BACKGROUND Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with a mutation in one copy of the neurofibromin gene (NF1+/-). Even though approximately 40-60% of children with NF1 meet the criteria for attention deficit hyperactivity disorder (ADHD), very few preclinical studies, if any, have investigated alterations in impulsivity and risk-taking behavior. Mice with deletion of a single NF1 gene (Nf1+/-) recapitulate many of the phenotypes of NF1 patients. METHODS We compared wild-type (WT) and Nf1+/- mouse strains to investigate differences in impulsivity and hyperactivity using the delay discounting task (DDT), cliff avoidance reaction (CAR) test, and open field. We also investigated whether treatment with the clinically effective alpha-2A adrenergic receptor agonist, guanfacine (0.3 mg/kg, i.p.), would reverse deficits observed in behavioral inhibition. RESULTS Nf1+/- mice chose a higher percentage of smaller rewards when both 10- and 20-s delays were administered compared to WT mice, suggesting Nf1+/- mice are more impulsive. When treated with guanfacine (0.3 mg/kg, i.p.), Nf1+/- mice exhibited decreased impulsive choice by waiting for the larger, delayed reward. Nf1+/- mice also exhibited deficits in behavioral inhibition compared to WT mice in the CAR test by repetitively entering the outer edge of the platform where they risk falling. Treatment with guanfacine ameliorated these deficits. In addition, Nf1+/- mice exhibited hyperactivity as increased distance was traveled compared to WT controls in the open field. This hyperactivity in Nf1+/- mice was reduced with guanfacine pre-treatment. CONCLUSIONS Overall, our study confirms that Nf1+/- mice exhibit deficits in behavioral inhibition in multiple contexts, a key feature of ADHD, and can be used as a model system to identify alterations in neural circuitry associated with symptoms of ADHD in children with NF1.

中文翻译：

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胍法辛治疗可改善1型神经纤维瘤病小鼠模型中冲动和活动亢进的ADHD表型。

背景技术1型神经纤维瘤病（NF1）是一种常染色体显性遗传疾病，在一个神经纤维蛋白基因（NF1 +/-）拷贝中有突变。即使大约40-60％的NF1儿童符合注意缺陷多动障碍（ADHD）的标准，但极少的临床前研究（如果有的话）研究冲动和冒险行为的改变。缺失单个NF1基因（Nf1 +/-）的小鼠概括了NF1患者的许多表型。方法我们比较了野生型（WT）和Nf1 +/-小鼠品系，使用延迟贴现任务（DDT），避壁反应（CAR）测试和开阔地带，研究了冲动性和多动性的差异。我们还调查了是否使用临床上有效的α-2A肾上腺素能受体激动剂胍法辛（0.3 mg / kg，ip）治疗，会逆转行为抑制中观察到的缺陷。结果与WT小鼠相比，当延迟10和20 s时，Nf1 +/-小鼠选择了更高百分比的较小奖励，这表明Nf1 +/-小鼠更具冲动性。当用胍法辛（0.3 mg / kg，腹膜内）治疗时，Nf1 +/-小鼠通过等待更大，延迟的奖励而表现出冲动选择减少。与WT小鼠相比，Nf1 +/-小鼠在CAR测试中还表现出行为抑制缺陷，因为它们反复进入平台的外部边缘而有跌倒的危险。胍法辛治疗改善了这些缺陷。此外，与野生动物中的WT对照相比，随着距离的增加，Nf1 +/-小鼠表现出活动过度。Nf1 +/-小鼠的这种多动症通过胍法辛预处理得以降低。结论总体而言，