Cognitive and neuroinflammatory consequences of mild repeated stress are exacerbated in aged mice

https://doi.org/10.1016/j.psyneuen.2008.02.013Get rights and content

Summary

Peripheral immune stimulation as well as certain types of psychological stress increases brain levels of inflammatory cytokines such as interleukin-1β (IL-1β), IL-6 and tumor necrosis factor α (TNFα). We have demonstrated that aged mice show greater increases in central inflammatory cytokines, as well as greater cognitive deficits, compared to adults in response to peripheral lipopolysaccharide (LPS) administration. 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 the physiological and cognitive effects of mild stress than adult mice. Here, adult (3–5 months) and aged (22–23 months) male BALB/c mice were trained in the Morris water maze for 5 days. Mice were then exposed to a mild restraint stress of 30 min before being tested in a working memory version of the water maze over a 3-day period. On day 4 mice were stressed and then killed for collection of blood and brain. In a separate group of animals, mice were killed immediately after one, two or three 30 min restraint sessions and blood was collected for peripheral corticosterone and cytokine protein measurement, and brains were dissected for central cytokine mRNA measurement. Stress disrupted spatial working memory in both adult and aged mice but to a much greater extent in the aged mice. In addition, aged mice showed an increase in stress-induced expression of hippocampal IL-1β mRNA and MHC class II protein compared to non-stressed controls while expression in adult mice was unaffected by stress. These data show that aged mice are more sensitive to both the cognitive and inflammatory effects of mild stress than are adult mice and suggest a possible role for IL-1β.

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.

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