Brain-wide input and output wiring diagram of oxytocin neurons and its function in claustrum-endopiriform complex

摘要 社会行为反映了高度复杂的、多模式的内部/外部刺激整合，对于 包括人类在内的许多动物的生存。受损的社交行为与许多不同的 精神错乱。尽管它很重要，但我们对潜在的神经回路机制知之甚少。 以产生与情境相适应的社会行为反应。催产素(OT)是一种神经肽，它发挥着 在规范社会行为方面的重要作用。影响OT信号的基因突变已经严重 与具有社会行为障碍的大脑障碍有关，如自闭症谱系障碍。OT神经元 主要位于下丘脑，从感觉系统和其他大脑区域接受输入，以 整合外部刺激和内部信息。反过来，下丘脑OT神经元将OT释放到 血液通过脑下垂体影响身体新陈代谢，并向大脑其他区域提供中央投射。至 支持OT功能，OT受体(OTR)在具有重要社会意义的脑区高度表达。特别是，OT 众所周知，在不同的大脑区域通过OTR发出的信号可以增加社会信息的处理能力 抑制背景噪声，实现电路特定的神经调制。尽管OT的作用突出 催产素在社会行为中的信号传递、精确的神经解剖连通性和回路特异性效应 信号仍不清楚。在这里，我们建议研究下丘脑OT的详细解剖组织 并研究其在一个新的小鼠大脑区域的功能。在技术上很难想象 并分析整个哺乳动物大脑的微观结构(例如轴突)。要克服这一点 障碍，我们以前开发了一种新的方法，结合序列双光子断层成像(STPT)成像 使用病毒和遗传工具在细胞分辨率下实现整个小鼠大脑的量化输入和输出 细胞类型特定群体的地图。使用这种方法，我们将检查地形隔离的输出 (AIM1)和输入(AIM2)图，并将开发网络可视化平台来 显示高分辨率图像以供进一步分析。此外，我们还将研究OT信号在体内的作用。 根据我们的初步结果(Aim3)，屏蔽门-内分泌复合体用于指导正常的社会行为。我们 相信这些研究将建立一个非常需要的OT神经元的详细解剖线路图 为阐明健康和疾病中成熟社会行为的神经回路基础提供了基础。

Abstract Social behavior reflects highly complex, multimodal, internal/external stimuli integration and is critical to the survival of many animals, including humans. Impaired social behavior has been implicated in many different mental disorders. Despite its importance, we know relatively little about underlying neural circuit mechanisms to generate context appropriate social behavioral response. Oxytocin (OT) is a neuropeptide that plays an essential role in regulating social behavior. Genetic mutations that affect OT signaling have been heavily implicated in brain disorders with social behavioral impairments such as autism spectrum disorder. OT neurons predominately located in the hypothalamus receive input from the sensory system and other brain regions to integrate both external stimuli and internal information. In turn, hypothalamic OT neurons release OT to the bloodstream via the pituitary to affect body metabolism and provide central projection to other brain regions. To support OT function, OT receptor (OTR) is highly expressed in socially important brain areas. Particularly, OT signaling via OTR in different brain regions is known to increase social information processing while suppressing background noise to achieve circuit specific neural modulation. Despite prominent roles of OT signaling during social behavior, precise neuroanatomical connectivity and circuit specific effects of OT signaling remain unclear. Here, we propose to study the detailed anatomical organization of hypothalamic OT neurons and to investigate its function in a novel mouse brain area. It has been technically challenging to image and analyze microscopic structures (e.g., axons) throughout the entire mammalian brain. To overcome this barrier, we previously developed a novel method that combines serial two-photon tomography (STPT) imaging of whole mouse brains at cellular resolution with viral and genetic tools to achieve quantitative input and output maps of cell type specific populations. Using this approach, we will examine topographically segregated output (Aim1) and input (Aim2) maps of hypothalamic OT neurons and will develop web visualization platform to display high-resolution images for further analysis. Moreover, we will investigate OT signaling function in the claustrum-endopiriform complex to guide normal social behavior based on our preliminary results (Aim3). We believe these studies will establish a much-needed detailed anatomical wiring diagram of OT neurons and will provide a foundation to elucidate the neural circuit basis of mature social behavior in health and disease.