IL-1RA blocks E. coli-induced suppression of Arc and long-term memory in aged F344 × BN F1 rats
Introduction
In older animals, the CNS exhibits a sensitized neuroinflammatory response to peripheral as well as central administration of pro-inflammatory agents (Abraham et al., 2008, Barrientos et al., 2009, Barrientos et al., 2006, Chen et al., 2008, Godbout et al., 2005). Induction of neuroinflammatory processes or treatment with neuroinflammatory mediators/products has profound effects on learning and memory, in particular hippocampus-dependent memory processes (Barrientos et al., 2009, Barrientos et al., 2006, Barrientos et al., 2002, Barrientos et al., 2003, Barrientos et al., 2004, Gibertini et al., 1995, Hauss-Wegrzyniak et al., 1998, Hein et al., 2007, Oitzl et al., 1993, Pugh et al., 2000, Pugh et al., 1998, Shaw et al., 2001, Tanaka et al., 2006, Thomson and Sutherland, 2005). The time course of hippocampal-dependent memory deficits occurs in parallel with a protracted neuroinflammatory response to peripheral infection in aged animals (Barrientos et al., 2009, Barrientos et al., 2006). It is important to note that peripheral infection in young animals (3 months) does not induce a protracted neuroinflammatory response as well as a deficit in hippocampal-dependent memory (Barrientos et al., 2009). However, how the neuroinflammatory response to peripheral infection may compromise memory processes in older animals is unknown and is the focus of the present investigation.
Mediators of neuroinflammation, including pro-inflammatory cytokines (IL-1β, IL-6, TNFα, and IL-18), are known to modulate the putative neurobiological substrates (LTP) of memory formation (Cumiskey et al., 2007, Curran and O’Connor, 2003, Tancredi et al., 2000, Vereker et al., 2000). Aged animals show deficits in LTP, which are accompanied by increases in pro-inflammatory cytokines (Lynch, 1998). However, the molecular mechanism(s) mediating pro-inflammatory cytokine suppression of LTP has yet to be fully characterized.
Investigations into the molecular basis of LTP have yielded several genetic targets (Tzingounis and Nicoll, 2006). Of these targets, the effector immediate early gene (IEG) Arc (activity-dependent cytoskeletal-associated protein) exhibits several unique features, which underscore its importance in memory consolidation (Bramham et al., 2008). Arc mRNA is rapidly and specifically distributed throughout the dendritic arbor post-induction (Link et al., 1995, Lyford et al., 1995) and localized to regions receiving direct synaptic activation (Steward et al., 1998). Suppression of Arc impairs long-term memory (LTM) consolidation, whereas acquisition and short-term memory (STM) are unaffected (Guzowski et al., 2000). This is noted because we have previously found that a peripheral immune challenge in older animals impairs LTM, but not STM (Barrientos et al., 2006).
To understand how the neuroinflammatory sequelae of peripheral infection may impair LTM in older animals, we examined whether (1) a peripheral Escherichia coli infection suppresses hippocampal Arc expression, and (2) central pro-inflammatory cytokines (IL-1β and IL-6) mediate the effects of peripheral E. coli infection on Arc as well as LTM.
Section snippets
Subjects
As in our prior investigations (Barrientos et al., 2009, Barrientos et al., 2006, Frank et al., 2006), the present set of experiments compared 3 and 24 months old male F344 × BN F1 rats. Twenty-four months was selected as the older age because at this age animals do not show major age-related pathologies and in the absence of a peripheral immune challenge, STM and LTM processes do not differ between 24 and 3 months old animals in this hybrid strain. Therefore, differences in basal and contextual
Experiment 1: Peripheral E. coli reduced basal hippocampal Arc gene expression in 24 months animals (Fig. 1)
As an initial experiment to assess whether a peripheral immune challenge differentially alters Arc expression in 3 and 24 months animals, E. coli was administered to animals at a dose that induces increased hippocampal IL-1β along with memory impairments in older animals 4-day post-infection (Barrientos et al., 2006). Here, the effects of E. coli on Arc expression were measured 2, 4, 24, and 96 h post-infection. In the absence of E. coli, basal Arc expression was similar in 3 and 24 months animals
Discussion
Prior work has shown that aging renders hippocampal-based LTM formation vulnerable to disruption by peripheral immune challenge (Barrientos et al., 2009, Barrientos et al., 2006). At 24 months of age, male F344 × BN F1 rats show normal memory formation in both contextual fear conditioning and spatial water maze tasks. However, for a number of days after infection with E. coli these subjects are impaired in forming LTM for both contextual fear and spatial water maze escape (hippocampal). However,
Acknowledgments
The present work was supported by an NIH Grant (AG028271) to M.G.F., R.M.B, and S.F.M.
References (54)
- et al.
Aging sensitizes mice to behavioral deficits induced by central HIV-1 gp120
Neurobiol. Aging
(2008) - et al.
Basic local alignment search tool
J. Mol. Biol.
(1990) - et al.
Time course of hippocampal IL-1 beta and memory consolidation impairments in aging rats following peripheral infection
Brain Behav. Immun.
(2009) - et al.
Peripheral infection and aging interact to impair hippocampal memory consolidation
Neurobiol. Aging
(2006) - 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.
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-1beta administration
J. Neuroimmunol.
(2004) - et al.
Cognitive function after anaesthesia in the elderly
Best Pract. Res. Clin. Anaesthesiol.
(2003) - et al.
Effects of interleukin-1 receptor antagonist on the behavioral effects of lipopolysaccharide in rat
Brain Res.
(1992) - et al.
Neuroinflammation and disruption in working memory in aged mice after acute stimulation of the peripheral innate immune system
Brain Behav. Immun.
(2008)
Single-step method of RNA isolation by acid guanidinium thiocyanate–phenol–chloroform extraction
Anal. Biochem.
A role for inflammatory mediators in the IL-18 mediated attenuation of LTP in the rat dentate gyrus
Neuropharmacology
The inhibition of long-term potentiation in the rat dentate gyrus by pro-inflammatory cytokines is attenuated in the presence of nicotine
Neurosci. Lett.
How necessary is the activation of the immediate early gene zif268 in synaptic plasticity and learning?
Behav. Brain Res.
Interleukin-1
Cytokine Growth Factor Rev.
MRNA up-regulation of MHC II and pivotal pro-inflammatory genes in normal brain aging
Neurobiol. Aging
Spatial learning impairment in mice infected with Legionella pneumophila or administered exogenous interleukin-1-beta
Brain Behav. Immun.
Hematologic and immunomodulatory effects of an interleukin-1 receptor antagonist coinfusion during low-dose endotoxemia in healthy humans
Blood
Chronic neuroinflammation in rats reproduces components of the neurobiology of Alzheimer’s disease
Brain Res.
Prostaglandins are necessary and sufficient to induce contextual fear learning impairments after interleukin-1 beta injections into the dorsal hippocampus
Neuroscience
Exaggerated sickness behavior and brain proinflammatory cytokine expression in aged mice in response to intracerebroventricular lipopolysaccharide
Neurobiol. Aging
The role of IL-1beta in stress-induced sensitization of proinflammatory cytokine and corticosterone responses
Neuroscience
Analysis of relative gene expression data using real-time quantitative PCR and the method
Methods
Arc, a growth factor and activity-regulated gene, encodes a novel cytoskeleton-associated protein that is enriched in neuronal dendrites
Neuron
Age-related impairment in long-term potentiation in hippocampus: a role for the cytokine, interleukin-1 beta?
Prog. Neurobiol.
Interleukin-1 beta, but not interleukin-6, impairs spatial navigation learning
Brain Res.
Arc/Arg3.1 is essential for the consolidation of synaptic plasticity and memories
Neuron
Cited by (66)
Effects of sex and pro-inflammatory cytokines on context discrimination memory
2023, Behavioural Brain ResearchCD8<sup>+</sup> T cells contribute to diet-induced memory deficits in aged male rats
2023, Brain, Behavior, and ImmunityDietary DHA prevents cognitive impairment and inflammatory gene expression in aged male rats fed a diet enriched with refined carbohydrates
2021, Brain, Behavior, and ImmunityPostoperative cognitive dysfunction is made persistent with morphine treatment in aged rats
2021, Neurobiology of Aging