Neonatal lipopolysaccharide treatment alters hippocampal neuroinflammation, microglia morphology and anxiety-like behavior in rats selectively bred for an infantile trait

- Neonatal immune challenge increases anxiety-like behavior in a low-anxiety rat line.
- Neonatal immune challenge reduces anxiety-like behavior in a high-anxiety rat line.
- Neonatal immune challenge alters peripheral inflammation in a phenotypic-dependent manner.
- Sex and phenotype interact after neonatal LPS to alter anxiety-like behavior.

Disruptions in homeostasis, such as the induction of inflammation, occurring during the neonatal period of development often produce changes in the brain, physiology, and behavior that persist through the life span. This study investigated the potential effects that an immune challenge delivered during neonatal development would have on anxiety behavior and stress reactivity later in life within a selectively-bred strain of rat. The rats have been bred for multiple generations to display either high or low anxiety-like phenotypic behavior. On postnatal day (P)3 and P5, male and female neonates were injected with saline or lipopolysaccharide (LPS). Brains were collected from a subset of neonates following injections. At P7, one male and one female per litter were tested for ultrasonic vocalizations (USVs). In adulthood, remaining litter mates were tested on the open field apparatus and the elevated zero maze (EZM) or on the EZM following 3 days of acute stress. Overall, we saw differences between the High and Low lines in neonatal anxiety-like behavior (USVs), neonatal peripheral immune response, adult anxiety-like behavior on the EZM, and adult anxiety-like behavior after stress induction, such that the High line rats display significantly more anxiety-like behavior than the Low line. Furthermore, we observed an effect of neonatal LPS during the neonatal peripheral immune response (e.g., increased inflammatory cytokine expression) and adult anxiety-like behavior on the EZM. We also observed an effect of sex within the anxiety-like behavior of LPS-treated adults exposed to stress paradigm. The combined results shed light on the relationships between neural development, early-life inflammation and anxiety throughout the lifespan.