疑核对心率控制的分子层面解析

文献信息

中文摘要

疑核（nAmb）既提供对心肺功能的副交感控制，也提供对上气道和食管的运动控制。nAmb神经元的一个亚群通过迷走神经支配心脏，以在静息时以及哺乳动物潜水反射等关键自主神经反射期间控制心脏功能。然而，这些心脏迷走性nAmb神经元与成年大脑中其他nAmb神经元有何不同仍不清楚。因此，我们从分子、解剖和功能层面对成年雄性和雌性小鼠的nAmb神经元进行了分类。首先，我们对单核RNA测序数据的整合分析预测出nAmb神经元的多个分子亚型。对其中一种nAmb神经元亚型——表达Npy2r的nAmb神经元——的轴突投射进行图谱绘制显示，它们支配心脏神经节，但不支配上气道或食管。通过化学遗传学方法刺激Npy2r+ nAmb神经元，可通过外周毒蕈碱型乙酰胆碱受体显著降低心率。最后，自主水下潜水会降低心率并激活Npy2r+ nAmb神经元，这与该nAmb亚型具有心脏迷走功能相一致。这些结果共同揭示了nAmb神经元的分子组织及其对心率的控制。意义声明：脑干的疑核通过迷走神经控制心率，但所涉及的具体神经元一直难以识别，因为它们与调节呼吸和吞咽的神经元混杂在一起。在此，我们结合单细胞转录组学、解剖示踪和生理学实验，鉴定出疑核神经元的一个独特亚型，其以Npy2r基因表达为标志，支配心脏但不支配食管或上气道，并强效控制心率。我们还表明，这些神经元在自主水下潜水期间被激活——这是一种强烈减慢心率的自然反射。这些发现揭示了一个关键脑-心回路的细胞组织，并为研究其在健康和疾病中的作用提供了一个分子切入点。

英文摘要

The nucleus ambiguus (nAmb) provides parasympathetic control of cardiorespiratory functions as well as motor control of the upper airways and esophagus. A subset of nAmb neurons innervates the heart through the vagus nerve to control cardiac function at rest and during key autonomic reflexes such as the mammalian diving reflex. Yet, how these cardiovagal nAmb neurons differ from other nAmb neurons in the adult brain remains unclear. We therefore classified adult male and female mouse nAmb neurons molecularly, anatomically, and functionally. First, our integrated analysis of single-nucleus RNA-sequencing data predicted multiple molecular subtypes of nAmb neurons. Mapping the axon projections of one nAmb neuron subtype, Npy2r-expressing nAmb neurons, showed that they innervate cardiac ganglia but not the upper airways or esophagus. Chemogenetically stimulating Npy2r+ nAmb neurons robustly decreased heart rate through peripheral muscarinic acetylcholine receptors. Finally, voluntary underwater diving decreases heart rate and activates Npy2r+ nAmb neurons, consistent with a cardiovagal function for this nAmb subtype. These results together reveal the molecular organization of nAmb neurons and its control of heart rate.Significance statement The nucleus ambiguus of the brainstem controls heart rate through the vagus nerve, but the specific neurons involved have been difficult to identify because they are intermixed with neurons that regulate breathing and swallowing. Here we combine single-cell transcriptomics, anatomical tracing, and physiological experiments to identify a distinct subtype of nucleus ambiguus neuron, marked by Npy2r gene expression, that innervates the heart but not the esophagus or upper airways, and powerfully controls heart rate. We also show that these neurons become activated during voluntary underwater diving - a natural reflex that strongly slows the heart. These findings reveal the cellular organization of a key brain-heart circuit and a molecular entry point for studying its role in health and disease.