Sex-Dependent Effects of Neonatal Inflammation on Adult Inflammatory Markers and Behavior

Abstract

Inflammatory molecules, such as cyclooxygenase (COX), a prostaglandin synthetic enzyme, have been identified as a marker of depressive symptomology. Previously, we have observed elevated basal COX-2 expression in the hypothalamus of adult male rats treated neonatally with lipopolysaccharide (LPS), which might suggest a phenotype for disrupted hedonic behavior, a symptom of depression. However, COX-2 and its contribution to the expression of anhedonic behavior has not been investigated in these males or in female rats across the estrous cycle, which is the purpose of the current work. Here, we examine the effects of a neonatal LPS challenge or saline on the sucrose preference test as a measure of anhedonia, and hypothalamic COX-2 expression, in adult male and freely cycling female rats. Our data indicate a sex difference in that neonatal LPS at postnatal d 14 causes elevated basal expression of hypothalamic COX-2 in male, but not in female, rats. Additionally, baseline sucrose preference in male and female rats was unaltered as a function of neonatal LPS treatment or estrous cycle stage. In both male and female animals, 50 microg/kg LPS in adulthood caused elevated plasma IL-6 and hypothalamic COX-2 expression in neonatally saline-treated rats but significantly less so in neonatally LPS-treated rats of both sexes; this neonatal programming was not evident for sucrose preference or for total fluid intake (even after much higher doses of LPS). Our data are suggestive of a dissociation between inflammation and anhedonic behavior and a differential effect of neonatal inflammation in males and females.

Sex effects on neurodevelopmental outcomes of innate immune activation during prenatal and neonatal life

“…The mechanism underlying the amplified CORT response appears to be associated with higher levels of TLR4 and COX-2 in the liver that provide an early bolus of circulating prostaglandin E1 (PGE1) to activate the HPA axis (Mouihate et al, 2010). An equally dramatic reduction in febrile responses was also seen in adult nLPS treated female rats (Spencer et al, 2006) as well as similar reductions in plasma IL-6 and in brain COX-2 following adult LPS challenge (Kentner et al, 2010). In the latter study, females were assessed at all stages of the estrous cycle.…”

Neonatal programming of innate immune function

“…These findings therefore describe a long-lasting altered innate immune response following a single low-dose immune challenge that is encountered, in the rat, at a developmental period after P7 and before P28. These alterations in innate immune function with neonatal LPS also appear to be independent of any changes in both the anorectic and anhedonic responses to LPS (47,79).…”

“…Thus, circulating concentrations of the proinflammatory cytokines IL-1␤, IL-6, and TNF␣ are significantly attenuated after an adult LPS challenge in neonatally LPS-treated rats compared with saline-treated controls (25,47). This reduction in circulating proinflammatory cytokine production is associated with reduced IB phosphorylation in the liver and spleen (25), which would lead to attenuated NF-B release, reduced translocation, and less initiation of cytokine transcription.…”

“…Neonatal LPS does affect circulating proinflammatory cytokine responses to a further LPS challenge, and it is this difference that is likely responsible for the attenuated fever, at least in males (47). Thus, circulating concentrations of the proinflammatory cytokines IL-1␤, IL-6, and TNF␣ are significantly attenuated after an adult LPS challenge in neonatally LPS-treated rats compared with saline-treated controls (25,47).…”

“…This reduction in circulating proinflammatory cytokine production is associated with reduced IB phosphorylation in the liver and spleen (25), which would lead to attenuated NF-B release, reduced translocation, and less initiation of cytokine transcription. The resultant dampening of circulating cytokine production also results in reduced activation of PGE 2 -catalyzing COX-2 in the brain (11,47). It is noteworthy that cytokine levels in adult Fischer 344 rats are not attenuated if the first exposure to LPS occurs earlier in life, i.e., at P3 and P5 (86), indicating that age-, dose-, or strain-specific mechanisms may be involved.…”