PROJECT SUMMARY/ABSTRACT Neurofibromatosis type 1 (NF1) is a common inherited genetic disorder with a variety of symptoms, most commonly as neurocutaneous lesions and developmental disorders, and less commonly with tumors. Cognitive symptoms such as attentional deficits affect up to 80% of patients, with diagnosis of attention deficit hyperactivity disorder (ADHD) estimated at 50% in NF1 patients. Few studies have investigated the underlying mechanisms contributing to high incidence of ADHD diagnosis in NF1. Male mice haploinsufficient for the neurofibromin gene (Nf1+/-) recapitulate the cognitive deficits evident in patients. Our recent data suggest that male Nf1+/- mice exhibit hyperactivity in an open field, increased risky behavior in a cliff avoidance test, and increased impulsivity in a delay discounting task compared to wild-type (WT) males. These behavioral deficits were all attenuated with systemic treatment with a commonly prescribed, non-stimulant ADHD drug, guanfacine. Our data suggest that Nf1+/- mice exhibiting ADHD phenotypes rescued by pharmacotherapy used in NF1 patients not only provides an experimental system for translational research in NF1, but also yields a novel direction in the ADHD research field by addressing a monogenic cause of ADHD phenotypes. Dysfunction of the dopamine (DA) and/or norepinephrine neural systems is a commonly proposed mechanism that leads to ADHD. Dysfunction of these systems is evident in NF1 mouse models, but the mechanism by which dopamine plays a role in cognitive dysfunction in NF1 is still unclear. Our overall hypothesis is that abnormal regulation of DA homeostasis in cortical-striatal circuitry due to NF1 mutation contributes to deficits in behavioral inhibition in Nf1+/- mice. The first aim of the proposed study will elucidate the role of neurofibromin in cortical and striatal neural regions in behavioral inhibition. We hypothesize that selective deletion of neurofibromin in the prefrontal cortex (PFC) and/or nucleus accumbens (NAc) will result in behavioral inhibition deficits. In the second aim, we will determine whether Nf1+/- mice demonstrate alterations in dopamine (DA) homeostasis within cortical-striatal circuitry. We predict that Nf1+/- mice will display decreased DA as well as increased D1 receptor mRNA expression in the PFC. Furthermore, we anticipate that Nf1+/- mice will exhibit decreased D2 receptor levels in the NAc. Finally, we will explore the role of DA receptors in the cognitive deficits observed in Nf1+/- mice. We hypothesize that selective deletion of Nf1 within D1 receptor-expressing neurons in the PFC or D2-receptor-expressing neurons in the NAc will result in increased impulsivity similar to that observed in Nf1+/- mice. Overall, the studies proposed here will identify dysfunctional neuronal circuit(s) and signaling mechanisms associated with behavioral inhibition in NF1 using a translational experimental system.