Systemic inflammatory event induces persistent dysregulation of memory and gene expression

Abstract

A systemic inflammatory event occurring during illness or surgery may result in memory deficits that last for years after recovery. To understand how transient inflammatory signaling induces persistent alterations in memory, we used subchronic systemic immune challenge and examined long-lasting changes in memory, gene expression, and epigenetic modifications. Since males and females differ in immune responses and susceptibility to persistent memory deficits, we compared both sexes. Our paradigm used intermittent systemic injections of either lipopolysaccharide (LPS: 250 μg/kg) or polyI:C (6 mg/kg). Persistent changes in hippocampal-dependent memory were assessed eight weeks after the last injection using contextual fear conditioning and novel-object recognition. We observed sex-specific dysregulation of hippocampal-dependent memory that depended on type of immune challenge. Males showed impairments in contextual fear conditioning after polyI:C treatment and impairments in object recognition after both types of immune challenges while females showed increased fear-associated memory but impairments in object recognition after LPS treatment. Sex-specific, enduring changes in gene expression in the hippocampus were detected using RNA-sequencing, with differential expression of growth factor signaling, activity-dependent transcription factors, and immune related pathways in males and monoaminergic-associated signaling in females. Histone acetylation marks associated with changes in gene expression were of particular interest. Collectively, these data demonstrate that a systemic immune challenge induces sustained dysregulation of hippocampal-dependent memory and enduring differences in gene expression that may underlie the changes in memory.