Behavioural and Molecular Outcomes of Early Life Immune Challenge in Mice

Abstract

<p> Although historically treated as separate systems, there is considerable interaction between the immune system and brain. It has become increasingly clear that immunebrain communication is important to both health and disease. An immunogenic challenge given during the first postnatal week in rodents impacts the developing central nervous system (CNS) leading to long-term behavioural and molecular alterations reflective of enhanced stress-reactivity. Anxiety and depression are stress-related pathologies with a proposed neurodevelopmental origin suggesting that perturbation to neonatal immunebrain signalling may contribute to psychopathology. The current body of work examined the long-term impact of an early immune challenge on behavioural and molecular phenotypes associated with anxiety and depression. Mice were administered lipopolysaccharide (LPS) on postnatal days three and five. The emergence of anxietyrelated behaviour was characterized along the developmental trajectory of LPS-mice concurrent with changes to serotonergic neurocircuitry. Adult depressive-related behaviour was assessed in the forced swim test (FST) along with hippocampal neurogenesis as revealed by immunoreactivity for bromodeoxyuridine (BrdU) and doublecortin (DCX). The results demonstrated a sex-specific alteration in both the temporal emergence and phenotypic variant of anxiety-related behaviours displayed by LPS-mice. This was accompanied by changes to CNS serotonergic-related gene expression that coincided with a critical developmental time window essential to the establishment of emotionality. Adult LPS-mice exhibited hyperactivity during the FST that was accompanied by increased doublecortin immunoreactivity in the dorsal and ventral hippocampus, reflecting enhanced immature neuronal differentiation. The current results demonstrate that an early immune challenge impacts the developing CNS leading to enhanced emotional-reactivity. Altered serotonergic neurocircuitry and adult hippocampal neurogenesis may underlie behavioural abnormalities. The current body of work demonstrates a preeminent role for early-life immune disturbance in psychopathology and advances understanding of how immune-brain signalling impacts the developing CNS and confers risk for later disease. </p>