Inhibitory Deficits in Mania and Hyperdopaminiergic Mice

描述（由申请人提供）：抑制性缺陷是双相情感障碍（BD）躁狂的特征，为转化研究提供了一个行为目标。这个转化项目的主要重点是评估躁狂双相障碍患者的三个抑制领域的缺陷，以及基于药理学挑战和基因工程技术的平行动物模型。大量的动物数据以及最近的发现将双相障碍与多巴胺转运蛋白（DAT）基因附近基因序列的改变联系起来，支持了躁狂状态涉及多巴胺能系统失调的基本假设。该项目使用并进一步发展反映多巴胺能系统异常的跨物种测量方法，以提高我们对双相障碍及其治疗的理解。该设计涉及在躁狂双相障碍患者和小鼠中进行平行研究，其中DAT已被药理学（安非他明）或遗传学（DAT敲除和敲除小鼠）操纵。具体来说，将评估三个领域的抑制缺陷：1。惊吓前脉冲抑制对感觉运动抑制的影响2. 使用适合物种的动态监测设备的新环境中的运动亢进；, 3。坚持使用创新的非线性分析的空间和时间模式的运动反应。躁狂双相障碍住院患者将在入院时进行研究，当有高度症状时，并在抗躁狂和/或非典型抗精神病药物治疗期间进行纵向研究。正常对照受试者也将进行纵向研究，但不进行治疗。该应用的一个重要创新方面是开发了一种明确的人类模拟开放场，这是用于评估多巴胺能精神兴奋剂作用的经典啮齿动物行为范式。小鼠实验将验证缺乏正常DAT补体的突变小鼠可能作为BD抑制缺陷模型的假设，并且DAT缺陷小鼠可能为抗躁狂药物的鉴定提供具有预测有效性的动物模型。跨物种双相障碍核心特征的平行表征将实现躁狂的客观测量，可用于监测双相障碍患者的治疗效果，并促进对啮齿动物双相障碍的同源预测模型的验证。这种临床前模型，以及对其验证至关重要的人体测量，对未来发现这种疾病的新治疗方法至关重要。

DESCRIPTION (provided by applicant): Inhibitory deficits are characteristic of the mania of Bipolar Disorder (BD) and provide a behavioral target for translational research. The primary focus of this translational project is to assess deficits in three domains of inhibition in manic BD patients and in parallel animal models based on pharmacological challenges and gene engineering technology. Extensive animal data as well as recent findings linking BD to alterations in the genetic sequence in the vicinity of the dopamine transporter (DAT) gene support the basic hypothesis that the manic state involves a dysregulation of dopaminergic systems. This project uses and further develops cross-species measures that reflect abnormalities in dopaminergic systems to advance our understanding of BD and its treatment. The design involves parallel studies in manic BD patients and in mice in which the DAT has been manipulated either pharmacologically (amphetamine) or genetically (DAT knockdown and knockout mice). Specifically, inhibitory deficits in three domains will be assessed: 1. Impaired sensorimotor inhibition using prepulse inhibition of startle; 2. Motor hyperactivity in a novel environment using species-appropriate ambulatory monitoring devices; and, 3. Perseveration using innovative non-linear analyses of spatial and temporal patterns of motor responses. Manic BD inpatients will be studied at hospital admission, when highly symptomatic, and longitudinally during treatment with antimanic and/or atypical antipsychotic drugs. Normal comparison subjects will also be studied longitudinally, although in the absence of treatment. An important innovative aspect of this application is the development of an explicit human analog of the open field, the classic rodent behavioral paradigm used to assess dopaminergic psychostimulant effects. Experiments with mice will test the hypothesis that mutant mice lacking the normal complement of DAT might serve as a model of the inhibitory deficits in BD and that DAT-deficient mice might provide an animal model with predictive validity for the identification of antimanic agents. The parallel characterization of core features of BD across species will enable objective measures of mania that can be used to monitor treatment efficacy in BD patients and facilitate the validation of homologous predictive models of BD in rodents. Such preclinical models, and the human measures essential to their validation, are critical to the future discovery of novel treatments of this condition.