CHARACTERIZATION OF OXYTOCIN RECEPTORS IN AUTISM SPECTRUM DISORDER

 描述(申请人提供)：数十年的研究表明，催产素(OT)可以作为一种强大的神经调节剂，在各种物种中影响复杂的社会行为，包括社会纽带、联系和社会奖励。越来越多的研究表明，鼻腔给人类注射催产素可以影响一系列社会行为，如信任、眼神接触、情感识别和与配对联系相关的行为。由于OT在动物和人类中都具有调节社会功能的能力，OT系统在自闭症谱系障碍(ASD)的生物学和治疗中被高度涉及，ASD的部分特征是社会性缺陷。在美国，大约每68名儿童中就有1名患有自闭症(CDC，2014)。最近的研究表明，鼻腔催产素可以改善ASD患者的某些方面的社会功能。然而，目前尚不清楚ASD患者和神经典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敏感的神经底物，我们将能够更好地理解OT影响人类行为的机制。本研究的目的是利用一种新的、药物优化的方法来检测ASD患者和匹配的对照组脑组织中的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。由于催产素和加压素(AVP)受体系统之间的药理交叉反应，定位OXTR在人脑组织中的表达位置一直是一项困难的工作。OT和AVP之间以及OXTR和加压素1a受体(AVPR1a)之间具有高度的结构同源性，这使得这两种神经肽对彼此的受体具有很高的亲和力。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尤其高。同样，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的OXTR和AVPR1a具有很高的亲和力。因此，OXTR和AVPR1a在灵长类动物中的基本生理研究受到了明显的阻碍，尤其是定位这些受体在脑组织中分布的基础神经解剖学研究。按顺序 为了克服在灵长类动物组织中可靠地检测OXTR的这些限制，Freeman博士(合作者)先前设计了一种可靠的、在药理学上知情的方案，通过确定这些配体可以选择性地占据一个受体而不是另一个受体的准确浓度，来可视化死后灵长类动物脑组织中的OXTR。这种对OXTR受体放射自显影进行了药物优化的改进是在人类和非人类灵长类脑组织中识别OXTR的第一项可靠技术。通过在人脑组织中使用这项优化的技术，我们首次能够独特地识别OT的人类神经目标。

 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.