Cognitive and neuroinflammatory consequences of mild repeated stress are exacerbated in aged mice
Introduction
Activation of the peripheral innate immune system or exposure to stress can induce peripheral and central inflammatory cytokines such as interleukin-1β (IL-1β), IL-6 and tumor necrosis factor α (TNFα) in both adult and aged animals (Chen et al., 2008; Godbout et al., 2005; Johnson et al., 2002a). During infection, central inflammatory cytokines induce sickness behaviors (e.g. fever, anorexia, decreased social behavior, sleep) and activate the hypothalamic–pituitary–adrenal (HPA) axis (Dantzer and Kelley, 2007). In addition to mediating sickness behaviors associated with infection, inflammatory cytokines also play a role in learning and memory (Gibertini et al., 1995; Pugh et al., 2001). Importantly, exposure to stressful stimuli can induce responses similar to those observed after an inflammatory insult (Deak et al., 2005; Galea et al., 1997; Johnson et al., 2002a, Johnson et al., 2003; O’Connor et al., 2003).
In addition to inducing inflammatory cytokines, stress can disrupt learning and memory (Holscher, 1999; Wright et al., 2006). Acute stress can also cause activation of resident microglia (Sugama et al., 2007) and upregulate MHC class II (de Pablos et al., 2006; Frank et al., 2007), and chronic stress can activate microglia and induce microglial proliferation (Nair and Bonneau, 2006). Frank et al. (2007) hypothesized that it is this change in microglia during stress that can “prime” or sensitize the CNS to respond in a heightened fashion when presented with a subsequent peripheral immune stimulus such as lipopolysaccharide (LPS) (de Pablos et al., 2006; Johnson et al., 2002b, Johnson et al., 2003).
A similar circumstance may be occurring with age. Age is often associated with microglia changes indicative of activation (Frank et al., 2006; McGeer et al., 1987; Perry et al., 1993), and brain inflammation (Kirkwood et al., 2005; Richwine et al., 2005; Ye and Johnson, 1999), and aged mice show greater increases in central inflammatory cytokines compared to adults following both peripheral and central LPS administration (Chen et al., 2008; Godbout et al., 2005; Huang et al., 2007). This exaggerated inflammatory response is accompanied by prolonged sickness behavior and greater deficits in spatial working memory than is seen in adult mice (Chen et al., 2008; Godbout et al., 2005). Thus, just as stress appears to sensitize the immune system to subsequent inflammatory insults, so may aging sensitize the immune system to stress.
Stress-induced neuroinflammation appears to greatly depend upon the stressor. For instance, stressors such as forced swim (Deak et al., 2003), predator odor (Plata-Salaman et al., 2000), and restraint stress (Deak et al., 2003, Deak et al., 2005; Maier et al., 1999; Sugama et al., 2007) fail to induce inflammatory cytokines in the periphery or brain. However, if restraint is accompanied by another stressor such as a shock (Johnson et al., 2002a, Johnson et al., 2003; O’Connor et al., 2003) or orbital shaking (Deak et al., 2005), there is a significant increase in peripheral and central inflammatory cytokines, specifically IL-1β. All these studies were performed on adult rodents and although there is evidence that stress can influence susceptibility and immune response to infection in older adults (Kiecolt-Glaser et al., 1996) and elderly humans are more likely to report memory failures on days when they experienced stress (Neupert et al., 2006), the direct effects of a mild stressor on cognitive and neuroinflammatory parameters in the aged are largely unknown. Given that older adults are at greater risk of health complications and mortality stemming from immune dysfunction (Castle, 2000; Graham et al., 2006), and age can be a significant factor for risk of infection after trauma (Saito et al., 2003; Thomas and Hall, 2004), the effects of stress on the immune system in the elderly are of particular importance.
Because aged mice are typically more sensitive to systemic stressors such as LPS, and certain psychological stressors induce physiological responses similar to those that follow LPS, we hypothesized that aged mice would be more sensitive to a mild stress than adult mice. More specifically, a stressor that has little or no effect on inflammation in adult mice (such as short-term restraint stress) would disrupt spatial working memory and elicit neuroinflammation in aged mice. Here we report that a 30 min restraint stress disrupted spatial working memory more severely in aged mice than it did in adult mice and this disruption was correlated with increased levels of IL-1β expression in the hippocampus of aged mice. These results show that aged mice are more sensitive to both the cognitive and neuroinflammatory effects of a mild stress and suggest a possible role for IL-1β in stress-induced disruption of spatial working memory in aged mice.
Section snippets
Animals
Adult (3–5 months) and aged (22–24 months) male BALB/c mice from our in-house specific-pathogen-free colony were used. Mice were housed in polypropylene cages and maintained at 23 °C under a reverse phase 12 h light–dark cycle with ad libitum access to water and rodent chow. At the end of the study, mice were examined postmortem for gross signs of disease (e.g. splenomeglia and tumors). Data from mice determined to be unhealthy were excluded from analysis. All procedures were in accordance with
Stress-induced weight loss is exacerbated in aged mice
Throughout the study, mice were weighed daily to observe the effects of repeated stress on body weight in adult and aged mice. Figure 1 shows the change in body weight over the course of 4 days of stress. Both adult and aged mice in the stressed group lost weight compared to non-stressed controls (main effect of condition, p<0.0001). In addition, there was a main effect of age (p<0.01) and an age×condition interaction (p<0.02) in which aged mice that were stressed lost significantly more weight
Discussion
Here we show that aged mice are not only more sensitive to the effects of mild stress on spatial working memory, but also more sensitive to the neuroinflammatory consequences of stress. Both adult and aged mice displayed impaired spatial working memory in response to a 30 min restraint stress however, adult mice performed as well as non-stressed controls by day 2 of testing while aged mice continued to perform poorly after successive days of stress. The behavioral results are consistent with
Role of funding sources
Funding for this study was provided by NIH Grants AG16710 and MH069148 to R.W.J. and by a Ruth L. Kirchstein NRSA Postdoctoral Fellowship to J.B. These funding sources had no further role in study design; collection, analysis and interpretation of data; in the writing of the manuscript or the decision to submit the paper for publication.
Conflict of interest
All authors declare that they have no conflicts of interest.
Acknowledgments
This work was supported by NIH Grants AG16710 and MH069148 to R.W.J. and by a Ruth L. Kirchstein NRSA Postdoctoral Fellowship to J.B.
References (48)
- et al.
Age-related deficits as working memory load increases: relationships with growth factors
Neurobiol. Aging
(2003) - et al.
Neuroinflammation and disruption in working memory in aged mice after acute stimulation of the peripheral innate immune system
Brain Behav. Immun.
(2008) - et al.
Twenty years of research on cytokine-induced sickness behavior
Brain Behav. Immun.
(2007) - et al.
Exposure to forced swim stress does not alter central production of IL-1
Brain Res.
(2003) - et al.
Stress-induced increases in hypothalamic IL-1: a systematic analysis of multiple stressor paradigms
Brain Res. Bull.
(2005) - et al.
mRNA up-regulation of MHC II and pivotal pro-inflammatory genes in normal brain aging
Neurobiol. Aging
(2006) - et al.
Microglia serve as a neuroimmune substrate for stress-induced potentiation of CNS pro-inflammatory cytokine responses
Brain Behav. Immun.
(2007) - et al.
Sex differences in dendritic atrophy of CA3 pyramidal neurons in response to chronic restraint stress
Neuroscience
(1997) - et al.
Spatial learning impairment in mice infected with Legionella pneumophila or administered exogenous interleukin-1-beta
Brain Behav. Immun.
(1995) - et al.
Stress, age, and immune function: toward a lifespan approach
J. Behav. Med.
(2006)
Stress impairs performance in spatial water maze learning tasks
Behav. Brain Res.
Prior stressor exposure primes the HPA axis
Psychoneuroendocrinology
Prior stressor exposure sensitizes LPS-induced cytokine production
Brain Behav. Immun.
What accounts for the wide variation in life span of genetically identical organisms reared in a constant environment?
Mech. Ageing Dev.
Salivary cortisol and memory function in human aging
Neurobiol. Aging
Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: comparison of stressors
Neuroscience
Reactive microglia in patients with senile dementia of the Alzheimer type are positive for the histocompatibility glycoprotein HLA-DR
Neurosci. Lett.
Lifelong corticosterone level determines age-related decline in neurogenesis and memory
Neurobiol. Aging
Investigation of age-related cognitive decline using mice as a model system: behavioral correlates
Am. J. Geriatr. Psychiatry
Stress-induced elevation of glucocorticoids increases microglia proliferation through NMDA receptor activation
J. Neuroimmunol.
Peripheral and central proinflammatory cytokine response to a severe acute stressor
Brain Res.
Neither acute nor chronic exposure to a naturalistic (predator) stressor influences the interleukin-1 beta system, tumor necrosis factor-alpha, transforming growth factor-beta 1, and neuropeptide mRNAs in specific brain regions
Brain Res. Bull.
Role of interleukin-1 beta in impairment of contextual fear conditioning caused by social isolation
Behav. Brain Res.
Improved psychomotor performance in aged mice fed diet high in antioxidants is associated with reduced ex vivo brain interleukin-6 production
Brain Behav. Immun.
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