Time course of hippocampal IL-1 β and memory consolidation impairments in aging rats following peripheral infection

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Abstract

We previously reported that aging F344XBN rats are more vulnerable to disruptions of memory consolidation processes following an injection of Escherichia coli than are young rats. Furthermore, this disruption was specific to hippocampal-dependent memory. In the present study we examined the time course of the proinflammatory cytokine IL-1 β in young and old rats following a peripheral injection of E. coli. Compared to young rats, aging rats treated with E. coli showed an exaggerated and prolonged up-regulation of IL-1 β protein in the hippocampus, but not in hypothalamus, parietal cortex, prefrontal cortex, serum or spleen. Aging rats showed greater hippocampal IL-1 β protein levels than their young counterparts 4 h after E. coli, and these levels remained significantly elevated for 8 but not 14 days after E. coli. In a second experiment, aging rats exhibited anterograde memory consolidation impairments 4 and 8 days after an E. coli injection, but not after 14 days. A third experiment revealed that following an E. coli injection, bacterial clearance from the spleen and peritoneum was not impaired in aged rats, suggesting that elevations in hippocampal IL-1 β were not mediated by impaired clearance in the periphery in aging rats. These data suggest that the exaggerated and prolonged elevation of IL-1 β, specifically in the hippocampus, may be responsible for hippocampal-dependent memory impairments observed in aging rats following a bacterial infection.

Introduction

There has been increasing interest in the role of proinflammatory cytokines in modulating learning and memory processes (Barrientos et al., 2006a, Barrientos et al., 2002, Bilbo et al., 2005, Cunningham et al., 1996, Godbout et al., 2005, Hauss-Wegrzyniak et al., 1998, Pugh et al., 1998, Yirmiya et al., 2002). In large part, this interest comes from findings that Alzheimer’s disease is associated with significantly elevated levels of the proinflammatory cytokines interleukin-1 β (IL-1 β), IL-6 and TNFα and/or decreased levels of the anti-inflammatory cytokines IL-1ra, and IL-10 (Griffin et al., 1989, Lombardi et al., 1999, Lue et al., 2001, Mrak and Griffin, 2005, Paganelli et al., 2002, Tarkowski et al., 2001). These altered cytokine levels have been found both peripherally and centrally. This is important because peripheral cytokines are capable of signaling the brain via both blood-borne and neural routes (Dantzer, 2004) and can lead to de novo production of proinflammatory cytokines within the brain (Van Dam et al., 1995). Thus, bacterial infections that are initiated in the periphery have the potential to result in inflammation in the brain.

Elevated levels of IL-1 β in the brain, particularly in the hippocampus, are especially relevant to memory function because it has been shown to impair hippocampal long-term potentiation (LTP) (Cunningham et al., 1996, Vereker et al., 2000a, Vereker et al., 2000b), a form of synaptic plasticity that is characterized by a persistent increase in synaptic efficacy following titanic stimulation (Bliss and Lomo, 1973). Importantly, inhibition of LTP results in hippocampal-dependent memory impairments (Morris et al., 1986, Shimizu et al., 2000), and elevated levels of IL-1 β in the hippocampus have been repeatedly shown to impair hippocampal-dependent memory (Barrientos et al., 2002, Barrientos et al., 2003, Barrientos et al., 2004, Bilbo et al., 2005, Hauss-Wegrzyniak et al., 1998, Hauss-Wegrzyniak et al., 2002, Hauss-Wegrzyniak et al., 1999, Pugh et al., 1998, Pugh et al., 1999). It should be emphasized that we are referring here to IL-1 β elevated above basal levels, as basal levels of IL-1 β have been shown to be necessary for plasticity and hippocampal-dependent memory performance (Yirmiya et al., 2002). It is important to note that the literature is muddled with inconsistencies pertaining to basal levels of IL-1 β in young vs. old subjects. Some laboratories report basal differences (Gemma et al., 2005, Godbout et al., 2005, Riancho et al., 1994), while others do not (Beloosesky et al., 2002, Fagiolo et al., 1993, Gayle et al., 1999, Gee et al., 2006, Kyrkanides et al., 2001). Whether these inconsistencies are due to differences in species (human, rat, mice, etc.), and/or strains of animals used or the age of the “aged” subject is unclear at this time. We have never observed a basal difference in IL-1 β levels in any tissue samples between our young and old subjects. However, it is worth noting that we are using 24 month old F344xBN rats which are considered to be a “younger” than, say, a 24 month old F344 rat, which is considered to be senescent at this age. We purposely chose the older group to be at an age below senescence (perhaps 36 months in this strain) to minimize memory impairments between young and old rats in the absence of an immune challenge.

Because (a) peripheral cytokines induce the production of brain cytokines, and (b) brain cytokines can interfere with hippocampal memory consolidation, individuals that have either increased peripheral inflammatory responses to immune activating agents such as bacteria, or exaggerated brain proinflammatory responses to signaling events within the brain, are likely to be more susceptible to infection-induced memory impairments. Aged individuals fall into this vulnerable category. Healthy aged animals show antigenic and morphological markers of glial activation (Frank et al., 2006, McGeer et al., 1987, Perry et al., 1993, Smith et al., 2001, Wagner et al., 1993). This is noted because glia are the predominant source of cytokines induced within the brain parenchyma (Van Dam et al., 1995), and were found to be the source of proinflammatory cytokines observed in the brains of AD patients (Lue et al., 2001). As stated earlier, basal proinflammatory cytokine levels in healthy aged subjects are not always found to be elevated (Beloosesky et al., 2002, Fagiolo et al., 1993, Kyrkanides et al., 2001). It has been suggested that glial cells with this profile may be sensitized, or primed, so that they show morphological markers of activation, but do not express elevated levels of proinflammatory cytokines unless the organism is challenged and glia therefore signaled (Perry et al., 2003). When the organism with primed glial cells is challenged, the resulting expression of proinflammatory cytokines is exaggerated (Cunningham et al., 2005), thus exacerbating local brain inflammation.

In the current study, we (1) determined the duration of brain and peripheral IL-1 β protein changes after a peripheral administration of Escherichia coli (E. coli) in young and aging rats. This timecourse is not known. Assessments were made 2 h, 4 h, 24 h, 4 d, 8 d, and 14 d after E. coli. (2) Determined whether the duration of memory impairment in aging animals after E. coli parallels the duration of hippocampal IL-1 β elevation. To do this we measured long-term memory for contextual fear conditioning. The duration of any such effect is not known. (3) Examined aging rats’ ability to clear the E. coli bacteria from the peritoneal cavity, spleen, hippocampus, and blood, compared to that of young rats. This was done to determine whether the effects of aging on E. coli-induced increases in IL-1 β and memory impairments could be explained by decreased clearance of E. coli.

Section snippets

Subjects

Subjects were male F344xBN F1 rats obtained from the National Institute on Aging (Bethesda, MD). Upon arrival at our facility, old rats were 24 months old and weighed approximately 575 g. Young rats were 3 months old and weighed approximately 280 g. All rats were housed 2 to a cage (52 L × 30 W × 21 H, cm), in a standard animal colony shared by several experimenters. The animal colony was maintained at 23 °C on a 12-h light/dark cycle (lights on at 07:00 h). All rats were allowed free access to food and

Experiment 1

In this experiment we examined the influence of a peripheral infection on the production of the proinflammatory cytokine interleukin-1 β (IL-1 β) in both the periphery as well as the brain at several different time points following bacterial challenge. Among our vehicle-injected rats, there was no significant difference between 3 h and 24 h time points (data not shown) for any of the tissues sampled. This lack of an effect of vehicle injection further justified omitting examination of cytokines

Discussion

Results from Experiment 1 showed that following a peripheral E. coli administration, aging rats had an exaggerated and longer lasting IL-1 β response, specifically in the hippocampus, relative to young rats. E. coli treatment led to increases in hippocampal IL-1 β levels from 2 h to 24 h in both age groups. It was not until 4 days after E. coli that the age groups differed significantly. At 4 and 8 days, old E. coli-treated rats exhibited significantly elevated levels of IL-1 β compared to E. coli

Disclosure statement

None of the authors have any actual or potential conflicts of interest.

Acknowledgments

The present work was supported by Grants F32 MH064339 and RO1 AG028271.

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