Genetic background and sex moderate the effects of adolescent nicotine exposure on adult functional neural circuits and behavior

Adolescence is a critical neurodevelopmental stage marked by heightened plasticity and vulnerability to environmental influences such as nicotine. Nicotine disrupts neural function via nicotinic acetylcholine receptors, leading to long-term impairments in reward processing, cognition, and emotional regulation. While links between adolescent nicotine exposure and adult psychiatric or cognitive deficits are established, the influence of genetics and sex remains unclear. We examined the long-term effects of adolescent nicotine exposure on adult behavior and neural circuitry in male and female C57BL/6J and DBA/2J mice. Nicotine (24 mg/kg/day) or saline was administered via subcutaneous osmotic minipumps from postnatal day 37 for 12 days. Behavioral assessments 4 weeks later included the elevated plus maze for anxiety-related behavior and the open field test for locomotor activity after acute nicotine (0.81 mg/kg). Resting-state functional magnetic resonance imaging evaluated brain connectivity changes. Nicotine exposure altered both behavior and functional connectivity, depending on strain and sex. Adult female C57BL/6J mice exposed to nicotine during adolescence had lower anxiety-like behavior and higher locomotor activity, along with increased striatal-hippocampal connectivity, suggesting adaptations either directly related to nicotine exposure or compensatory adaptations. In contrast, adult female DBA/2J mice exposed to nicotine during adolescence showed widespread disruptions in cortico-striatal-thalamic, polymodal association, and hippocampal networks critical for cognitive and emotional regulation. Overall, greater effects were seen in female mice. Findings reveal that adolescent nicotine exposure drives enduring, strain- and sex-dependent changes in adult brain connectivity and behavior. Considering genetics and sex is essential for tailoring interventions for nicotine addiction and its neuropsychiatric consequences.