We investigated the potentially positive neurodevelopmental and enduring effects of neonatal handling (NH) on specific behavioral processes and gene expression in the prefrontal cortex of RHA versus RLA rats. Additionally, we explored associations between gene expression and behavioral responses. Male rats from both the RLA and RHA strains received NH or were left untreated (controls). Two different age groups were considered: adolescent and adults. The assessment encompassed exploratory behavior, social behavior, sensorimotor gating (PPI), and the analysis of gene expression associated with synaptic processes, cortical maturation, and neuroplasticity. In adolescent rats, NH increased novelty exploration and activity, and reduced anxiety-related self-grooming in RLAs, whereas it improved PPI in RHAs. In adult rats, NH increased novelty-induced activity in both strains, reduced self-grooming in RLA rats, and enhanced social interaction and PPI in RHAs. NH produced significant effects on gene expression in adolescent RHA rats. These effects were observed at the presynaptic level by a reduction of Snap25 and increases of Cables1 and Cdk5, and at the postsynaptic level by increases of Grin2b, Homer1 and Nrg1, as well as by a NH-induced enhancement of Bdnf. NH also increased Nrg1 and Bdnf expression in adult RLA rats.These findings show for the first time that NH treatment is able to modulate several genetically-linked behavioral and synaptic/neuroplasticity alterations in RHA/RLA rats, in line with the wide evidence on the positive long-lasting effects of NH on many emotional responses, social behavior, attention-related processes and cognition. Acknowledgements.- Supported by grant PID2020-114697GB-I00 (ref. AEI/10.13039/501100011033).