Central inhibition of interleukin-1beta ameliorates sickness behavior in aged mice

Abstract

In elderly individuals high levels of interleukin-1beta (IL-1beta) in the brain have been implicated in infection-related behavioral pathologies but this has not been directly tested. Therefore, the current study investigated if sickness behavior in aged animals elicited by peripheral injection of lipopolysaccharide (LPS) is mediated through central IL-1beta. Adult and aged mice were injected intracerebroventricularly with either saline or IL-1ra (4mug) immediately prior to intraperitoneal administration of saline or LPS (10mug) and locomotor and social behaviors were assessed. As anticipated, LPS depressed locomotor activity and social behavior in both adult and aged mice but the behavioral deficits were markedly greater in the aged at 24h. Pretreatment with IL-1ra did not affect LPS-induced sickness behavior in adults; however, in aged mice IL-1ra attenuated LPS-induced sickness behavior, restoring it to the level exhibited by young adults. Twenty-four hours post-injection hippocampal and hypothalamic tissues were collected to determine IL-1beta mRNA expression. Neither LPS nor IL-1ra affected IL-1beta mRNA levels in adults, presumably because any effect of LPS had dissipated by 24h. In contrast, IL-1beta mRNA was markedly higher in aged mice 24h after LPS, and prior treatment with IL-1ra either blocked or attenuated this effect in the hippocampus and hypothalamus, respectively. Taken together these data provide the first direct evidence that central IL-1beta is responsible for the severe sickness behavior observed in aged animals after LPS treatment. Thus, inhibiting the central actions of IL-1beta may be useful for minimizing behavioral complications in older individuals with an infection.

Figure 1. IL-1ra protected aged mice but not adult mice from LPS-induced deficits in locomotor behavior

Adult and aged mice were injected ICV with saline or IL-1ra and then injected i.p. with saline or LPS. Locomotor activity in adult mice (A) and locomotor activity in aged mice (B) were measured before injections and 2, 4, 8 and 24 h after injections. Data points represent the mean ± S.E.M. (n=10–11). Means with * are significantly different (p<0.05) from age-matched controls and means with ‡ are significantly different from mice given IL-1ra and LPS. Locomotor behavior for both adult and aged mice at 24 h is also shown (C). Bars represent the mean ± S.E.M. (n=10–11). Means with different letters (a, b or c) are significantly different (p<0.05) from each other.

Figure 2. IL-1ra protected aged mice but not adult mice from LPS-induced deficits in social behavior

Adult and aged mice were injected ICV with saline or IL-1ra and and then injected i.p. with saline or LPS. Social behavior in adult mice (A) and social behavior in aged mice (B) were measured before injections and 2, 4, 8 and 24 h after injections. Data points represent the mean ± S.E.M. (n=10–11). Means with * are significantly different (p<0.05) from baseline controls and means with ‡ are significantly different from mice given IL-1ra and saline. Social behavior for both adult and aged mice at 24 h is also shown (C). Bars represent the mean ± S.E.M. (n=10–11). Means with different letters (a, b or c) are significantly different (p<0.05) from each other.

Figure 3. Pretreatment with IL-1ra inhibited the LPS-induced increase in IL-1β mRNA in aged mice

Adult and aged mice were injected ICV with saline or IL-1ra and then injected i.p. with saline or LPS. After the final behavioral test (24 h after injection) hippocampal tissue (A) and hypothalamic tissue (B) were collected and IL-1β mRNA was measured by quantitative real-time PCR. Bars represent means ± SEM (n=10–11). Means with different letters (a, b or c) are significantly different (p<0.05) from each other.