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，其特征是躁狂和抑郁状态。抑制性缺陷是BD的特征，并在疾病的各个阶段发生。BD患者的抑制问题可能会导致冒险行为增加，以及难以完成日常生活的重要任务和遵守治疗。因此，在整个BD谱中研究去抑制的概况可以阐明无论疾病学如何都存在的疾病的特征。此外，抑制赤字可以在人类和动物中使用平行的方法进行研究，从而有助于开发急需的BD躁狂症动物模型。在过去的资助期间，开发了一种新技术来研究人类的抑制缺陷（人类行为模式监测器：hBPM）。躁狂型BD患者表现出一种“签名”模式的抑制赤字，区分他们与精神分裂症和非病人的科目。此外，在小鼠中选择性操纵多巴胺转运蛋白，无论是遗传（敲除小鼠）还是基因敲除（GBR 12909给药），都与躁狂BD患者的抑制特征唯一匹配。本申请试图测试在躁狂BD患者中发现的抑制谱是否特异于躁狂状态或在BD的其他阶段期间持续，即，情绪正常抑郁和轻躁狂状态此外，本研究将以跨物种的方式研究认知抑制的多个方面。BD参与者在其疾病的不同阶段将使用hBPM进行测试以测量多动和去抑制探索，使用康纳持续表现测试评估注意力抑制，使用爱荷华州赌博任务评估冒险抑制，使用威斯康星州卡片分类任务评估持续抑制。将在类似的啮齿动物BPM范例中以及在最近开发的上述三种认知抑制测量的小鼠版本中测试小鼠。为了与该计划的跨物种翻译方法保持一致，其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逻辑步骤提供信息，另一个目的是测试健康人的药理学操作是否可以模拟躁狂BD概况的各个方面。因此，将在健康非患者受试者中使用多巴胺激动剂化合物（安非他明和莫达非尼）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。还将在平行小鼠模型中测试这些药物，以检查啮齿动物任务的预测有效性。最后，将使用上述认知和行为范例在基线和对抗精神病药和抗躁狂药治疗的反应中测试BD小鼠模型。研究BD的人类和平行动物模型将促进翻译模型的完善，评估推定的靶向内表型，并确定用于评估BD新型治疗干预的潜在疗效的概念验证研究的行为生物标志物。 公共卫生相关性：患有双相情感障碍（BD）的人在抑制他们的思想和行为方面有很大的困难，这对他们进行日常活动和恢复独立功能的能力产生了不利影响，即使他们没有主动生病。该应用旨在测量BD多个阶段的抑制，并平行研究该疾病的人类和动物模型。这项工作的完成将有助于了解BD的潜在脑功能障碍，并有助于发现和开发新的治疗方法。

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.