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，既可以测试病因学假设，也可以作为开发新治疗策略的平台。然而，由于精神疾病学的复杂性及其众多且知之甚少的原因，难以开发有效且有用的精神疾病动物模型。 在这里，我们提出了一种新的方法来发展的病理生理学接地模型的复杂精神疾病。而不是基于一个模型的表面表型相似性的症状的障碍，对目前使用的药物，或在假定的致病因素的影响小（如疾病相关的等位基因的候选基因），我们建议基于最近的尸检结果的模型。 这种方法具有显著的优点。首先，在尸检研究中发现的异常效应量必然很大，因为样本量必然很小（与在大型遗传研究中发现的真实的但很小的效应相反）;基于效应大的异常的模型更有可能产生与疾病相关的下游后果。其次，该方法在病因学方面是中立的;对复杂疾病核心特征的洞察可以通过对核心病理生理特征而不是个别假设原因进行建模来产生。最后，我们已经开发的技术方法允许灵活性的时间和程度的神经元病变的基础模型，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。 我们将这种概念性方法应用于Tourette综合征（TS）的建模，该模型基于Vaccarino实验室的神经病理学发现，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群体的减少，这是以前与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。然后在与TS特定相关的行为分析中对这些动物进行检测，包括前脉冲抑制和纹状体依赖性程序性学习;将研究具有抗妥瑞症疗效的药物对观察到的行为异常的影响。最后，由于TS的发育学通常在个体发育过程中起起伏伏，我们将通过在年轻动物中诱导它并测定青春期和成年期的行为来探索神经元间消融的影响的发展轨迹。 这些研究有几个重要目的。首先，他们提供了一个创新的策略来模拟精神疾病的病理生理学的概念证明。其次，他们探索了TS的特定假设，并可能为开发新的治疗方法提供平台。第三，与B.R.A.I.N.S.的目标相一致。RFA，他们提供了关键的支持，以创新的年轻研究者和他的努力，应用新的，诡辩的方法，在精神疾病的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.