INHIBITORY DEFICITS IN HUMAN AND ANIMAL MODELS OF BIPOLAR DISORDER

描述(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。抑制缺陷是BD的特征，发生在疾病的不同阶段。BD患者的抑制问题可能会导致更多的冒险行为，以及在完成日常生活和遵守治疗的重要任务方面的困难。因此，研究整个BD谱的去抑制特征可能会阐明该病的特征，而不考虑其症状。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，从而有助于发展急需的BD躁狂症动物模型。在过去的资助期间，开发了一项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“标志性”的抑制缺陷模式，将他们与精神分裂症和非患者对象区分开来。此外，在小鼠中选择性地操作多巴胺转运体，无论是从基因上(击倒小鼠)还是从药物上(GBR12909给药)，都与躁狂症BD患者的抑制特征独特地匹配。本申请试图测试在躁狂的BD患者中发现的抑制曲线是专用于躁狂状态还是在BD的其他阶段，即，欣快期、抑郁和低躁狂期期间持续存在。此外，这项研究还将以跨物种的方式研究认知抑制的多个方面。BD患者在疾病的不同阶段将接受HBPM测试，以测量多动和不受限制的探索，使用Conner的持续表现测试来评估注意抑制，使用爱荷华州赌博任务来评估冒险抑制，以及使用威斯康星卡分类任务来评估持续性抑制。小鼠将在类似的啮齿动物BPM范式和最近开发的上述三种认知抑制措施的小鼠版本中进行测试。为了与该计划的跨物种转换方法保持一致，即人类研究为动物调查提供信息，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物操作是否可以模仿躁狂BD特征的某些方面。因此，将使用多巴胺激动剂化合物(苯丙胺和莫达非尼)评估健康非患者受试者的抑制功能，并将其与非多巴胺能兴奋剂(咖啡因)和安慰剂进行比较。这些药物也将在平行的小鼠范例中进行测试，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，并使用上面提到的认知和行为范式对抗精神病和抗躁狂治疗做出反应。研究BD的人类和平行动物模型将有助于改进翻译模型，评估假定的靶内表型，并识别用于评估新的BD治疗干预措施潜在疗效的概念验证研究中的行为生物标记物。 与公共卫生相关：双相情感障碍(BD)患者在抑制自己的思想和行为方面有很大困难，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，即使他们不是很严重的疾病。这项应用旨在测量BD多个阶段的抑制程度，并同时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潜在的脑功能障碍，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.