Pre-clinical evaluation of oxytocin for ASD treatment discovery

描述（由申请人提供）：虽然在生命早期进行强化行为干预可以改善一些自闭症谱系障碍（ASD）儿童的社会功能，但目前的药物治疗仅限于针对外围症状，如攻击性、焦虑和抑郁。专门针对社会行为的新型药物干预与行为干预同时进行，有望改善许多ASD患者的生活质量。亲社会药理学治疗的发展将取决于基础神经科学研究成功转化为安全有效的药物，并需要使用复杂的动物模型。虽然目前的ASD药物发现工作主要依赖于小鼠模型来评估复方疗效，但针对ASD复杂的社交和交流缺陷的药理学干预可能最终需要使用与人类更密切相关的动物模型。恒河猴被认为是生物医学模型物种的选择，因为它们在生理、神经解剖学和行为上与人类相似。虽然目前还没有证实的ASD的非人类灵长类动物模型，但我们相信恒河猴社交能力的自然变异为评估亲社会药物治疗的效果提供了一个新的模型。我们已经建立了行为表型协议，以识别低社会性和高社会性的幼年猴在他们的出生野外笼子和可靠量化在实验室设置的社会功能的变化。我们的一系列行为分析可用于直接比较小鼠模型（即社交能力的高通量分析）和临床人群（即非侵入性眼动追踪）的社会结果测量。随着这些进展，非人类灵长类动物模型有望为评估针对ASD核心社交缺陷的创新治疗提供有价值的试验平台。我们建议首先利用这个模型来评估最有前途的ASD治疗研究途径之一-催产素系统。尽管鼻后叶催产素疗法作为一种“安全且有前景”的治疗ASD的方法被推广，但我们对催产素治疗人类的疗效或机制知之甚少。在这里，我们建议利用一个特征良好的猕猴幼猴种群来系统地评估鼻内催产素对灵长类动物社交能力的影响。我们预计，在拟议的研究中开发的方法将导致一个标准的非人类灵长类动物测试平台，可用于评估许多针对ASD社交缺陷的未来药物干预措施。

DESCRIPTION (provided by applicant): While intensive behavioral intervention delivered early in life improves social functioning for some children with autism spectrum disorder (ASD), current pharmacological treatments are limited to targeting only peripheral symptoms such as aggression, anxiety, and depression. Novel pharmacological interventions specifically targeting social behavior delivered in parallel with behavioral intervention holds the promise of improving quality of life for many individuals with ASD. Development of pro-social pharmacological treatments will depend upon the successful translation of basic neuroscience research into safe and effective medicines and will require the use of sophisticated animal models. While current ASD drug discovery efforts have relied primarily upon mouse models to evaluate compound efficacy, pharmacological interventions targeting the complex social and communication deficits of ASD may ultimately require the use of an animal model more closely related to humans. Rhesus monkeys are considered the biomedical model species of choice due to their resemblance in human physiology, neuroanatomy and behavior. Although there are currently no validated nonhuman primate models of ASD, we believe that natural variation in sociability of rhesus monkeys provides a novel model to evaluate the efficacy of pro-social pharmacological treatments. We have established behavioral phenotyping protocols to identify low-social and high-social juvenile monkeys in their natal field cages and to reliably quantify changes in social functioning in a laboratory setting. Our battery of behavioral assays can be used to directly compare social outcome measures with both mouse models (i.e., high-throughput assays of sociability) and clinical populations (i.e., non-invasive eye tracking). With these developments, the nonhuman primate model is poised to provide a valuable test bed for evaluating innovative treatments targeting the core social deficits of ASD. We propose to first utilize this model to evaluate one of the most promising avenues of ASD treatment research - the oxytocin system. Although nasal oxytocin therapy is being promoted as a "safe and promising" therapy for ASD, we know very little about the efficacy or mechanism of oxytocin treatment in humans. Here we propose to utilize a well-characterized population of juvenile macaque monkeys to systematically evaluate the effects of intranasal oxytocin administration on primate sociability. We anticipate that the methods developed in the proposed research will result in a standard nonhuman primate testing platform that can be used to evaluate numerous future pharmacological interventions targeting the social deficits of ASD.