Regulation of Oxytocin Receptor Signaling in Neurons

项目摘要/摘要 社会缺陷是自闭症谱系障碍和其他许多疾病的一个显著特征 神经精神疾病。因为目前还没有治疗这些衰弱的药物 症状，关键是破译社会行为背后的神经机制及其 精神疾病中的障碍。催产素，最早被发现是一种荷尔蒙，可以增强 产程中的宫缩和促进哺乳，后来被发现有一个关键的 扮演调节社会行为的神经调节器的角色。最近的研究已经开始澄清如何 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，在对细胞内信号通路的理解上有很大的差距 作用于神经元上的催产素受体而激活的。特别是监管机制， 神经元中控制催产素受体信号的机制仍未被探索。我们的初步调查结果 建议在多个区域对催产素受体反应进行强健和快速的脱敏 老鼠的大脑。在这里，我们建议研究分子机制和行为 这一过程在大脑中的作用。基于我们这一代新型催产素受体突变体 不经历脱敏，我们将表征控制 催产素诱导的脱敏机制、G蛋白偶联和受体的募集 神经元和大脑的内在化。催产素受体脱敏的行为学作用 在控制社会行为方面将通过在特定情况下取代内源性催产素受体进行测试 使用CRISPR-Cas9技术和病毒传递的非脱敏突变体的脑区。 此外，这项提案还将剖析一种新的蛋白质复合体的抑制作用 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有关。这个 这里提出的调查将对我们的总体假设进行全面测试 神经元催产素受体处于受体脱敏的严格调控之下，限制了 它的信号和抑制这一过程将增强催产素信号和催产素- 依赖的社会行为。这项工作的完成将为监管部门提供深入的见解 大脑中一种重要的G蛋白偶联受体的调控机制，并可能揭示 治疗药物未来发展的新目标，以缓解社会缺陷 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.