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，其特征为发声和运动抽搐，以及先兆冲动、强迫、强迫和注意力缺陷。目前治疗TS的药物可以减轻一些患者的抽搐严重程度，但对最具损害性的TS症状无效，并伴有显著的不良反应。因此，迫切需要有效靶向TS症状但不太容易产生有害副作用的新药物。TS的病因仍然未知，但遗传和神经病理学研究的新证据已经导致了这种疾病的某些形式的病因学的合理假设。TS的新药物的发现，以及对其原因的新假设的评估，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来对大鼠“抽动样”或刻板行为的测量，这些行为与功能上最严重的TS症状几乎没有神经生物学相关性。大多数这些过时的模型在预测除多巴胺D2受体拮抗剂以外的化合物的功效方面是有限的，多巴胺D2受体拮抗剂在治疗TS方面仅具有有限的功效。新的TS模型是需要的，是敏感的神经生物学基板的最损害的认知和感觉运动障碍，这种疾病。本申请的目标是开发和应用基于TS患者中的视觉空间启动（VSP）缺陷的用于TS的新型预测动物模型。VSP范式是反应抑制和易化的定量心理生理学测量，其中TS患者相对于健康对照表现出过度易化和抑制不足。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TS的有效对照治疗。这表明VSP缺陷的动物模型可能是新型TS疗法的有价值的预测模型。正在开发一种大鼠操作性VSP模型，该模型再现了人类表现出的正常VSP模式。训练大鼠对目标刺激作出反应，但抑制对同时呈现的干扰刺激作出反应。这个歧视任务，然后扩展到模拟一个完整的人类VSP任务，与总理和探针试验和测量的反应时间，以检测促进和抑制启动的水平。正常的VSP表现将受到挑战，使用药物，在概念上与TS患者的神经化学异常。这种新模型的预测有效性将首先使用“已知”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TS新药，据信该新药通过一种新的治疗机制发挥作用。未来的研究将探讨大鼠VSP的神经调节机制，并将使用这一措施来测试新的遗传和神经发育假说的TS病因。如果成功的话，本申请可以提供一个关键的工具来弥合TS研究中的重大差距，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基于TS患者中的视觉空间启动（VSP）缺陷的用于图雷特综合征（TS）的新型预测动物模型。TS患者的VSP缺陷与习惯逆转疗法（HRT）的治疗结果密切相关，且高度显著，HRT是TS的一种新兴临床控制治疗形式。这表明大鼠VSP缺陷模型在预测TS治疗成功方面可能很有价值，并最终有助于弥合从临床前研究到TS新疗法的转化差距。

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.