CHARACTERIZATION OF OXYTOCIN RECEPTORS IN AUTISM SPECTRUM DISORDER

自闭症谱系障碍中催产素受体的特征

• 批准号: 9134888
• 负责人: Karen L. Bales
• 金额: $ 19.63万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9134888
• 关键词: Affect; Affinity; Age; Amygdaloid structure; Animals; Autopsy; Autoradiography; Basal Nucleus of Meynert; Behavior; Binding; Biology; Brain; Centers for Disease Control and Prevention (U.S.); Child; Competitive Binding; Complex; Emotions; Eye; Female; Health; High Prevalence; Hippocampus (Brain); Hormones; Human; Hypothalamic structure; Incubated; Individual; Label; Ligand Binding; Ligands; Location; Macaca mulatta; Maps; Memory; Methods; Modification; National Institute of Child Health and Human Development; Neurobiology; Neurologic; Neuromodulator; Neuropeptides; Nucleus Accumbens; Oxytocin; Oxytocin Receptor; Pair Bond; Paper; Patients; Pattern; Peptides; Physiology; Pilot Projects; Population; Primates; Protocols documentation; Publications; Publishing; Radiation; Receptor Gene; Research; Research Personnel; Rewards; Rodent; Role; Social Behavior; Social Functioning; Social Interaction; Specimen; System; Techniques; Time; Tissues; Trust; United States; Variant; Vasopressin Receptor; Vasopressins; autism spectrum disorder; brain tissue; cross reactivity; density; design; human tissue; improved; interest; male; nonhuman primate; novel; radioligand; receptor; receptor binding; receptor expression; relating to nervous system; sex; social; social attachment; social communication; superior colliculus Corpora quadrigemina; tool

 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.

 描述（由申请人提供）：数十年的研究表明，肽催产素（OT）可以作为多种物种的有效神经调节剂，影响越来越多的复杂社会行为，包括社会联系、归属和社会奖励。大量研究表明，由于鼻内 OT 能够调节社交，因此对人类进行鼻内 OT 会影响一系列社会行为，例如信任、目光接触、情绪识别和配对相关行为。 OT 系统在动物和人类中都发挥着重要作用，与自闭症谱系障碍 (ASD) 的生物学和治疗密切相关，这种疾病的部分特征是社交能力缺陷，在美国，大约每 68 名儿童中就有 1 人受到自闭症谱系障碍的影响。最近的研究表明，鼻内 OT 可以改善 ASD 患者的某些社会功能，但目前尚不清楚催产素受体 (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，我们将能够更好地了解 OT 影响人类行为的机制。了解检测 ASD 患者和匹配对照组织的脑组织中的 OXTR，以确定 OT 系统的神经变化是否可能是 ASD 生物学的一部分，绘制人类脑组织中 OXTR 表达的位置一直是一个困难。应尽的努力OT 和加压素 (AVP) 受体系统之间的药理学交叉反应性 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，这导致两种神经肽具有高亲和力。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，目前可用于研究这些的大多数药理学工具。灵长类动物中的 OXTR 和 AVPR1a 受体也具有高亲和力，因此，灵长类动物中 OXTR 和 AVPR1a 的基础生理学研究受到明显阻碍，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 的这些限制，Freeman 博士（共同研究者）之前设计了一种可靠的、药理学知情的方案，通过确定这些配体可以在死后脑组织中可视化的精确浓度。这种对 OXTR 受体放射自显影的药理学优化修饰是第一种在人类和非人类灵长类动物脑组织中识别 OXTR 的可靠技术。在人类大脑组织中，我们首次有能力专门识别人类中 OT 的神经目标。