Pre-clinical evaluation of oxytocin for ASD treatment discovery

描述（由申请人提供）：虽然在生命早期提供的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周症状，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并行提供，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化合物的疗效，但针对ASD复杂的社交和沟通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式物种的选择，因为它们在人类生理学，神经解剖学和行为学上相似。虽然目前还没有经过验证的非人灵长类动物ASD模型，但我们认为恒河猴社交能力的自然变化提供了一种新的模型来评估亲社会药物治疗的疗效。我们已经建立了行为表型分析方案，以确定低社会和高社会的幼年猴在他们的纳塔尔场笼子里，并可靠地量化在实验室环境中的社会功能的变化。我们的一系列行为测定可用于直接比较两种小鼠模型的社会结果测量（即，社交性的高通量测定）和临床群体（即，非侵入性眼睛跟踪）。随着这些发展，非人灵长类动物模型有望为评估针对ASD核心社会缺陷的创新治疗提供有价值的测试平台。我们建议首先利用这个模型来评估ASD治疗研究中最有前途的途径之一-催产素系统。虽然鼻腔催产素治疗被推广为ASD的“安全和有前途的”治疗方法，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青少年猕猴群体系统地评估鼻内催产素给药对灵长类动物社会性的影响。我们预计，在拟议的研究中开发的方法将产生一个标准的非人灵长类动物测试平台，可用于评估未来针对ASD社会缺陷的许多药物干预措施。

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.