Regulation of Oxytocin Receptor Signaling in Neurons

项目总结/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没有药物可用于治疗这些衰弱 症状，这是至关重要的破译神经机制的社会行为和他们的 精神疾病的损害。催产素，最初被发现是一种激素， 在劳动和促进泌乳收缩，随后被发现有一个关键的 作为调节社会行为的神经调节剂。最近的研究已经开始阐明 催产素作用于神经元回路以改变神经元间通信和回路特性。 然而，在理解细胞内信号通路方面存在很大的差距， 由催产素作用于神经元中的受体而激活。特别是监管机制 控制神经元中催产素受体信号的神经元仍然没有被探索。我们的初步研究结果 表明在多个区域中催产素受体反应稳健和快速起效的脱敏 老鼠的大脑。在这里，我们建议调查的分子机制和行为 这个过程在大脑中的作用。基于我们新一代的催产素受体突变体， 不经历脱敏，我们将描述控制的分子决定因素， 催产素诱导的脱敏机制的募集，G蛋白偶联和受体 在神经元和大脑中的内化。催产素受体脱敏的行为学作用 在控制社会行为方面的作用将通过取代特定的内源性催产素受体来测试。 使用CRISPR-Cas9技术和病毒递送的具有非脱敏突变体的脑区域。 此外，这项建议将剖析一种新的蛋白质复合物的抑制作用，我们 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。的 这里提出的调查将为我们的总体假设提供全面的测试， 神经元催产素受体处于受体脱敏的严格调节控制之下， 它的信号和抑制这一过程将增强催产素信号和催产素- 依赖性社会行为这项工作的完成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，并可能揭示 未来开发治疗剂的新靶点， 神经精神障碍

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.