Pathophysiologically Based Mouse Models of Psychiatric Disease: Tourette Syndrome

描述（由申请人提供）：疾病病理生理学的动物模型是研究复杂疾病的重要工具，既可以测试病因假设，也可以作为开发新治疗策略的平台。然而，有效和有用的精神疾病动物模型一直难以开发，因为其症状的复杂性和它们的众多和知之甚少的原因。在这里，我们提出了一种新的方法来发展复杂精神疾病的病理生理学基础模型。与其将模型建立在与疾病症状的表面表型相似性、对当前使用的药物的反应或影响较小的推定致病因素（如候选基因的疾病相关等位基因）上，我们建议将模型建立在最近的尸检结果上。这种方法具有显著的优点。首先，死后研究中发现的异常效应必然很大，因为样本量必然很小（与大规模基因研究中发现的真实但很小的效应相反）；基于大影响异常的模型更有可能产生与疾病相关的下游后果。其次，该方法在病因方面是中性的；通过模拟核心病理生理特征，而不是单个假设的原因，可以深入了解复杂疾病的核心特征。最后，我们已经开发的技术方法允许灵活的时间和程度的神经元损伤的基础模型，并推广到其他重要的神经生物学问题和其他精神疾病的建模。我们将这一概念方法应用于基于Vaccarino实验室神经病理学发现的抽动秽语综合征（TS）建模，该实验室正在合作进行当前的研究。在最近的两篇论文中，他们记录了纹状体中某些关键的中间神经元种群的减少，这是一种先前与TS有关的结构。我们将使用转基因和病毒试剂在小鼠中产生这些中间神经元的等效消融。然后，这些动物将在与TS具体相关的行为分析中进行测试，包括脉冲前抑制和纹状体依赖性程序学习；抗抽动症药物对观察到的行为异常的影响将被调查。最后，由于TS的症状通常在个体发生过程中起落，我们将通过在幼龄动物中诱导神经元间消融并分析青春期和成年期的行为来探索其影响的发展轨迹。这些研究有几个重要的目的。首先，他们为精神疾病病理生理学建模的创新策略提供了概念证明。其次，他们探讨了TS的一个特定假设，并有可能为开发新的治疗方法提供一个平台。第三，与B.R.A.I.N.S. RFA的目标一致，他们为富有创新精神的年轻研究者提供关键支持，帮助他将新的、复杂的方法应用于精神疾病生物学研究的核心问题。

DESCRIPTION (provided by applicant): Animal models of disease pathophysiology are essential tools in the investigation of complex disorders, both testing etiological hypotheses and serving as a platform for the development of novel therapeutic strategies. However, valid and useful animal models of psychiatric conditions have been difficult to develop, because of the complex nature of their symptomatology and their multitudinous and poorly understood causes. Here we propose a new approach to the development of pathophysiologically grounded models of complex psychiatric disease. Rather than base a model on superficial phenotypic resemblance to the symptoms of a disorder, on response to currently used medications, or on putative causative factors of small effect (such as disease-associated alleles of candidate genes), we propose to base a model on recent post-mortem findings. This approach has significant advantages. First, the effect size of abnormalities seen in postmortem studies is necessarily large, because sample size is necessarily small (in contrast to the real but small effects that can be found in huge genetic studies); basing a model on an abnormality of large effect is more likely to produce disease-relevant downstream consequences. Second, the approach is neutral with respect to etiology; insight into the core features of complex disorders can be generated by modeling core pathophysiological features rather than individual hypothesized causes. Finally, the technical approach we have developed allows flexibility in the timing and extent of the neuronal lesion that underlies the model, and is generalizable to other important neurobiological questions and modeling of other psychiatric conditions. We apply this conceptual approach to the modeling of Tourette syndrome (TS) based on neuropathological findings from the Vaccarino lab, which is collaborating on the current studies. In a pair of recent papers they have documented a reduction of certain key populations of interneurons in the striatum, a structure previously implicated in TS. We will use transgenic and viral reagents to produce an equivalent ablation of these interneurons in mice. These animals will then be tested in behavioral analyses of specific relevance to TS, including prepulse inhibition and striatum-dependent procedural learning; the effect of medications with anti- Tourettic efficacy on observed behavioral abnormalities will be investigated. Finally, since the symptomatology of TS typically waxes and wanes over ontogeny, we will probe the developmental trajectory of the effects of interneuronal ablation by inducing it in young animals and assaying behavior in adolescence and adulthood. These studies serve several important purposes. First, they provide proof of concept for an innovative strategy to modeling the pathphysiology of mental illness. Second, they probe a specific hypothesis of TS, and potentially provide a platform for the development of novel therapeutics. Third, consistent with the goals of the B.R.A.I.N.S. RFA, they provide critical support to an innovative young investigator and his efforts to apply new, sophisiticated methodologies to core problems in the biological study of mental illness. PUBLIC HEALTH RELEVANCE: Animal models of the mechanisms of disease are a critical tool for understanding the mechanisms of complex diseases and for developing new therapies; unfortunately, producing useful models of major psychiatric disorders has proven a daunting challenge, and progress has been slow. Here we describe a new strategy to the development of such models of complex brain disorders, by using molecular tools in mice to reproduce the changes found in post-mortem studies of the brains of patients. This approach is developed in the specific case of Tourette syndrome; but the principal and many of the technical aspects of our approach are generalizable to the modeling and investigation of other neuropsychiatric conditions.