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

描述（由申请人提供）：图雷特综合征（TS）是一种神经发育障碍，其特征是声音和运动抽搐，以及先兆冲动、强迫、强迫和注意力缺陷。目前治疗TS的药物减轻了一些患者的抽动严重程度，但对最严重的TS症状无效，并伴有明显的不良反应。因此，迫切需要有效针对TS症状，但不易产生有害副作用的新药物。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经为这种疾病的某些形式的病因提出了合理的假设。由于缺乏针对TS的动物模型，新的治疗TS药物的发现和对其病因的新假设的评估受到了限制。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，这些行为可能与最具功能损害的TS症状几乎没有神经生物学相关性。大多数过时的模型在预测多巴胺d2受体拮抗剂以外的化合物的疗效方面能力有限，而多巴胺d2受体拮抗剂在治疗TS方面的疗效有限。需要新的TS模型，这些模型对这种疾病中最严重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TS预测动物模型。VSP范式是反应抑制和促进的定量心理生理测量，相对于健康对照，TS患者表现出过度的促进和抑制不足。TS患者的VSP缺陷与习惯逆转治疗的治疗结果显著相关，习惯逆转治疗是一种有效的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模型，用于新的TS治疗方法。目前正在开发一种大鼠VSP的操作模型，该模型再现了人类正常VSP的模式。老鼠被训练对目标刺激作出反应，而对同时出现的干扰刺激则抑制反应。然后，这个区分任务扩展到模拟一个完整的人类VSP任务，通过启动和探针试验以及反应时间的测量来检测促进和抑制启动的水平。正常的VSP表现将在药理学上受到挑战，使用概念上与TS患者神经化学异常相关的药物。该新模型的预测有效性将首先使用“已知的”抗抽搐药物来评估，以使VSP缺陷正常化，然后将测试一种潜在的治疗TS的新药物，该药物被认为是通过一种新的治疗机制发挥作用。未来的研究将探讨大鼠VSP的神经调节机制，并将利用这一措施来检验TS病因的新的遗传和神经发育假说。如果成功，目前的应用可能会提供一个重要的工具，以弥合TS研究的重大差距，并最终推进我们对这种疾病的理解和治疗。

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.