Impact of Early Immune Challenge by LPS on Nitric Oxide Release Dynamics in the Neonatal Rat Brain: Triggering Long-lasting Sex- and Age-Related Affective Behavioral Alterations in Adolescence
Impact of Early Immune Challenge by LPS on Nitric Oxide Release Dynamics in the Neonatal Rat Brain: Triggering Long-lasting Sex- and Age-Related Affective Behavioral Alterations in Adolescence
Laila Ibouzine-Dine1*, Inssaf Berkiks1,2, Hasnaa Mallouk1, Mouloud Lamtai1, Zineb El Marzouki1, Amal Dimaoui1, Abdelhalem Mesfioui1, Aboubaker El Hessni1
ABSTRACT
Early-life immune challenges, like lipopolysaccharide (LPS) exposure, can induce lasting changes in brain structure, neurochemistry, and function, a process known as “early-life programming.” These changes are associated with neuropsychiatric disorders, including depression. While the nitric oxide (NO) pathway is implicated in depression, how changes in NO kinetics impact sex-dependent affective behaviors has not been thoroughly investigated. This study focuses on the effects of LPS-induced early immune challenge on NO release kinetics in the neonatal rat brain, as well as the link between these effects and long-term sex- and age-related behavioral changes in adolescence. Two cohorts of neonatal rats were used in the study. The first cohort included 80 male and female rats, which were sacrificed at various times after LPS (250 µg/kg) or phosphate buffer saline (PBS) injection on postnatal day 2 (PND2). Brain regions were collected for biochemical analysis. The second cohort consisted of 20 rats, with equal gender distribution, divided into PBS- and LPS-injected groups. At PND60, these rats underwent behavioral tests (Open Field, Elevated Plus Maze, and Forced Swim), followed by biochemical analysis of brain structures. The findings showed a prolonged elevation of NO following the early immune challenge with LPS in males. Furthermore, behavioral assessments conducted during adolescence demonstrated that male rats consistently showed more pronounced anxiety-like and depressive-like behaviors with higher biomarker levels than females. Understanding these sex-specific NO release patterns and how they affect adolescents could be crucial to understanding the neurochemical processes that underlie the development of depression and other mental health disorders.
Keywords | Neonatal, Early-life programming, Sex differences, Wistar rat, Nitric oxide, Central nervous system, Bacterial endotoxin
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