ADHD is a major societal problem with increasing incidence and a stagnant track record for treatment advances. A lack of appropriate animal models has partly contributed to the incremental advance of this field. Hence, our goal was to generate a novel mouse model that could be useful for ADHD medication development. We reasoned that hyperactivity is a core feature of ADHD that could easily be bred into a population, but to what extent other hallmark features of ADHD would appear as correlated responses was unknown. Hence, starting from a heterogeneous population, we applied within-family selection over 16 generations to produce a High-Active line, while simultaneously maintaining an unselected line to serve as the Control. We discovered that the High-Active line demonstrated motor impulsivity in two different versions of the Go/No-go test, which was ameliorated with a low dose of amphetamine, and further displayed hypoactivation of the prefrontal cortex and dysregulated cerebellar vermal activation as indexed by c-Fos immunohistochemical staining. We conclude that the High-Active line represents a valid model for the Hyperactive-Impulsive subtype of ADHD and therefore may be used in future studies to advance our understanding of the etiology of ADHD and screen novel compounds for its treatment.

Early environmental conditions are increasingly appreciated as critical in shaping behavior and cognition. Evidence suggests that stressful rearing environments can have an enduring impact on behaviors in adulthood, but few studies have explored the possibility that rearing environment could exacerbate genetic hyperactivity disorders. Uncovering a strong environmental influence on the transmission of hyperactivity could provide novel avenues for translational research. Recently we developed a selectively bred High-Active line of mice to model ADHD, providing a unique resource to address the question of environmental transmission. The High-Active line demonstrates transgenerational hyperactivity, but the influence of the postnatal environment (i.e. maternal care provided by dams) on hyperactivity had not been systemically quantified. This study employed a cross-fostering method to simultaneously address 1) whether High-Active and Control pups are provided with similar levels of care in the early environment, and 2) whether any differences in rearing environment influence hyperactive behavior. High-Active dams demonstrated impairment in all measures of maternal competence relative to Controls, which reduced survival rates and significantly reduced the body mass of offspring in early life and at weaning. While the deteriorated postnatal environment provided by High-Active dams was ultimately sufficient to depress Control activity, the hyperactivity of High-Active offspring remained unaffected by fostering condition. These data not only confirm the power of genetics to influence hyperactivity across generations, but also provide evidence that early rearing environments may not have a significant impact on the extreme end of hyperactive phenotypes.