Impaired attention in the TRB Transgenic Mouse

描述(由申请人提供)： 据估计，甲状腺疾病影响了1300万美国人。甲状腺激素三碘甲腺原氨酸(T3)和甲状腺激素(T4)对大脑的发育至关重要，而T3和T4状态的改变会导致各种神经心理症状，包括注意力受损。大多数罕见的遗传综合征甲状腺激素抵抗(RTH)患者符合注意力缺陷多动障碍的诊断标准。RTH是由甲状腺受体β(TRbeta)基因的显性负突变引起的，其特征是在促甲状腺激素浓度异常正常或升高的情况下，T3和T4浓度升高。TRbetaPV转基因小鼠的T3和T4浓度升高，TSH浓度不适当升高。此外，TRbetaPV基因敲入的小鼠活动过度，在持续注意力方面表现出缺陷，在同一测试中对哌醋甲酯(MPH)有矛盾的反应。注意力受损和对mph的异常反应表明儿茶酚胺能系统发生了变化。这项提议的目的是检验这样一个假设，即TRbetaPV基因敲除小鼠的儿茶酚胺能系统发生了变化。

DESCRIPTION (provided by applicant): Thyroid disease is estimated to affect 13 million Americans. The thyroid hormones, triiodothyronine (T3) and thyroxine (T4), are critical for the development of the brain, and altered T3 and T4 status can cause a variety of neuropsychological symptoms, including impaired attention. The majority of patients with the rare genetic syndrome Resistance to Thyroid Hormone (RTH) meet the diagnostic criteria for Attention Deficit-Hyperactivity Disorder. RTH is caused by a dominant negative mutation in the thyroid receptor beta (TRbeta) gene and is characterized by elevated concentrations of T3 and T4 in the presence of inappropriately normal or elevated concentrations of thyroid stimulating hormone. The TRbetaPV knock-in mice have elevated concentrations of T3 and T4 and inappropriately elevated concentrations of TSH. In addition, the TRbetaPV knock-in mice are hyperactive, show a deficit on a measure of sustained attention, and have a paradoxical response to methylphenidate (MPH) on the same test. The impaired attention and abnormal response to MPH suggest changes in the catecholaminergic systems. The goal of this proposal is to test the hypothesis that the TRbetaPV knock-in mice have alterations in the catecholaminergic systems.