Attention-related impairment and contributing neuroinflammatory signaling in the prefrontal cortex of perinatal nicotine-exposed mice.

Abstract

Objective: Previous studies on the etiology of attention deficit/hyperactivity disorder (ADHD) highlight high heritability, structural/functional brain abnormalities, and dopamine/noradrenaline imbalances, emphasizing gene-environment interactions. While maternal smoking during pregnancy and low-grade peripheral inflammation have been implicated, its neurobiological basis remains incompletely understood. Our aim was to elucidate neuroinflammatory signaling contributing to ADHD and investigate behavioural and molecular changes in a mouse model.

Methods: We examined neuroinflammatory signaling using prenatal nicotine exposed (PNE) mice via immunohistochemistry combined with cortical thickness (CT) measurement in the subregions of the prefrontal cortex (PFC). Mice were exposed to nicotine via drinking water containing 300 μg/ml nicotine and 2% sucrose until weaning 2 weeks prior to mating to induce ADHD-like symptoms, as opposed to controls receiving drinking water containing 2% sucrose alone. Behavioral tests were conducted to assess ADHD-like behaviors and accompanying anxiety on postnatal week 5. Inflammatory pathways in the anterior cingulate cortex (ACC), prelimbic cortex (PL) and infralimbic cortex (IL) were examined using Iba-1 and NF-κB immunolabeling, and microglial morphology was analyzed.

Results: Findings showed increased CT, microglial cell number, activity, and NF-κB activation in the ACC, which correlated with attention-related impairment in PNE mice. Increased Iba-1 levels in the PL and IL, along with elevated NF-κB activation in the IL, were observed in PNE mice, which corresponded with a significant increase in anxiety-like behaviors compared to controls. PNE mice also morphologically exhibited microglia activation in all three subregions.

Conclusion: Perinatal nicotine exposure contributes to ADHD development through neuroinflammatory signaling, a common end pathway.