INHIBITORY DEFICITS IN HUMAN AND ANIMAL MODELS OF BIPOLAR DISORDER

描述（由申请人提供）：双相情感障碍（BD）是一种严重的精神疾病，以躁狂和抑郁状态为特征。抑制性缺陷是双相障碍的特征，发生在疾病的各个阶段。双相障碍患者的抑制问题可能导致冒险行为增加，以及难以完成日常生活的重要任务和遵守治疗。因此，研究整个双相障碍谱的去抑制谱可以阐明与症状无关的疾病特征。此外，抑制缺陷可以在人类和动物中使用平行方法进行研究，从而有助于开发急需的双相障碍躁狂症动物模型。在过去的资助期内，开发了一种新的技术来研究人类的抑制缺陷（人类行为模式监测：hBPM）。躁狂双相障碍患者表现出一种“标志性”的抑制缺陷模式，将他们与精神分裂症和非患者区分开来。此外，小鼠多巴胺转运体的选择性操作，无论是基因（敲除小鼠）还是药理学（GBR12909给药），都与躁狂双相障碍患者的抑制谱相匹配。本应用旨在测试在躁狂双相患者中发现的抑制谱是特定于躁狂状态还是在双相的其他阶段持续存在，即平静状态，抑郁状态和轻躁状态。此外，本研究将以跨物种的方式研究认知抑制的多个方面。在不同阶段的双相障碍参与者将接受hBPM测试以测量多动症和去抑制探索，Conner's连续表现测试以评估注意力抑制，爱荷华赌博任务以评估冒险抑制，威斯康星卡片分类任务以评估持续性抑制。小鼠将在类似的啮齿动物BPM范式中进行测试，并在最近开发的小鼠版本中进行上述三种认知抑制措施的测试。为了与这个项目的跨物种转化方法保持一致，在这种方法中，人类研究为动物研究提供信息，动物研究为人类工作的下一个合乎逻辑的步骤提供信息，另一个目标是测试健康人类的药理学操作是否可以模拟躁狂双相障碍的各个方面。因此，将在使用多巴胺激动剂化合物（安非他明和莫达非尼）的健康非患者受试者中评估抑制功能，并与非多巴胺能兴奋剂（咖啡因）和安慰剂进行比较。这些药物还将在平行小鼠范式中进行测试，以检验啮齿动物任务的预测有效性。最后，BD小鼠模型将在基线上进行测试，并使用上述认知和行为范式测试抗精神病和抗躁狂治疗的反应。研究双相障碍的人类和平行动物模型将有助于改进翻译模型，评估假定的靶点内表型，并确定行为生物标志物，用于评估双相障碍新治疗干预措施的潜在疗效的概念验证研究。

DESCRIPTION (provided by applicant): Bipolar Disorder (BD) is a severe psychiatric illness that is hallmarked by manic and depressive states. Inhibitory deficits are characteristic of BD and occur throughout the various phases of the illness. Problems with inhibition in people with BD may result in increased risk-taking behavior as well as difficulties in completing important tasks of daily living and complying with treatment. Consequently, studying profiles of disinhibition throughout the BD spectrum may elucidate traits of the disease that are present regardless of symptomatology. Furthermore, inhibitory deficits can be studied in both humans and animals using parallel methodology, thus contributing to the development of much-needed animal models of BD mania. During the past funding period, a novel technology was developed to study inhibitory deficits in humans (the human Behavioral Pattern Monitor: hBPM). Manic BD patients exhibited a "signature" pattern of inhibitory deficits that distinguished them from schizophrenia and nonpatient subjects. Furthermore, selective manipulation of the dopamine transporter in mice, either genetically (knockdown mice) or pharmacologically (GBR12909 administration), uniquely matched the inhibitory profile of manic BD patients. The present application seeks to test whether the inhibitory profile found among manic BD patients is specific to the manic state or persists during the other phases of BD, i.e., euthymic, depressed, and hypomanic states. Additionally, this investigation will examine multiple aspects of cognitive inhibition in a cross-species fashion. BD participants in various phases of their illness will be tested with the hBPM to measure hyperactivity and disinhibited exploration, the Conner's Continuous Performance Test to assess attentional inhibition, the Iowa Gambling Task to assess risk-taking inhibition, and the Wisconsin Card Sorting Task to assess perseverative inhibition. Mice will be tested in an analogous rodent BPM paradigm and in recently developed mouse versions of the three measures of cognitive inhibition listed above. In keeping with this program's cross-species translational approach, in which human studies inform animal investigations and animal studies inform the next logical step in the human work, an additional aim is to test whether pharmacological manipulations in healthy humans can mimic aspects of the manic BD profile. Thus, inhibitory functioning will be assessed in healthy non-patient subjects using dopamine agonist compounds (amphetamine and modafinil) and compared to a non-dopaminergic stimulant (caffeine) and placebo. These drugs will also be tested in the parallel mouse paradigms to examine the predictive validity of the rodent tasks. Finally, the BD mouse models will be tested at baseline and in response to antipsychotic and antimanic treatments using the cognitive and behavioral paradigms mentioned above. Studying human and parallel animal models of BD will facilitate the refinement of translational models, evaluate putative target endophenotypes, and identify behavioral biomarkers for use in proof-of-concept studies assessing the potential efficacy of novel therapeutic interventions for BD. PUBLIC HEALTH RELEVANCE: Individuals with Bipolar Disorder (BD) have significant difficulty in inhibiting their thoughts and behavior, which adversely impacts their ability to carry out daily activities and resume independent functioning, even when they are not actively ill. This application aims to measure inhibition across the multiple phases of BD and also to study human and animal models of the disease in parallel. Completion of this work will assist in understanding the underlying brain dysfunction of BD as well as assist in discovering and developing novel treatments.