CHARACTERIZATION OF OXYTOCIN RECEPTORS IN AUTISM SPECTRUM DISORDER

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 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.