIDS patients and at post-mortem brain examination. Importantly, while IL-1 is elevated in AIDS brain tissue, it is signicantly higher in demented AIDS patients [109]. The idea that IL-1b is involved in affecting neurological changes associated with the development of ADC is also suggested because neurons, which are not infected by HIV-1, are destroyed throughout the disease process. Because pathology occurs in cells not infected with the virus, it is probable that infected (and therefore activated) microglia release IL-1b that is then involved in producing the neurological changes associated with ADC. Evidence for this hypothesis comes from the ndings that the HIV-1 coat protein gp120 activates glia both in vivo and in vitro to release IL-1b [41,110,111]. In vitro gp120 even activates transcription of IL-1b [112].

C. Rachal Pugh et al. / Neuroscience and Biobehavioral Reviews 25 (2001) 2941

39

8. Conclusions The role of IL-1b in producing many of the physiological and behavioral adjustments that occur during sickness is well-documented. New evidence suggests that increased levels of IL-1b adversely affect memory consolidation processes. The present data suggests this conclusion because environmental agents or events that induce IL-1b activity impair contextual fear conditioning even when they are given after the conditioning session has ended. In addition, blocking the actions of IL-1b prevents the impairment in contextual fear conditioning produced by all three manipulations presently examined. The idea that IL-1b is involved in memory consolidation processes is consistent with other literatures suggesting a role for IL-1b in producing memory impairments associated with stress, aging, Alzheimer's disease, and AIDS related dementia complex. While it is unclear whether IL-1b impairs memory formation through the same mechanisms in all of these cases, it is important to realize that IL-1b has been implicated and hypothesized as critical in each case. Therefore, in addition to its role in mediating inammation and coordinating the sickness response, adversely affecting cognitive function should be added to the list of changes induced by central IL-1b activity. Acknowledgements This research was supported by Grants NIH MH5528, NIH MH4505, RDA MH00314, and NIH F31 MH1214801 as well as the Undergraduate Research Opportunities Program at the University of Colorado. References
[1] Maier SF, Watkins LR. Cytokines for psychologists: implications of bi-directional immune to brain communication for understanding behavior, mood, and cognition. Psych Rev 1998;105(1):83107. [2] Dantzer R, Bluthe RM, Kent S, Kelley KW. Behavioral effects of cytokines. In: Rothwell N, Dantzer R, editors. Interleukin-1 in the brain, Oxford: Pergamon, 1991. p. 13550. [3] Sims JE, Gayle MA, Slack JL, Alderson MR, Bird TA, Giri JG, Colotta F, Re F, Mantovani A, Shanebeck K, Grabstein K, Dower SK. Interleukin-1 signaling occurs exclusively via the type I receptor. Proc Natl Acad Sci 1993;90:6155. [4] Rothwell NJ, Luheshi G. Pharmacology of interleukin-1 actions in brain. Adv in Pharmacol 1994;25:320. [5] Schobitz B, DeKloet ER, Holsboer F. Gene expression and function of interleukin-1, interleukin-6, and tumor necrosis factor in brain. Prog in Neurobiol 1994;44:34297. [6] Pugh CR, Kumagawa K, Fleshner M, Watkins LR, Maier SF, Rudy JW. Selective effects of peripheral lipopolysaccharide administration on contextual and auditory-cue fear conditioning. Brain, Behav & Immun 1998;12:21229. [7] Pugh CR, Nguyen KT, Gonyea JL, Fleshner M, Watkins LR, Maier SF, Rudy JW. Role of interleukin-1b in impairment of contextual fear conditioning caused by social isolation. Behav Brain Res 1999;106:10918. [8] Farrar WL, Kilian PC, Ruff MR, Hill JM, Pert CB. Visualization and [9]

[10]

[11] [12]

[13]

[14]

[15]

[16]

[17] [18] [19]

[20]

[21] [22]

[23] [24] [25] [26] [27] [28]

[29]

[30] [31] [32]

characterization of interleukin-1 receptors in brain. J Immunol 1987;139:45963. Takao T, Tracey DE, Mitchell WM, DeSouza EB. Interleukin-1 receptors in mouse brain: characterization and neuronal localization. Endocrinol 1990;127(6):30708. Ban E, Milon G, Prudhomme N, Filion G, Haour F. Receptors for interleukin 1 (a and b) in mouse brain mapping and neuronal localization in hippocampus. Neurosci 1991;43:2130. Cunningham Jr ET, de Souza EB. Interleukin-1 receptors in the brain and endocrine tissue. Immunol Today 1993;14:1716. Ban E, Haour F, Lenstra R. Brain interleukin-1 gene expression induced by peripheral lipopolysaccharide administration. Cytokine 1992;4(1):4854. Laye S, Parnet P, Goujon E, Dantzer R. Peripheral administration of lipopolysaccharide induces the expression of cytokine transcripts in the brain and pituitary of mice. Brain Research Mol Brain Res 1994;27:15762. Laye S, Bluthe RM, Kent S, Combe C, Medina C, Parnet P, Kelley K, Dantzer R. Subdiaphragmatic vagotomy blocks induction of IL-1 beta mRNA in mice brain in response to peripheral LPS. Amer J Physiol 1995;268:32731. Watkins LR, Hansen MK, Nguyen KT, Lee JE, Maier SF. Dynamic regulation of the proinammatory cytokine interleukin-1 beta: molecular biology for non-molecular biologists. Life Sci 1999;65(5):44981. Nguyen KT, Deak T, Owens SF, Kohno T, Fleshner M, Watkins LR, Maier SF. Exposure to acute stress induces brain interleukin-1 protein in the rat. J Neurosci 1998;18(6):17. Lynch MA. What is the biological signicance of an age-related increase in IL-1b in hippocampus? Mol Psych 1999;4:1518. Elgersma Y, Silva AJ. Molecular mechanisms of synaptic plasticity and memory. Curr Opinions Neurobiol 1999;9:20913. Bellinger FP, Madamba S, Siggins GR. Interleukin-1 beta inhibits synaptic strength and long-term potentiation in the rat CA1 hippocampus. Brain Res 1993;628:22734. Katsuki H, Nakai S, Hirai Y, Akaji K, Kiso Y, Satoh M. Interleukin1 beta inhibits long-term potentiation in the CA3 region of mouse hippocampal slices. Euro J Pharmacol 1990;181(3):3236. O'Connor JJ, Coogan AN. Actions of the proinammatory cytokine IL-1b on central synaptic transmission. Exp Physiol 1999;84:60114. Cunningham AJ, Murray CA, O'Neill LA, Lynch MA, O'Connor JJ. Interleukin-1 beta (IL-1b) and tumor necrosis factor (TNF) inhibit long-term potentiation in the rat dentate gyrus in vitro. Neurosc Lett 1996;203(1):1720. Squire LR. Memory and the hippocampus: a synthesis from ndings with rats, monkeys, and humans. Psych Rev 1992;99:195231. Milner B, Squire LR, Kandel ER. Cognitive neuroscience and the study of memory. Neuron 1998;20(3):44568. Squire LR. Mechanisms of memory. Sci 1986;232:16129. Nadel L. The hippocampus and space revisited. Hippo 1991;1(3):2219. Hirsh R. The hippocampus and contextual retrieval of information from memory: a theory. Beh Biol 1974;12(4):42144. Sutherland RJ, Rudy JW. Congural association theory: the role of the hippocampal formation in learning, memory, and amnesia. Psychobiol 1989;17(2):12944. Bourtchouladze R, Abel T, Berman N, Gordon R, Lapidus K, Kandel ER. Different training procedures recruit either one or two critical periods for contextual memory consolidation, each of which requires protein synthesis and PKA. Learning & Memory 1998;5(4-5):36574. LeDoux JE. Emotion. Memory, and the Brain Scien Amer 1994;270(6):3239. Maren S, Fanselow MS. The amygdala and fear conditioning: has the nut been cracked? Neuron 1996;16:23740. Fendt M, Fanselow MS. The neuroanatomical and neurochemical basis of conditioned fear. Neurosci Biobehav Rev 1999;23:74360.

40

C. Rachal Pugh et al. / Neuroscience and Biobehavioral Reviews 25 (2001) 2941 after schedules of partial delay or partial reinforcement in rats with hippocampal lesions. Exp Brain Res 1985;59(2):27381. Rawlins JN, Feldon J, Butt S. The effects of delaying reward on choice preference in rats with hippocampal or selective septal lesions. Behav Brain Res 1985;15(3):191203. Morris RG, Anderson E, Lynch GS, Baudry M. Selective impairment of learning and blockade of long-term potentiation by an N-methyl-Daspartate receptor antagonist AP5. Nature 1986;319:7746. Morris RGM. Synaptic plasticity and learning: selective impairment of learning in rats and blockade of long-term potentiation in vivo by the N-methyl-D-aspartate receptor antagonist AP5. J Neurosci 1989;9:304057. Manabe T, Noda Y, Mamiya T, Katagiri H, Houtani T, Nishi M, Noda T, Takahashi T, Sugimoto T, Nabeshima T, Takeshima H. Facilitation of long-term potentiation and memory in mice lacking nociceptin receptors. Nature 1998;394:57781. Maren S, De Oca B, Fanselow MS. Sex differences in hippocampal long-term potentiation (LTP) and Pavlovian fear conditioning in rats: positive correlation between LTP and contextual learning. Brain Res 1994;661(1-2):2534. Kiyama Y, Manabe T, Sakimura K, Kawakami F, Mori H, Mishina M. Increased thresholds for long-term potentiation and contextual learning in mice lacking the NMDA-type glutamate receptor epsilon1 subunit. J Neuroscience 1998;18:670412. Schneider H, Pitossi F, Balschun D, Wagner A, del Rey A, Besedovsky HO. A neuromodulatory role of interleukin-1b in the hippocampus. Proc Natl Acad Sci 1998;95:777883. Luk WP, Zhang Y, White TD, Lue FA, Wu C, Jiang CG, Zhang L, Moldofsky H. Adenosine: a mediator of interleukin-1b induced hippocampal synaptic inhibition . J Neurosci 1999;19(11):423844. Miller LG, Galpern WR, Dunlap K, Dinarello CA, Turner TJ. Interleukin-1 augments GABAA receptor function in brain. Molec Pharm 1990;39:1058. Plata-Salaman CR, French-Mullen JMH. Intracerebroventricular administration of a specic IL-1 receptor antagonist blocks food and water intake suppression induced by interleukin-1b. Physiol & Behav 1992;51:12779. Dunn AJ. Role of cytokines in infection-induced stress. Ann NY Acad Sci 1993;697:189202. Zalcman S, Green-Johnson JM, Murray L, Nance DM, Dyck D, Anisman H, Greenberg AH. Cytokine-specic central monoamine alterations induced by interleukin-1, -2, and -6. Brain Res 1994;643:4049. Lupien SJ, Gaudreau S, Tchiteya BM, Maheu F, Sharma S, Nair NP, Hauger RL, McEwen BS, Meaney MJ. Stress-induced declarative memory impairment in healthy elderly subjects: relationship to cortisol reactivity. J Clin Endocrinol Metab 1997;82(7):20705. Conrad CD, Galea LA, Kuroda Y, McEwen BS. Chronic stress impairs rat spatial memory on the Y-maze, and this effect is blocked by tianeptine pretreatment. Behav Neurosci 1996;110(6):132134. McEwen BS, Conrad CD, Kuroda Y, Frankfurt M, Magarinos AM, McKittrick C. Prevention of stress-induced morphological and cognitive consequences. Europ J Neuropsychopharmacol 1997;7(3):S3238. Luine V, Villegas M, Martinez C, McEwen BS. Repeated stress causes reversible impairments of spatial memory performance. Brain Res 1994;639(1):16770. Nishimura J, Endo Y, Kimura F. A long-term stress exposure impairs maze learning performance in rats. Neurosci Lett 1999;273(2):1258. Diamond DM, Fleshner M, Ingersoll N, Rose GM. Psychological stress impairs spatial working memory: relevance to electrophysiological studies of hippocampal function. Behav Neurosci 1996;110(4):66172. Foy MR, Stanton ME, Levine S, Thompson RF. Behavioral stress impairs long-term potentiation in rodent hippocampus. Behav Neural Biol 1987;48:13849. Diamond DM, Fleshner M, Rose GM. Psychological stress

[33] Kim JJ, Fanselow M. Modality-specic retrograde amnesia of fear. Sci 1992;256:6756. [34] Phillips RG, LeDoux JE. Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav Neurosci 1992;106:27485. [35] Phillips RG, LeDoux JE. Lesions of the dorsal hippocampal formation interfere with background but not foreground contextual fear conditioning. Learning & Memory 1994;1:3445. [36] Buttini M, Boddeke H. Peripheral lipopolysaccharide stimulation induces interleukin-1 beta messenger RNA in rat brain microglial cells. Neurosci 1995;65(2):52330. [37] Quan N, Stern EL, Whiteside MB, Herkenham M. Induction of proinammatory cytokine mRNAs in the brain after peripheral injection of subseptic doses of lipopolysaccharide in the rat. J Neuroimmunol 1999;93(1-2):7280. [38] Fanselow MS. Factors governing one trial contextual conditioning. Animal Learning & Behav 1990;18:26470. [39] Pugh CR, Tremblay D, Fleshner M, Rudy JW. A selective role for corticosterone in contextual-fear conditioning. Behav Neurosci 1997;111(3):50311. [40] Rudy JW, O'Reilly RC. Contextual fear conditioning, conjunctive representations, pattern completion, and the hippocampus. Behav Neurosci 1999;113(5):86780. [41] Koka P, He K, Zack JA, Kitche S, Peacock W, Fried I, Tran T, Yashar SS, Merrill JE. Human immunodeciency virus 1 envelope proteins induce interleukin 1, tumor necrosis factor alpha, and nitric oxide in glial cultures derived from fetal, neonatal, and adult human brain. J Exp Med 1995;182:94151. [42] Opp MR, Rady PL, Hughes Jr TK, Cadet P, Tyring SK, Smith EM. Human immunodeciency virus envelope glycoprotein 120 alters sleep and induces cytokine mRNA expression in rats. Amer J Physiol 1996;270:R96370 (5 pt 2). [43] Sundar SK, Cierpial MA, Kamaraju LS, Long S, Hsieh S, Lorenz C, Aaron M, Ritchie J, Weiss JM. Human Immunodeciency virus glycoprotein (gp120) infused into rat brain induces interleukin-1 to elevate pituitary-adrenal activity and decrease peripheral cellular immune responses. Proc Natl Acad Sci 1991;88:1124650. [44] Pugh CR, Johnson JD, Martin D, Rudy JW, Maier SF, Watkins LR. Human immunodeciency virus-1 coat protein gp120 impairs contextual fear conditioning: a potential role in AIDS related learning and memory impairments. Brain Res 2000;861:815. [45] Catania A, Lipton J. a-Melanocyte stimulating hormone peptides in host responses. Ann NY Acad Sci 1993;680:41223. [46] Minami M, Kuraishi Y, Yagaguchi T, Nakai S, Hirai Y, Satoh M. Immobilization stress induces interleukin-b mRNA in the rat hypothalamus. Neurosci Lett 1991;123:2546. [47] Shintani F, Nakaki T, Kanba S, Sato K, Yagi G, Shiozawa M, Aiso S, Kato R, Asai M. Involvement of interleukin-1 in immobilization stress-induced increase in plasma adrenocorticotropic hormone and in release of hypothalamic monoamines in the rat. J Neurosci 1995;15(3):196170. [48] Rudy JW. Post-conditioning isolation disrupts contextual fear conditioning: an experimental analysis. Behav Neurosci 1996;110:23846. [49] Rudy JW, Kumagawa K, Pugh CR. Isolation reduces contextual but not auditory-cue fear conditioning: a role for endogenous opioids. Behav Neurosci 1999;113(2):31623. [50] Oitzl MS, van Oers H, Schobitz B, deKloet ER. Interleukin-1 beta, but not interleukin-6 impairs spatial navigation learning. Brain Res 1993;613(1):1603. [51] Gibertini M, Newton C, Klein TW, Friedman H. Legionella pneumophila-induced visual learning impairment reversed by anti-interleukin-1 beta. Proc Soc Exp Biol Med 1995;210(1):711. [52] Aubert A, Vega C, Dantzer R, Goodall G. Pyrogens specically disrupt the acquisition of a task involving cognitive processing in the rat. Brain, Behav & Immun 1995;9(2):12948. [53] Rawlins JN, Feldon J, Ursin H, Gray JA. Resistance to extinction

[54] [55] [56]

[57]

[58]

[59]

[60] [61] [62] [63]

[64] [65]

[66]

[67] [68]

[69] [70] [71]

[72] [73]

C. Rachal Pugh et al. / Neuroscience and Biobehavioral Reviews 25 (2001) 2941 repeatedly blocks hippocampal primed burst potentiation in behaving rats. Behav Brain Res 1994;62(1):19. Murray CA, Lynch MA. Evidence that increased hippocampal expression of the cytokine interleukin-1b is a common trigger for age- and stress-induced impairments in long-term potentiation. J Neurosci 1998;18(8):297481. Maier SF, Watkins LR. Intracerebroventricular interleukin-1 receptor antagonist blocks the enhancement of fear conditioning and interference with escape produced by inescapable shock. Brain Res 1995;695:27982. Linthorst AC, Flachskamm C, Holsboer F, Reul JM. Local administration of recombinant human interleukin-1 beta in the rat hippocampus increases serotonergic neurotransmission, hypothalamicpituitary-adrenocortical axis activity, and body temperature. Endocrinol 1994;135:52032. Linthorst AC, Flachskamm C, Muller-Preuss P, Holsboer F, Reul JM. Effect of bacterial endotoxin and interleukin-1 beta on hippocampal serotonergic neurotransmission, behavioral activity, and free corticosterone levels: an in vivo microdialysis study. J Neurosci 1995;15:292034. Soininen HS, Partanen K, Pitkanen A, Vainio P, Hanninen T, Hallikainen M, Koivosto K, Riekkinen PJ. Sr Volumetric MRI analysis of the amygdala and the hippocampus in subjects with age-associated memory impairment: correlation to visual and verbal memory. Neurol 1994;44(9):16608. Lynch MA, Voss KL. Membrane arachidonic acid concentration correlates with age and induction of long-term potentiation in the dentate gyrus in the rat. Europ J Neurosci 1994;6:100814. McGahon B, Clements MP, Lynch MA. The ability of aged rats to sustain long-term potentiation is restored when the age-related decrease in membrane arachidonic acid concentration is reversed. Neurosci 1997;81:916. Lynch MA. Age-related changes in synaptic plasticity in rat hippocampus. J Physiol 1997;501:56S. Grifn WS, Stanley LC, Ling C, White L, MacLeod V, Perrot LJ, White 3d CL, Araoz C. Brain interleukin-1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc Natl Acad Sci 1989;86(19):76115. Mrak RE, Sheng JG, Grifn ST. Glial cytokines in Alzheimer's disease: review and pathogenic implications. Prog Pathol 1995;26(8):81623. Grifn WS, Sheng JG, Roberts GW, Mrak RE. Interleukin-1 expression in different plaque types in Alzheimer's disease: signicance in plaque evolution. J Neuropathol Exp Neurol 1995;54(2):27681. Cacabelos R, Alvarez XA, Fernandez-Novoa L, Franco A, Mangues R, Pellicer A, Nishimura T. Brain interleukin-1b in Alzheimer's disease and vascular dementia. Mthds Findings Exp Clin Pharmacol 1994;16:14151. Araujo DM, Lapchak PA. Induction of immune system mediators in the hippocampal formation in Alzheimer's and Parkinson's diseases: selective effects on specic interleukins and interleukin receptors. Neurosci 1994;61(4):74554. Cacabelos R, Barquero M, Garcia P, Alvarez XA, Varela de Seijas E. Cerbrospinal uid interleukin-1b (IL-1b) in Alzheimer's disease and neurological disorders. Mthds Findings Exp Clin Pharmacol 1991;13:4558. Garlind A, Brauner A, Hojeberg B, Basun H, Schultzberg M. Soluble interleukin-1 receptor type II levels are elevated in cerebrospinal uid in Alzheimer's disease patients. Brain Res 1999;826:1126. Selkoe DJ. Physiological production of the beta-amyloid protein and the mechanism of Alzheimer's disease. TINS 1993;16(10):4039. Donnelly RJ, Friedhoff AJ, Beer B, Blume AJ, Vitek MP. Interleukin-1 stimulates the beta-amyloid precursor protein promoter. Cell Molec Neurobiol 1990;10(4):48595. Forloni G, Demicheli F, Giorgi S, Bendotti C, Angeretti N. Expression of amyloid precursor protein mRNAs in endothelial, neuronal,

41

[74]

[92]

[75]

[93]

[76]

[94]

[77]

[95] [96] [97] [98]

[78]

[79]

[80]

[99] [100] [101] [102]

[81] [82]

[83]

[84]

[103] [104] [105] [106] [107] [108] [109] [110] [111] [112]

[85]

[86]

[87]

[88]

[89] [90]

[91]

and glial cells: modulation by interleukin-1. Molec Brain Res 1992;16:12834. Goldgaber D, Harris HW, Hla T, Maciag T, Donnelly RJ, Jacobsen MP, Vitek MP, Gajdusek DC. Interleukin-1 regulates synthesis of amyloid b-protein precursor mRNA in human endothelial cells. Proc Natl Acad Sci 1989;86:760610. Buxbaum JD, Oishi M, Chen HI, Pinkas-Kramarski R, Jaffe E, Gandy EA, Gandy SE, Greengard P. Cholinergic agonists and interleukin-1 regulate processing and secretion of the Alzheimer b/A4 amyloid protein precursor. Proc Natl Acad Sci 1992;89:100758. Brugg B, Lemaigre-Dubreuil Y, Huber G, Kopmels B, DelhyeBouchaud N, Wollman E, Mariani J. Neuronal death, proinammatory cytokines and amyloid precursor protein: studies on staggerer mutant mice. In: Kosik KS, Christen Y, Selkoe DJ, editors. Alzheimer's disease: lessons from cell biology, Berlin Heidelberg: Springer-Verlag, 1995. p. 20216. Malek-Ahmadi P. Cytokines in dementia of the Alzheimer's type (DAT) relevance to research and treatment. Neurosci Biobehav Rev 1998;22(3):38994. Araujo DM, Couman CW. b-amyloid stimulates glial cells in vitro to produce growth factors that accumulate in senile plaques in Alzheimer's disease. Brain Res 1992;569:1415. Forloni G, Mangiarotti F, Angeretti N, Lucca E, De Simoni MG. bamyloid fragment potentiates IL-6 and TNFa secretion by LPS in astrocytes but not in microglia. Cytokine 1997;9:75962. Grifn WST, Sheng JG, Gentleman SM, Graham DI, Mrak RE, Roberts GW. Microglial interleukin-1 alpha expression in human head injury: correlations with neuronal and neuritic beta-amyloid precursor protein expression. Neurosci Lett 1994;176:1336. Rasmusson DX, Brandt J, Martin DB, Folstein MF. Head injury as a risk factor in Alzheimer's disease. Brain Inj 1987;9:2139. Graves AB, White E, Koepsell TD, Reier BV, van Belle G, Larson EB, Raskind M. The association between head trauma and Alzheimer's disease. Amer J Epidemiol 1990;131:491501. Rogers J, Kirkby LC, Hempelman SR, Berry DL, McGeer PL, Kaszniak AW, Zalinski J, Coeld M, Mansukhani L, Wilson P. Clinical trial of indomethacin in Alzheimer's disease. Neurol 1993;43(8):160911. Breitner JCS, Gau BA, Welsh KA, Plassman BL, McDonald WM, Helm MJ, Anthony JC. Inverse association of anti-inammatory treatments and Alzheimer's disease. Initial results of a co-twin study Neurol 1994;44:22732. Andersen K, Launer LJ, Ott A, Hoes AW, Breteler MMB, Hofman A. Do nonsteroidal anti-inammatory drugs decrease the risk for Alzheimer's disease? The Rotterdam study Neurol 1995;45:14415. Merrill JE, Chen ISY. HIV-1, macrophages, glial cells, and cytokines in AIDS nervous system disease. FASEB 1991;5:23917. Harrison MJG, McArthur JC. AIDS and Neurology. Edinburgh: Churchill Livingstone, 1995. Navia BA, Jordan BD, Price RW, The AIDS. dementia complex: I. Clinical features. Ann Neurol 1986;19(6):51724. Levy RM, Bredesen DE. Central nervous system dysfunction in Acquired Immunodeciency Syndrome. In: Rosenblum ML, editor. AIDS and the nervous system, New York: Raven Press, 1988. p. 2963. Price RW, Brew BJ. The AIDS dementia complex. J Infect Dis 1988;158:107983. Tyor WR, Glass JD, Grifn JW, Becker PS, McArthur JC, Bezman L, Grifn DE. Cytokine expression in the brain during the acquired Immunodeciency syndrome. Ann Neurol 1992;31:34960. Lipton SA, Yeh M, Dreyer EB. Update on current models of HIVrelated neuronal injury: platelet-activating factor, arachidonic acid and nitric oxide. Adv Neuroimmunol 1994;4:1818. Merrill JE, Koyanagi Y, Zack J, Thomas L, Martin F, Chen IS. Induction of interleukin-1 and tumor necrosis factor alpha in brain cultures by human Immunodeciency virus type 1. J Virol 1992;66:221725. Benveniste EN, Benos D. TNF-alpha and IFN-gamma mediated signal transduction pathways: effects on glial cell gene expression and function. FASEB 1995;9:157784.