Hippocampal neuroinflammation causes sex-specific disruptions in action selection, food approach memories, and neuronal excitation

Abstract

Hippocampal neuroinflammation is present in multiple diseases and disorders that impact motivated behaviour in a sex-specific manner, but whether neuroinflammation alone is sufficient to disrupt such behaviour is unknown. We investigated this question here using mice. First, application of the endotoxin and neuroinflammatory mimetic Lipopolysaccharide (LPS) to primary hippocampal neurons alone did not alter their activity but triggered neuronal excitation in mixed neuronal/glial co- or tri-cultures, providing initial indications of the potential mechanism causing neuroinflammation and the associated behavioural change. We next demonstrated this directly, because intra-hippocampal administration of LPS disrupted both instrumental responding and Pavlovian approach in a sex-specific manner, whereas it enhanced goal-directed action control and locomotor activity consistently across sexes. Finally, we showed that although LPS elicited a similar neuroinflammatory response in male and female mice, it increased neuronal activation in females and decreased it in males, providing evidence of a sexually dimorphic effect.