Whole-Brain Wiring Diagram of Oxytocin System in Adult Mice.
Whole-Brain Wiring Diagram of Oxytocin System in Adult Mice.
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DOI：
10.1523/jneurosci.0307-22.2022
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发表时间：
2022-06-22
影响因子：
5.3
通讯作者：
Kim, Yongsoo
中科院分区：
文献类型：
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作者：
Son, Seoyoung;Manjila, Steffy B.;Newmaster, Kyra T.;Wu, Yuan-ting;Vanselow, Daniel J.;Ciarletta, Matt;Anthony, Todd E.;Cheng, Keith C.;Kim, Yongsoo
催产素（Oxt）神经元通过与不同的神经回路直接连接来调节不同的生理反应。然而，由于缺乏全面的Oxt神经元输入-输出接线图及其与Oxt受体（Oxtr）表达的定量关系，因此对理解电路特异性Oxt功能提出了挑战。在这里，我们建立了一个全脑分布和解剖连接地图的Oxt神经元，以及它们与Oxtr表达的关系，使用高分辨率的3D映射方法在成年雄性和雌性小鼠。我们使用一个平面图来描述Oxt神经元的表达在四个下丘脑域，包括在结节核（TU）的特点不足的Oxt神经元。室旁下丘脑（PVH）中的Oxt神经元广泛投射到控制认知、大脑状态和躯体内脏反应的九个功能回路。相比之下，在视上核（SO）和附件（AN）的Oxt神经元有有限的中央投射到一个小的子集的九个电路。令人惊讶的是，Oxt输出和Oxtr表达之间的定量比较显示在整个大脑中没有显著的相关性，这表明在Oxtr表达区域中存在丰富的间接Oxt信号传导。与输出不同，PVH和SO中的Oxt神经元从主要位于丘脑、下丘脑和脑核区的九个回路的子集接收类似的单突触输入。我们的研究结果表明，PVH-Oxt神经元作为一个中央调制器，整合外部和内部的信息，通过主要是相互连接的九个电路，而SO-Oxt神经元主要作为单向Oxt激素输出。总之，我们的Oxt接线图提供了关于大脑中Oxt信号传导的不同行为功能的解剖学见解。催产素（Oxt）神经元通过大脑中的中枢投射调节从亲社会行为到疼痛感觉的多种生理功能。因此，了解Oxt神经元的详细解剖连接可以提供对Oxt信号传导在调节不同生理功能中的回路特异性作用的见解。在这里，我们使用高分辨率映射方法来描述Oxt神经元的3D分布，单突触输入和远程输出，以及它们与整个小鼠大脑中Oxt受体（Oxtr）表达的关系。我们发现Oxt与控制认知、大脑状态和躯体内脏反应的九个功能回路有联系。此外，我们确定了一个定量不匹配的Oxt-Oxtr关系，表明广泛的间接Oxt信号。总之，我们全面的Oxt接线图推进了我们对Oxt神经元回路特定作用的理解。
Oxytocin (Oxt) neurons regulate diverse physiological responses via direct connections with different neural circuits. However, the lack of comprehensive input-output wiring diagrams of Oxt neurons and their quantitative relationship with Oxt receptor (Oxtr) expression presents challenges to understanding circuit-specific Oxt functions. Here, we establish a whole-brain distribution and anatomic connectivity map of Oxt neurons, and their relationship with Oxtr expression using high-resolution 3D mapping methods in adult male and female mice. We use a flatmap to describe Oxt neuronal expression in four hypothalamic domains including under-characterized Oxt neurons in the tuberal nucleus (TU). Oxt neurons in the paraventricular hypothalamus (PVH) broadly project to nine functional circuits that control cognition, brain state, and somatic visceral response. In contrast, Oxt neurons in the supraoptic (SO) and accessory (AN) nuclei have limited central projection to a small subset of the nine circuits. Surprisingly, quantitative comparison between Oxt output and Oxtr expression showed no significant correlation across the whole brain, suggesting abundant indirect Oxt signaling in Oxtr-expressing areas. Unlike output, Oxt neurons in both the PVH and SO receive similar monosynaptic inputs from a subset of the nine circuits mainly in the thalamic, hypothalamic, and cerebral nuclei areas. Our results suggest that PVH-Oxt neurons serve as a central modulator to integrate external and internal information via largely reciprocal connection with the nine circuits while the SO-Oxt neurons act mainly as unidirectional Oxt hormonal output. In summary, our Oxt wiring diagram provides anatomic insights about distinct behavioral functions of Oxt signaling in the brain. SIGNIFICANCE STATEMENT Oxytocin (Oxt) neurons regulate diverse physiological functions from prosocial behavior to pain sensation via central projection in the brain. Thus, understanding detailed anatomic connectivity of Oxt neurons can provide insight on circuit-specific roles of Oxt signaling in regulating different physiological functions. Here, we use high-resolution mapping methods to describe the 3D distribution, monosynaptic input and long-range output of Oxt neurons, and their relationship with Oxt receptor (Oxtr) expression across the entire mouse brain. We found Oxt connections with nine functional circuits controlling cognition, brain state, and somatic visceral response. Furthermore, we identified a quantitatively unmatched Oxt-Oxtr relationship, suggesting broad indirect Oxt signaling. Together, our comprehensive Oxt wiring diagram advances our understanding of circuit-specific roles of Oxt neurons.