Differential frontostriatal ΔFosB dynamics and behavioral flexibility in autism like- VPA-exposed mice

Autism spectrum disorder (ASD) involves social impairments, repetitive behaviors, and behavioral inflexibility, defined as an inability to adapt behavior to changing contingencies, and is linked to frontostriatal dysfunction. How behavioral training modulates these circuits is unclear, but ΔFosB, a marker of sustained neural activity, may be useful to establish their relationship. The aim was to evaluate frontostriatal ΔFosB expression following prenatal exposure to valproic acid (VPA) and to determine how experience in the midsession reversal (MSR) task modulates posterior ΔFosB expression. CD-1 mice were prenatally exposed to VPA (500mg/kg) or vehicle. Brains from postnatal day (PND) 30 mice were analyzed to quantify baseline ΔFosB+ cells in the medial prefrontal cortex (mPFC), orbitofrontal cortex (OFC), dorsal striatum (DS), and ventral striatum (VS). In the second experiment, mice performed the MSR task for 13 days. Then, ΔFosB was re-evaluated at PND43 to assess experience-dependent changes. At PND30, VPA-exposed mice showed a significant increase in ΔFosB+ cells in mPFC, OFC, DS, and VS, suggesting sustained activity-dependent engagement of the frontostriatal circuit. In the MSR task, mice adapted to contingency shifts using mixed strategies, including win-stay/lose-shift behavior and temporal estimation, whereas VPA mice showed less consistent strategy selection after reversal. After MSR, ΔFosB expression in the OFC and striatum of VPA mice normalized to control levels and remained persistently elevated in the mPFC at PND43. Thus, prenatal VPA induces long-term increases in neuronal transcriptional changes, suggesting activity-dependent plasticity in the frontostriatal circuit. Despite these neural alterations, behavioral flexibility was preserved, suggesting circuit-level adaptations underlying ASD-related strategies. Future studies could broaden these results by examining sex differences and characterizing the cellular and molecular changes dependent on frontostriatal ΔFosB dynamics.