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

大鼠视觉空间启动：抽动秽语综合征的新型动物模型

• 批准号: 7976831
• 负责人: Jared William Young
• 金额: $ 23.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-21 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7976831
• 关键词: Adverse effects; Agonist; Amphetamines; Animal Model; Apomorphine; Attention; Characteristics; Clonidine; Cognitive; Complement; Corpus striatum structure; Discrimination; Disease; Dopamine D2 Receptor; Dopaminergic Agents; Drug usage; Etiology; Exhibits; Figs - dietary; Future; Genetic; Gilles de la Tourette syndrome; Goals; Habits; Haloperidol; Human; Link; Measurement; Measures; Modeling; Motor Tics; Neurobiology; Neurodevelopmental Disorder; Obsession; Outcome; Patients; Pattern; Performance; Pharmaceutical Preparations; Phenotype; Property; Psychophysiology; Rattus; Reaction Time; Relative (related person); Research; Risperidone; Severities; Stereotyped Behavior; Stimulus; Symptoms; Techniques; Testing; Therapeutic; Training; Visual; Visuospatial; base; drug sensitivity; effective therapy; human subject; neurochemistry; neuromechanism; noradrenergic; novel; novel therapeutics; pramipexol; preclinical study; predictive modeling; prepulse inhibition; prevent; public health relevance; receptor; response; success; tool; visual stimulus

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.

描述（由申请人提供）：Tourette综合征（TS）是一种神经发育障碍，其特征是人声和运动抽动以及预先的冲动，痴迷，强迫和注意力缺陷。当前用于TS的药物在某些患者中降低了TIC的严重程度，但对最大的TS症状无效，并且与重大不良反应有关。因此，非常需要有效靶向TS症状但不易产生有害副作用的新药物。 TS的病因仍然未知，但是来自遗传和神经病理学研究的新证据导致了某些形式的这种疾病的病因的合理假设。发现新颖的TS药物，以及针对其原因的新假设的评估，受到TS动物模型的匮乏的限制。现有的动物模型主要基于数十年历史的大鼠“ TIC样”或刻板印象的措施，这些措施可能与功能最大的TS症状几乎没有神经生物学相关。这些过时的模型中的大多数在预测除多巴胺D2受体拮抗剂以外的其他化合物的功效的能力上受到限制，后者在治疗TS方面的功效仅有限。需要新的TS模型，这些模型对这种疾病中最受损的认知和感觉运动缺陷敏感。本应用的目的是基于TS患者的视觉空间启动（VSP）缺陷来开发和应用新颖的预测动物模型。 VSP范式是对反应抑制和促进的定量心理生理测量，其中TS患者相对于健康对照，表现出过度促进和不足的抑制作用。 TS患者的VSP缺陷与习惯逆转疗法的治疗结果显着相关，这是TS的有效控制治疗。这表明VSP缺陷的动物模型可能是新型TS疗法的有价值且预测的模型。正在开发一个VSP的大鼠操作模型，该模型再现了人类表现出的正常VSP的模式。对大鼠进行了训练以应对目标刺激，但会抑制同时提出的分散刺激的反应。然后将这种歧视任务扩展到建模完整的人类VSP任务，并通过对反应时间进行质量和探针试验，以检测促进性和抑制性启动的水平。然后，使用与TS患者的神经化学异常相关的药物，正常的VSP性能将在药理学上受到挑战。该新型模型的预测有效性将首先使用“已知”抗细胞药物来标准化VSP缺陷进行评估，然后将对TS的潜在新药物进行测试，该药物被认为可以通过一种新型的治疗机制进行功能。未来的研究将研究调节大鼠VSP的神经机制，并将使用此措施来检验TS病因的新型遗传和神经发育假设。如果成功，本应用可能会提供一个关键的工具，以弥合TS研究中的显着差距，并最终提高我们对这种疾病的理解和治疗。 公共卫生相关性：本应用的目的是开发和应用Tourette综合征（TS）的新型预测动物模型，该模型基于TS患者的Visuospatial Priming（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，并且高度显着，这是TS的出现和临床控制的治疗形式。这表明大鼠的VSP缺陷模型对于预测TS的治疗成功可能是有价值的，并最终有助于弥合从临床前研究到TS新型治疗剂的翻译差距。