Regulation of Oxytocin Receptor Signaling in Neurons

神经元中催产素受体信号传导的调节

• 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
• 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

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.

项目概要/摘要 社交缺陷是自闭症谱系障碍和许多其他疾病的一个突出特征 神经精神疾病。由于目前还没有药物可以治疗这些使人衰弱的疾病 症状，破译社会行为及其背后的神经机制至关重要 精神疾病的损害。催产素，最初被发现是一种增强体力的激素 分娩时收缩并促进哺乳，随后被发现具有关键作用 作为调节社会行为的神经调节剂。最近的工作已经开始阐明如何 催产素作用于神经元回路，改变神经元间的通讯和回路特性。 然而，对于细胞内信号通路的理解存在很大差距。 由作用于神经元受体的催产素激活。特别是监管机制 控制神经元催产素受体信号传导的机制仍未被探索。我们的初步调查结果 表明多个区域的催产素受体反应具有强大且快速的脱敏作用 老鼠的大脑。在这里，我们建议研究分子机制和行为 这个过程在大脑中的作用。基于我们新一代的新型催产素受体突变体 不进行脱敏，我们将表征控制的分子决定因素 催产素诱导的脱敏机制、G 蛋白偶联和受体的募集 神经元和大脑的内化。催产素受体脱敏的行为作用 通过替换特定的内源性催产素受体来测试控制社会行为的能力 使用 CRISPR-Cas9 技术和病毒递送，研究具有非脱敏突变体的大脑区域。 此外，该提案将剖析我们研究的一种新型蛋白质复合物的抑制作用。 在我们的蛋白质组学实验中发现与神经元中的催产素受体相关。这 这里提出的调查将对我们的总体假设进行全面检验 神经元催产素受体受到受体脱敏的严格调节控制，限制了 其信号传导，并且抑制该过程将增强催产素信号传导和催产素- 依赖的社会行为。完成这项工作将为监管提供深入的见解 控制大脑中重要的 G 蛋白偶联受体的机制可能会揭示 未来开发缓解社会缺陷的治疗药物的新目标 神经精神疾病。