Previous studies on the aetiology of attention-deficit/hyperactivity disorder (ADHD) emphasise high heritability and the influence of maternal smoking during pregnancy, highlighting the role of gene–environment interactions. Additionally, low-grade peripheral inflammation is frequently observed in individuals with ADHD. However, the underlying neurobiological mechanisms remain unclear. We aimed to investigate neuroinflammatory signalling contributing to ADHD and explore behavioural and molecular changes in a mouse model.

We examined neuroinflammatory signalling using a perinatal nicotine exposure (PNE) model 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 starting 2 weeks before mating until weaning to induce ADHD-like symptoms, as opposed to controls receiving drinking water containing 2% sucrose alone. Behavioural tests were conducted to assess ADHD-like behaviours 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 immunolabelling, and microglial morphology was analyzed.

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 behaviours compared to controls. PNE mice also morphologically exhibited microglia activation in all three subregions.

PNE contributes to ADHD development through neuroinflammatory signalling, a common end pathway.