CHARACTERIZATION OF OXYTOCIN RECEPTORS IN AUTISM SPECTRUM DISORDER

 描述（由申请人提供）：数十年的研究表明，肽催产素（OT）可以作为一种有效的神经调节剂在各种物种中影响复杂的社会行为，包括社会联系，归属和社会奖励。在越来越多的研究中，向人类施用鼻内OT已被证明会影响一系列社会行为，如信任，眼神接触，情感识别和配对相关行为。由于OT调节动物和人类社会功能的能力，OT系统与自闭症谱系障碍（ASD）的生物学和治疗密切相关，ASD是一种部分特征在于社交缺陷的病症。ASD影响美国约1/68的儿童（CDC 2014）。最近的研究表明，鼻内OT可以改善ASD患者社会功能的某些方面。然而，目前尚不清楚ASD患者和神经型个体之间催产素受体（OXTR）的神经分布是否存在差异。通过定位对OT敏感的神经基质，我们将能够更好地理解OT影响人类行为的机制。该提案的目的是采用一种新的和优化的方法来检测ASD患者和匹配的对照组织的脑组织中的OXTR，以确定OT系统中的神经学变化是否可能是ASD生物学的一部分。 由于OT和加压素（AVP）受体系统之间的药理学交叉反应性，绘制人脑组织中OXTR表达的位置一直是一项困难的奋进。OT和AVP之间以及OXTR和加压素1a受体（AVPR 1a）之间存在高度的结构同源性，这导致两种神经肽对彼此的受体具有高亲和力。与啮齿动物相比，这种混合亲和力在人类和非人类灵长类动物中特别高。类似地，目前可用于研究这些受体的大多数药理学工具也对灵长类动物中的OXTR和AVPR 1a具有高亲和力。因此，对灵长类动物中OXTR和AVPR 1a的基础生理学的研究受到明显阻碍，特别是定位这些受体在脑组织中分布的基础神经解剖学研究。为了 为了克服在灵长类动物组织中可靠检测OXTR的这些局限性，Freeman博士（共同研究者）先前设计了一种可靠的、预先知情的方案，用于通过确定这些配体可用于选择性地占据一种受体而不是另一种受体的精确浓度来可视化死后灵长类动物脑组织中的OXTR。这种对OXTR受体放射自显影的优化修饰是第一种用于鉴定人和非人灵长类动物脑组织中OXTR的可靠技术。通过在人脑组织中使用这种优化的技术，我们首次能够特异性地识别OT在人类中的神经靶点。

 DESCRIPTION (provided by applicant): Decades of research have shown that the peptide oxytocin (OT) can act as a potent neuromodulator in a variety of species to influence complex social behaviors, including social bonding, affiliation, and social reward. In a growing number of studies, administering intranasal OT to humans has been shown to affect a suite of social behaviors, such as trust, eye contact, emotion recognition, and pair-bonding-related behaviors. Due to the ability of OT to modulate social function in animals as well as humans, the OT system has been highly implicated in the biology and treatment of autism spectrum disorder (ASD), a condition that is characterized in part by deficits in sociality. ASD affects approximatel 1 in 68 children in the United States (CDC 2014). Recent research has now shown that intranasal OT can improve some aspects of social functioning in patients with ASD. However, it is currently unknown whether differences in the neural distribution of the oxytocin receptor (OXTR) exist between patients with ASD and neurotypical individuals. By locating the neural substrates that are sensitive to OT, we will become better able to understand the mechanisms by which OT can influence human behavior. The aim of this proposal is to employ a novel and pharmacologically optimized method to detect OXTR in brain tissue from patients with ASD and matched control tissue, in order to determine whether neurological changes in the OT system may be part of the biology of ASD. Mapping the locations of OXTR expression in human brain tissue has been a difficult endeavor due to the pharmacological cross reactivity between the OT and vasopressin (AVP) receptor systems. There is a high degree of structural homology between OT and AVP and between OXTR and the vasopressin 1a receptor (AVPR1a), which results in both neuropeptides having a high affinity for each other's receptors. This mixed affinit is particularly high in humans and nonhuman primates, compared to rodents. Similarly, most of the pharmacological tools that are currently available to study these receptors also have a high affinity for both OXTR and AVPR1a in primates. As a result, research on the basic physiology of OXTR and AVPR1a in primates has been markedly hindered, especially the fundamental neuroanatomical research to localize the distributions of these receptors in brain tissue. In order to overcome these limitations on reliably detecting OXTR in primate tissue, Dr. Freeman (co-investigator) has previously designed a reliable, pharmacologically informed protocol for visualizing OXTR in post-mortem primate brain tissue by determining the precise concentrations at which these ligands can be used to selectively occupy one receptor over the other. This pharmacologically optimized modification for OXTR receptor autoradiography is the first reliable technique for identifying OXTR in human and nonhuman primate brain tissue. By using this optimized technique in human brain tissue, we are uniquely capable of specifically identifying OT's neural targets in humans for the first time.