Sex-specific long-term effects of neonatal LPS exposure in rats: relevance for immune-mediated neurodevelopmental disorders

Early-life immune activation is increasingly recognized as a critical risk factor for the development of neurodevelopmental and neuropsychiatric disorders. Neonatal infections and associated inflammatory responses may impair brain development and contribute to long-term behavioral alterations in a sex-dependent manner. This study aims to investigate the effects of lipopolysaccharide (LPS) injection (1 mg/kg, i.p) on post-natal day (PND) 3 in both male and female young adult Wistar rats (PND 45). LPS challenge induced hyperactivity and anxiety-like behavior, with females displaying pronounced stereotyped movements, such as self-grooming and marble burying. Behavioral abnormalities were accompanied by region-specific alterations in GABAergic, dopaminergic, and serotonergic signaling within the cortico-striatal-thalamic circuit. LPS-induced immune activation triggered a long-lasting systemic inflammatory response and increased the expression of selected innate immune markers in the CNS. Additionally, oxidative stress was evidenced by increased striatal reactive oxygen species (ROS) production in females and enhanced lipid peroxidation characterized by overall higher 4-HNE levels observed in the striatum and thalamus of male rats. Our results suggest that early-life LPS exposure produces long-lasting behavioral and neurobiological alterations, with females showing greater susceptibility to selected behavioral and neurochemical outcomes. These findings support the utility of LPS-based models to explore how neonatal immune activation may predispose to neurodevelopmental vulnerability, offering translational insights into how early-life innate immune activation may contribute to neurodevelopmental vulnerability and psychiatric risk.