Given the strong evidence suggesting that oxytocin enhances social cognition and social motivation, it is essential to understand the neurobiological mechanisms and neural circuits underlying these effects, and to tease apart what aspects of social cognition may be mediated by central verses peripheral oxytocin receptors. This knowledge will have significant implications for novel drug development targeting the oxytocin system.
One of the main hurdles in understanding the neurobiological mechanisms of oxytocin action on primate social behavior has been the inability to localize oxytocin receptors in the nonhuman primate brain, due in part to the lack of selectivity of available oxytocin receptor radioligands. The Neurochemistry Core will utilize a three pronged approach to determine the neuroanatomical distribution of oxytocin receptors in the primate brain:
Use of validated RT-PCR neuronal phenotyping
Optimization of oxytocin receptor autoradiography to improve selectivity
Validation of novel OXTR PET ligands.
An understanding of the distribution of oxytocin receptor in the NHP brain, and the molecular phenotype of oxytocin receptor expressing neurons in the amygdala will greatly enhance the interpretation of the data generated by Projects 2 and 3.
The Neurochemistry Core will also have a significant impact on the Conte Center by providing essential, efficient services to the Projects, including 1) histology services to verify probe placement, 2) quantitative oxytocin receptor autoradiography in rodents, 3) novel selective oxytocin receptor antagonists for behavioral studies and 4) performing RT-PCR based neuronal phenotyping in identified single neurons from nonhuman primate and rodent amygdala.
The services, ligands, and data provided by the Neurochemistry Core complement the experimental aims in the Projects. With access to selective oxytocin receptor antagonists, Project scientists will be able to infer which behavioral effects of intranasal oxytocin are mediated by central oxytocin receptor or by other mechanisms. Synthesis of novel PET imaging radioligands selective for primate oxytocin receptor will provide in vivo localization and quantification of neural oxytocin receptor densities via PET imaging. The data will be used to correlate oxytocin receptor densities with experimental data and, in combination with MRI, can be used as a guide for insertion of neural probes to reach brain areas with the highest concentrations of oxytocin receptors. The PET ligand development will be an incredible resource for the oxytocin research community across the nation and will complement the human studies in Project 4.
In order to achieve our goals we have brought together in the Neurochemistry Core a multidisciplinary team of experts in primate neuroanatomy, brain imaging, synthetic chemistry and PET ligand development. In addition to being multidisciplinary, the approaches we utilize are highly innovative. We use an innovative combination of neurophysiology and RT-PCR molecular techniques to identify the molecular phenotype of amygdala oxytocin receptor positive neurons. The production of novel potent and selective oxytocin receptor antagonist for use in primates is innovative. Finally, the development of novel oxytocin receptor PET ligands for in vivo localization of oxytocin receptors in the primate brain will have a tremendous impact on the oxytocin research community.