Peripheral infection and aging interact to impair hippocampal memory consolidation

https://doi.org/10.1016/j.neurobiolaging.2005.03.010Get rights and content

Abstract

We report that a peripheral injection of Escherichia coli produces both anterograde and retrograde amnesia in 24 month old, but not 3 month old rats for memories that depend on the hippocampus, that is, memory of context, contextual fear, and place learning. The anterograde effect was restricted to measures of long-term memory. Short-term memory was not affected, nor did E. coli produce amnesia for auditory-cue fear conditioning. There were no age related effects on memory in vehicle-treated rats. In addition to these age-related cognitive effects of E.coli, we report that it produced a marked increased in IL-1β levels in the hippocampus, but not in parietal cortex or serum. These findings support the hypothesis that age is a vulnerability factor that increases the likelihood that an immune challenge will produce a cognitive impairment. It is possible that this cognitive vulnerability is mediated by age-related changes in the glial environment that results in an exaggerated brain pro-inflammatory response to infection.

Introduction

It has been well documented that the significantly elevated expression of pro-inflammatory cytokines above basal levels, particularly in the hippocampus, impairs both synaptic plasticity, as assessed by long-term potentiation (LTP) [46], [47], and hippocampal-dependent memory [1], [3], [4], [14], [16], [17], [18], [32], [36], [37]. Peripheral cytokines, which are induced by immune activating stimuli such as infectious agents are capable of signaling the brain via both neural and blood-borne routes [23]. Importantly, this immune-to-brain signaling results in the de novo production of pro-inflammatory cytokines within the brain [24], [30], [45], largely by glial cells [19]. Thus, populations or individuals that have either increased peripheral inflammatory responses to immune activating agents such as bacteria or viruses, or exaggerated brain pro-inflammatory responses to signaling events within the brain, are likely to be more susceptible to infection-induced memory impairments.

Peripheral inflammatory responses to immune activating agents, as well as brain cytokine responses to stimulation are altered with normal aging. For example, Saito et al. [40] reported that the levels of interleukin-6 (IL-6) in blood produced by cecal ligation and puncture, as well as by lipolysaccharide (LPS), were elevated more in aged than in young mice. Within the brain, IL-1β and tumor necrosis factor-α responses to peripheral LPS administration appear to increase with aging [42], [50]. Moreover, in the brain, healthy elderly subjects exhibit microglia with many phenotypic features consistent with a state of activation compared to younger control subjects. For example, aged subjects exhibit increases in the expression of complement type 3 receptor (CD11b), major histocompatibility complex II (MHC II), and CD4 at the protein level [29], [33], and MHC II, MHC II transcriptional activator (CIITA), interferon (IFN)-γ, and CD86 at the transcriptional level [13]. Astrocytic glial fibrillary acidic protein (GFAP) protein and mRNA have also been reported to be elevated in the hippocampus of aged subjects [41], [48]. As already noted, glial cells are important in the central nervous system with regard to inflammatory processes, as they are part of the neural cascade that is initiated by immune-to-brain signaling that involves the production of pro-inflammatory cytokines within the brain [27]. Because in the healthy, but aging organism both peripheral and central inflammatory functions are increased, it may be that a peripheral immune challenge in older subjects will produce an exaggerated cytokine response in the brain, and thereby produce greater impairments of memory. Moreover, since the immune-induced induction of cytokines such as IL-1β is especially prominent in the hippocampus [24], [30], [45], any interference with memory that is produced could be selective for forms of memory that require the hippocampus.

In the present experiments we assessed the impact of peripheral immune challenge/infection with live, replicating E. coli on memory formation in aging and young rats. To evaluate the effect of the E. coli challenge we used three memory paradigms that are known to depend on the hippocampus. Two versions of contextual fear conditioning were used. In the standard version, rats were simply placed into a conditioning chamber and presented with a tone-shock pairing. They were later tested for fear of the context (in the absence of the tone), and again for fear of the tone (in an altered context). It is important to note that the context test is a measure of hippocampal-dependent memory, whereas the tone test is not [22], [35]. In the other version, we used a paradigm that produces what is called the context pre-exposure facilitation effect (CPFE). It allows the study of the rat's memory of an explored context. The CPFE derives from Fanselow's [10] analysis of the failure of shock delivered immediately after the subject is placed into an experimental apparatus to produce fear conditioning to the experimental context. However, if the subject is pre-exposed to the experimental context the day before fear conditioning, then immediate shock produces substantial fear conditioning [49]. According to Fanselow, immediate shock fails to support conditioning because the rat does not have time to encode a representation of the context prior to immediate shock. Pre-exposure thus facilitates the amount of conditioning produced by immediate shock because it allows the rat to establish a memory representation of the context before the immediate shock. This memory is then retrieved prior to the immediate shock by a subset of features that make up the context or by cues associated with transporting the rat to the conditioning chamber [39]. It is this retrieved memory representation of the context that is then associated with the immediate shock, and this facilitation effect depends on the hippocampus [2], [28], [38]. The third paradigm was the Morris place learning task. It requires rats to learn and retain the location of a platform that is submerged in a circular pool of water.

We evaluated the ability of the E. coli infection to produce both anterograde and retrograde amnesia for these tasks. Retrograde amnesia was studied by injecting the E. coli immediately following training, and anterograde amnesia was studied by injecting E. coli several days prior to training on the task. These experiments compared 3 and 24 month old male F344XBN F1 rats. We purposely chose the older group to be at an age below senescence (perhaps 32 months in this strain). This was done to minimize the possibility that there would be large memory impairments in the absence of challenge. Thus, the present experiments were designed to examine the effects of aging rather than old age.

Section snippets

Subjects

Subjects were male F344XBN F1 rats obtained from the National Institute on Aging (Bethesda, MD). Upon arrival at our facility, older rats were 24 months old and weighed approximately 575 g. Younger rats were 3 months old and weighed approximately 280 g. Older and younger rats were housed 2 or 4 to a cage (52 cm × 30 cm × 21 cm; L × W × H), respectively. The animal colony was maintained at 22 °C on a 12-h light/dark cycle (lights on at 07:00 h). All rats were allowed free access to food and water and were

Experiment 1: retrograde effects of E. coli on context pre-exposure facilitation

Here, we examined the influence of a peripheral infection on the consolidation of the rat's memory for context, a hippocampal-dependent task. Rats were pre-exposed to either the conditioning context or a control context. Immediately following the exposure, they were injected with E. coli or vehicle. Seventy-two hours later, they were given an immediate shock in the conditioning context and a day later they were tested for fear of the context in which they were shocked.

A 2 × 2 × 2 analysis of

Discussion

The present results indicate that older organisms are especially vulnerable to memory impairments produced by peripheral immune activation. Aging alone did not result in significant memory losses. Both 3 and 24 month old vehicle-treated rats performed comparably on all memory tasks, although acquisition of the spatial Morris task was slowed in the older rats. However, challenge to the immune system with E. coli in older subjects substantially interfered with all of the hippocampal-dependent

Acknowledgement

The present work was supported by grant 5 F32 MH064339-03 (R.M.B.).

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