Peripheral infection and aging interact to impair hippocampal memory consolidation
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.).
References (51)
- et al.
Memory for context is impaired by a post context exposure injection of interleukin-1 beta into dorsal hippocampus
Behav Brain Res
(2002) - et al.
Memory for context is impaired by injecting anisomycin into dorsal hippocampus following context exploration
Behav Brain Res
(2002) - et al.
Brain-derived neurotrophic factor mRNA downregulation produced by social isolation is blocked by intrahippocampal interleukin-1 receptor antagonist
Neuroscience
(2003) - et al.
BDNF mRNA expression in rat hippocampus following contextual learning is blocked by intrahippocampal IL-1b administration
J Neuroimmunol
(2004) - et al.
Cognitive function after anaesthesia in the elderly
Best Pract Res Clin Anaesthesiol
(2003) - et al.
Peripheral infection evokes exaggerated sickness behaviour in pre-clinical murine prion disease
Neuroscience
(2002) - et al.
Plasma cytokine profiles in elderly humans
Mech Ageing Dev
(2003) - et al.
Spatial learning impairment in mice infected with Legionella pneumophila or administered exogenous interleukin-1-beta
Brain Behav Immun
(1995) - et al.
Chronic neuroinflammation in rats reproduces components of the neurobiology of Alzheimer's disease
Brain Res
(1998) - et al.
Chronic brain inflammation results in cell loss in the entorhinal cortex and impaired LTP in perforant path-granule cell synapses
Exp Neurol
(2002)
Peripheral administration of novel anti-inflammatories can attenuate the effects of chronic inflammation within the CNS
Brain Res
Cytokine-induced sickness behaviour: mechanisms and implications
Trends Neurosci
Effects of lipopolysaccharide and glucocorticoids on expression of interleukin-1 beta converting enzyme in the pituitary and brain of mice
J Neuroimmunol
Impact of psychological and endocrine factors on cytokine production of healthy elderly people
Mech Ageing Dev
Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR
Neurosci Lett
Interleukin-1 beta, but not Interleukin-6, impairs spatial navigation learning
Brain Res
Selective effects of peripheral lipopolysaccharide administration on contextual and auditory-cue fear conditioning
Brain Behav Immun
Role of interleukin-1 beta in impairment of contextual fear conditioning caused by social isolation
Behav Brain Res
Effects of aging on mortality, hypothermia, and cytokine induction in mice with endotoxemia or sepsis
Mech Ageing Dev
Effect of age and cognitive status on basal level AP-1 activity in rat hippocampus
Neurobiol Aging
Immune response gene expression increases in the aging murine hippocampus
J Neuroimmunol
Pro-inflammatory and anti-inflammatory cytokine mRNA induction in the periphery and brain following intraperitoneal administration of bacterial lipopolysaccharide
Brain Res Bull
Lipopolysaccharide inhibits long-term potentiation in the rat dentate gyrus by activating caspase-1
J Biol Chem
Evidence that V+ fibronectin, GFAP and S100 beta mRNAs are increased in the hippocampus of aged rats
Exp Gerontol
Aging and glial responses to lipopolysaccharide in vitro: greater induction of IL-1 and IL-6, but smaller induction of neurotoxicity
Exp Neurol
Cited by (276)
Impact of high-fat diet on cognitive behavior and central and systemic inflammation with aging and sex differences in mice
2024, Brain, Behavior, and ImmunityPost-operative cognitive dysfunction is exacerbated by high-fat diet via TLR4 and prevented by dietary DHA supplementation
2024, Brain, Behavior, and ImmunityProtective effects of apigenin on the brain transcriptome with aging
2024, Mechanisms of Ageing and DevelopmentJ147 affects cognition and anxiety after surgery in Zucker rats
2024, Physiology and BehaviorSex differences in microglia function in aged rats underlie vulnerability to cognitive decline
2023, Brain, Behavior, and Immunity