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Regulation of Oxytocin Receptor Signaling in Neurons

神经元中催产素受体信号传导的调节

基本信息

批准号：
10668537
负责人：
Mohiuddin Ahmad
金额：
$ 36.25万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-20 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10668537
关键词：
Agonist Animal Behavior Arrestins Behavioral Binding Brain Brain Diseases Brain region C-terminal CRISPR/Cas technology Communication Complex Coupling Data Disease Electrophysiology (science)Foundations Future G Protein-Coupled Receptor Signaling G protein coupled receptor kinase G-Protein-Coupled Receptors GTP-Binding Proteins Generations Hormones Impairment In Vitro Interneurons Intranasal Administration Investigation Knock-in Mouse Knowledge Label Lactation Mediating Mental disorders Modality Molecular Mus Mutagenesis Mutate Neuromodulator Neurons Oxytocin Oxytocin Receptor Palmitic Acylation Site Pharmaceutical Preparations Phosphorylation Phosphorylation Site Post-Translational Protein Processing Prevention Process Property Protein Isoforms Proteins Proteomics Receptor Activation Receptor Signaling Regulation Role Signal Pathway Signal Transduction Slice Social Behavior Social Controls Structure System Tail Techniques Testing Time Virus Work anxiety-related behavior autism spectrum disorder decay acceleration desensitization disabling symptom experimental study in vivo insight knock-down mutant neuronal circuitry neuropsychiatric disorder neuropsychiatry novel novel therapeutic intervention palmitoylation prevent protein complex receptor receptor internalization recruit response social social cognition social deficits therapeutic development

项目摘要

PROJECT SUMMARY/ABSTRACT Social deficits are a prominent feature of autism spectrum disorder and many other neuropsychiatric diseases. Since there are currently no drugs available to treat these debilitating symptoms, it is critical to decipher the neuronal mechanisms underlying social behavior and their impairments in mental illnesses. Oxytocin, first discovered as a hormone that strengthens contractions during labor and facilitates lactation, has subsequently been found to have a critical role as a neuromodulator regulating social behavior. Recent work has begun to clarify how oxytocin acts on neuronal circuits to modify inter-neuronal communication and circuit properties. However, there is a large gap in the understanding of the intracellular signaling pathways that are activated by oxytocin acting on its receptor in neurons. In particular, the regulatory mechanisms that control oxytocin receptor signaling in neurons remain unexplored. Our preliminary findings suggest robust and rapid-onset desensitization of oxytocin receptor response in multiple regions of the mouse brain. Here, we propose to investigate the molecular mechanisms and behavioral role of this process in the brain. Based on our generation of novel oxytocin receptor mutants that do not undergo desensitization, we will characterize the molecular determinants that control oxytocin-induced recruitment of the desensitizing machinery, G protein coupling and receptor internalization in neurons and the brain. The behavioral role of oxytocin receptor desensitization in controlling social behaviors will be tested by replacing endogenous oxytocin receptor in specific brain regions with non-desensitizing mutants using CRISPR-Cas9 technique and virus delivery. In addition, this proposal will dissect the inhibitory effect of a novel protein complex that we identified in our proteomics experiments to associate with oxytocin receptor in neurons. The investigations proposed here will provide a comprehensive test of our overall hypothesis that neuronal oxytocin receptor is under tight regulatory control of receptor desensitization that limits its signaling and that inhibiting this process would enhance oxytocin signaling and oxytocin- dependent social behaviors. Completion of this work will provide deep insights into regulatory mechanisms governing an important G protein-coupled receptor in the brain and may uncover novel targets for the future development of therapeutic agents that alleviate social deficits in neuropsychiatric disorders.

项目总结/文摘