Building Translational Research in Obsessive-Compulsive Disorder (R24)

描述（由申请人提供）：强迫症（OCD）是一种严重的精神障碍，是一个重大的公共卫生问题。强迫症的神经生物学尚不清楚，因为很难研究活人的大脑通路，而且既没有尸检研究，也没有经过验证的动物模型。我们建议在基础和临床研究人员之间建立一种新的伙伴关系，以开发强迫症特定神经生物学特征的动物模型，以指导未来的人类研究。我们的最终目标是阐明强迫症的神经生物学，并率先提出新的治疗方法。这个R24应用程序将使我们能够开发实验室和科学资源，以便能够进行这种类型的转化工作。作为第一步，我们将研究感觉运动门控缺陷和5-HT1B受体（在人类文献中称为5-HT1DJ3受体）的作用，这两者都与强迫症有关。我们在小鼠中的初步研究结果表明，急性5-HT1B激动剂刺激导致感觉运动门控缺陷，通过降低脉冲前抑制（PPI）和重复行为（即运动刻板印象）来测量；这些作用被血清素再摄取抑制剂（SRI）氟西汀慢性预处理阻断。强迫症患者也可能有PPI缺陷，并且确实有重复行为。这个R24将使我们能够开发所需的资源来测试5-HT1B功能增加导致小鼠PPI缺陷和运动刻板印象的工作假设，并可能导致强迫症的PPI缺陷和重复行为。具体而言，我们将：1)产生具有人类5-HT1B受体的转基因小鼠；2)观察强迫症治疗对5-HT1B激动剂诱导的行为（降低PPI和运动刻板印象）以及对5-HT1B受体表达和脑功能偶联的影响；3)检查强迫症患者的PPI缺陷是否与临床特征和/或SRI治疗反应相关。在此过程中，我们将为未来5 -羟色胺系统与强迫症神经回路相关的其他方面的转化研究奠定基础。我们期望我们的工作将导致R01或转化研究中心的合作应用，将动物和人类的工作结合起来，寻求新的治疗方法，以减轻强迫症的负担。因此，我们的申请与NIMH的使命直接相关：通过推进对强迫症等严重精神疾病的科学理解来改善精神健康。

DESCRIPTION (provided by applicant): Obsessive-compulsive disorder (OCD) is a severe mental disorder that is a significant public health problem. The neurobiology of OCD remains unclear because it is difficult to study brain pathways in living people, and neither post-mortem studies nor validated animal models exist. We propose to build a novel partnership between basic and clinical researchers to develop animal models of specific neurobiological features of OCD that can guide future human studies. Our ultimate goal is to elucidate the neurobiology of OCD and to spearhead novel treatment approaches. This R24 application will enable us to develop the laboratory and scientific resources to be able to conduct this type of translational work. As a first step, we will examine the role of sensorimotor gating deficits and the 5-HT1B receptor (known as the 5-HT1DJ3 receptor in the human literature), which have both been implicated in OCD. Our preliminary findings in mice indicate that acute 5-HT1B agonist challenge leads to sensorimotor gating deficits as measured by decreased prepulse inhibition (PPI) and repetitive behavior (i.e., locomotor stereotypy); these effects are blocked by chronic pretreatment with the serotonin reuptake inhibitor (SRI) fluoxetine. OCD patients may also have PPI deficits and do have repetitive behavior. This R24 will enable us to develop the resources needed to test the working hypothesis that increased 5-HT1B function leads to PPI deficits and locomotor stereotypy in mice and may contribute to the PPI deficits and repetitive behavior in OCD. Specifically, we will: 1) generate transgenic mice with human 5-HT1B receptors; 2) examine in these mice the effects of OCD treatments on the behaviors induced by 5-HT1B agonists (decreased PPI and locomotor stereotypy) and on 5-HT1B receptor expression and functional coupling in the brain; and 3) examine whether PPI deficits in OCD patients are associated with clinical features and/or SRI treatment response. In the process, we will lay the foundation for future translational research on other aspects of the serotonin system as they relate to the neurocircuitry of OCD. We expect that our work will lead to a collaborative R01 or Translational Research Center application that will integrate animal and human work in the quest for novel treatments to reduce the burden of OCD. Thus, our application is directly relevant to NIMH's mission: to improve mental health by advancing the scientific understanding of a severe mental illness like OCD.