Visuospatial priming in rats: A novel animal model for Tourette Syndrome

描述(申请人提供)：多发性抽动症(TS)是一种神经发育障碍，以发声和运动痉挛为特征，以及先兆冲动、强迫症、强迫症和注意力缺陷。目前治疗TS的药物减少了一些患者的抽搐严重程度，但对最严重的TS症状无效，并与显著的不良反应有关。因此，迫切需要有效针对TS症状、但不太容易产生有害副作用的新药。TS的病因尚不清楚，但来自遗传和神经病理学研究的新证据已导致对某些形式的这种疾病的病因提出可信的假说。治疗TS的新药的发现以及对其病因的新假说的评估，一直受到TS动物模型缺乏的限制。现有的动物模型主要是基于几十年前对大鼠“抽搐样”或刻板行为的测量，这些行为可能与大多数功能性损害的TS症状几乎没有神经生物学相关性。这些过时的模型中，大多数预测多巴胺D2受体拮抗剂以外的化合物的疗效的能力有限，这些化合物在治疗TS方面的疗效有限。需要新的TS模型，该模型对这种疾病中最具损害的认知和感觉运动缺陷的神经生物学底物敏感。本申请的目的是开发和应用一种新的基于TS患者视觉空间启动(VSP)缺陷的预测动物模型。VSP范式是一种定量的反应抑制和促进的心理生理学测量方法，与健康对照组相比，TS患者表现出过度的促进和缺乏的抑制。TS患者的VSP缺陷与习惯逆转疗法的治疗结果显著相关，习惯逆转疗法是一种有效的TS控制治疗方法。这表明，VSP缺陷的动物模型可能是一种有价值的预测新型TS治疗方法的模型。正在开发一种VSP的大鼠可操作模型，该模型再现了人类正常VSP的模式。训练大鼠对目标刺激做出反应，但抑制对同时出现的干扰刺激的反应。然后，这个辨别任务被扩展到模拟一个完整的人类VSP任务，通过启动和探测试验以及反应时间的测量来检测促进启动和抑制启动的水平。然后，使用概念上与TS患者神经化学异常有关的药物，对正常的VSP表现进行药理学挑战。这一新模型的预测有效性将首先用“已知的”抗抽搐药物来使VSP缺陷正常化，然后将测试一种潜在的治疗TS的新药，据信该新药通过一种新的治疗机制发挥作用。未来的研究将探索调节大鼠VSP的神经机制，并将使用这一措施来测试TS病因学的新的遗传和神经发育假说。如果成功，本申请可能提供一个关键的工具，以弥补在TS研究中的一个重大差距，并最终促进我们对这种疾病的理解和治疗。 公共卫生相关性：本申请的目标是开发和应用一种新的Tourette综合征(TS)预测动物模型，该模型基于TS患者的视觉空间启动(VSP)缺陷。TS患者的VSP缺陷与习惯逆转疗法(HRT)的治疗结果密切相关，HRT是一种新兴的临床可控治疗形式。这表明，大鼠VSP缺陷模型可能在预测TS的治疗成功方面有价值，并最终有助于弥合从临床前研究到TS新疗法的翻译差距。

DESCRIPTION (provided by applicant): Tourette Syndrome (TS) is a neurodevelopmental disorder characterized by vocal and motor tics, as well as premonitory urges, obsessions, compulsions and attention deficits. Current medications for TS reduce tic severity in some patients, but are ineffective against the most impairing TS symptoms and are associated with significant adverse effects. Thus, new medications that effectively target TS symptoms, but are less prone to produce deleterious side effects are critically needed. The etiology of TS remains unknown, but new evidence from genetic and neuropathological studies has led to plausible hypotheses for the etiology of some forms of this disorder. The discovery of novel medications for TS, and the assessment of new hypotheses for its causes, has been limited by the paucity of animal models for TS. Existing animal models are based primarily on decades-old measures of "tic-like" or stereotyped behaviors in rats that may have little neurobiological relevance to the most functionally impairing TS symptoms. Most of these antiquated models are limited in their ability to predict efficacy for compounds other than dopamine D2-receptor antagonists, which have only limited efficacy in treating TS. Novel TS models are needed that are sensitive to neurobiological substrates of the most impairing cognitive and sensorimotor deficits in this disorder. The goal of the present application is to develop and apply a novel predictive animal model for TS based on visuospatial priming (VSP) deficits in TS patients. The VSP paradigm is a quantitative psychophysiological measure of response inhibition and facilitation in which TS patients exhibit excessive facilitation and deficient inhibition, relative to healthy controls. VSP deficits in TS patients correlate significantly with the therapeutic outcome of habit reversal therapy, an effective controlled treatment for TS. This suggests that an animal model of VSP deficits may be a valuable and predictive model for novel TS therapeutics. A rat operant model of VSP is being developed that reproduces the patterns of normal VSP exhibited by humans. Rats are trained to respond to a target stimulus, but to inhibit responding to a simultaneously presented distracter stimulus. This discrimination task is then extended to model a full human VSP task, with prime and probe trials and measurements of reaction times to detect levels of facilitatory and inhibitory priming. Normal VSP performance will then be challenged pharmacologically, using drugs that are conceptually linked to neurochemical abnormalities in TS patients. The predictive validity of this novel model will first be assessed using "known" anti-tic medications to normalize VSP deficits, and a potential new medication for TS will then be tested that is believed to function via a novel therapeutic mechanism. Future studies will investigate the neural mechanisms regulating VSP in rats, and will use this measure to test novel genetic and neurodevelopmental hypotheses of TS etiology. If successful, the present application may provide a critical tool to bridge a significant gap in TS research, and ultimately advance our understanding and treatment of this disorder. PUBLIC HEALTH RELEVANCE: The goal of the present application is to develop and apply a novel predictive animal model for Tourette Syndrome (TS) that is based on visuospatial priming (VSP) deficits in TS patients. VSP deficits in TS patients correlate strongly, and highly significantly, with the therapeutic outcome of habit reversal therapy (HRT), an emerging and clinically controlled treatment form for TS. This suggests that a model of VSP deficits in rats may be valuable in predicting therapeutic success in TS, and ultimately help bridge the translational gap from preclinical studies to novel therapeutics for TS.