Background/Objectives: Environmental factors, including the differences in genotype-based housing (GbH), can act as confounding variables in studies using transgenic mouse models, potentially influencing experimental outcomes and limiting their reproducibility and translational value. Despite the widespread use of transgenic models in preclinical studies, the extent to which housing conditions can affect the behavioral and molecular parameters of interest remains poorly understood. This study aims to investigate how different GbH conditions influence visuo-spatial memory and gene expression in the A53T mouse model (JAX006823) of Parkinson’s disease (PD) during the pre-motor phase. Methods: A53T+ transgenic male mice and their non-transgenic littermates (A53T−) were housed in either mixed-genotype (MGH) or single-genotype (SGH) environments from postnatal day (PND) 30, with C57BL/6J mice serving as the controls. A behavioral assessment using the Novel Object Recognition and Object Location Tests was conducted at PND 180, followed by a qPCR analysis of Iba1, Gfapα, Bdnf, Tnfα, Il-1β, and Il-6 expression in the medial prefrontal cortex and the hippocampus. Results: The variations in GbH influenced behavior and mRNA expression differently in the A53T+ and A53T− animals. Specifically, the A53T− mice in SGH environments displayed behavioral and molecular profiles similar to the C57BL/6J controls, while the same was not evident in the MGH environments. In the A53T+ mice, the mRNA expression of Iba1, Gfapα, Bdnf, and Tnfα was sensitive to variations in GbH, while memory impairment was not. Conclusions: This study highlights the importance of considering environmental factors in studies using transgenic animal models. The obtained data suggests that GbH can influence the parameters of interest in preclinical research, implicating the need for the optimization of future study designs.

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Acquiring new experiences, especially in adolescence, shapes behavioral responses to life’s challenges. The absence of novelty-related experiences in laboratory rats raises concerns about their behavioral development and the reproducibility of research. This study examined changes in behavioral responses to novelty from early and late adolescence to adulthood, as well as the long-term effects of prior novelty exposure. To assess maturational differences, seven early adolescent, nine late adolescent, and seven adult male Wistar Han rats were tested once in a behavioral battery consisting of the novel arena, novel object exploration, light/dark box, and elevated plus maze. To evaluate the influence of prior experience, early and late adolescent groups were retested once more in adulthood. Late adolescents showed consistent patterns across spatial tasks, displaying increased anxiety-like behavior and reduced exploratory and risk-assessment activity. Early adolescents exhibited variable behaviors, resembling adult or late adolescent profiles depending on the task. Novelty exposure during adolescence produced subtle long-term effects, including reduced discomfort in mildly aversive environments, while late adolescent experience increased thigmotaxis in adulthood. Overall, adolescent responses to novelty were influenced more by spatial than nonspatial environmental features. These findings highlight stage-specific sensitivity to novelty, the influence of adolescent experience, and the potential reuse of experienced animals.