EARLY-LIFE IMMUNE ACTIVATION IN RATS INDUCES SEX-SPECIFIC ALTERATIONS IN SENSORIMOTOR GATING, BRAIN METABOLIC CONNECTIVITY AND GUT MICROBIOTA COMPOSITION

Early immune activation during critical neurodevelopmental periods represents a risk factor for persistent alterations in brain circuits involved in mental disorders. Neonatal administration of Escherichia coli lipopolysaccharide (LPS) induces inflammation that may interfere with central nervous system maturation and sensorimotor gating mechanisms. The long-term effects of early-life LPS challenge were assessed on prepulse inhibition (PPI) of auditory startle response, brain functional activity, and gut microbiota composition, considering sex differences.
Male and female Wistar rats received intraperitoneal LPS (0.5 mg/kg, E. coli, serotype O55: B5) or saline (controls) on postnatal day 14. Acoustic startle response was assessed during juvenile period (60 days). Brain metabolic activity was quantified by cytochrome c oxidase (CCO) histochemistry in cortico-striatal regions, with correlations of interregional functional connectivity of CCO activity. Gut microbiota was characterized through 16S rRNA sequencing of cecal content.
LPS induced sex-dependent alterations in PPI, affecting females more severely. LPS females showed decreased CCO activity in dorsal and ventral striatum. LPS males exhibited CCO hypofunction mainly in the cingulate cortex. Connectivity analyses revealed functional disconnection between cingulate cortex and striatal regions after LPS exposure, with significant neurobehavioral correlations only in females. LPS induced intestinal dysbiosis with taxon- and sex-dependent associations with PPI, supporting the involvement of a microbiota–brain–behavior axis.
These findings indicate that early immune activation disrupts sex-dependent maturation of key cortico-striatal circuits underlying sensorimotor gating. Research supported by grant PID2022-140980NB-I00 (AEI, MICNN, Spain) and PID2024-161852OB-I00 (MICIU, Spain)