Departmental of Medical Imaging and Radiation Sciences, Monash University, Clayton, VIC, Australia.
Monash Biomedical Imaging, Monash University, Clayton, VIC, Australia.
J Physiol. 2020 Dec;598(24):5771-5787. doi: 10.1113/JP280220. Epub 2020 Oct 7.
Unpleasant respiratory sensations contribute to morbidity in pulmonary disease. In rodents, these sensations are processed by nodose and jugular vagal sensory neurons, two distinct cell populations that differentially project to the airways and brainstem. Whether similar differences exist in bronchopulmonary sensory pathways in humans is unknown. We use functional magnetic resonance imaging during inhalation of capsaicin and ATP, showing that airway nodose pathways project centrally to the nucleus of the solitary tract, whereas jugular pathways input into the trigeminal brainstem nuclei. We also show differences between the efficacy of nodose and jugular stimuli to evoke cough and activity in motor control regions of the brain. Our data suggest that humans have two distinct vagal sensory neural systems governing airway sensations and this may have implications for the development of new antitussive therapies.
In rodents, nodose vagal sensory neurons preferentially innervate the distal airways and terminate centrally in the nucleus of the solitary tract. By contrast, jugular vagal sensory neurons preferentially innervate the proximal airways and terminate in the paratrigeminal nucleus in the dorsolateral medulla. This differential organization suggests distinct roles for nodose and jugular pathways in respiratory sensory processing. However, it is unknown whether bronchopulmonary afferent pathways are similarly arranged in humans. We set out to investigate this using high resolution brainstem and whole brain functional magnetic resonance imaging in healthy human participants when they were inhaling stimuli known to differentially activate nodose and jugular pathways. Inhalation of capsaicin or ATP evoked respiratory sensations described as an urge-to-cough, although ATP was significantly less effective compared to capsaicin at evoking the motor act of coughing. The nodose and jugular neuron stimulant capsaicin increased blood oxygen level-dependent (BOLD) signals extending across the dorsomedial and dorsolateral medulla, encompassing regions containing both the nucleus of the solitary tract and the paratrigeminal nucleus. By contrast, at perceptually comparable stimulus intensities, the nodose-selective stimulant ATP resulted in BOLD signal intensity changes that were confined to the area of the nucleus of the solitary tract. During whole brain imaging, capsaicin demonstrated a wider distributed network of activity compared to ATP, with significantly increased activity in regions involved with motor control functions. These data suggest that functional and neuroanatomical differences in bronchopulmonary nodose and jugular sensory pathway organization are conserved in humans and also that this has implications for understanding the neurobiological mechanisms underpinning cough.
不愉快的呼吸感觉会导致肺部疾病的发病率。在啮齿动物中，这些感觉是由结状和颈静脉迷走感觉神经元处理的，这两种不同的细胞群体分别投射到气道和脑干。在人类的支气管-肺感觉通路中是否存在类似的差异尚不清楚。我们在吸入辣椒素和 ATP 时使用功能磁共振成像，显示气道结状神经通路向孤束核中央投射，而颈静脉通路输入三叉脑干核。我们还显示了结状和颈静脉刺激诱发咳嗽和大脑运动控制区域活动的效果之间的差异。我们的数据表明，人类有两个不同的迷走感觉神经系统来调节气道感觉，这可能对新的镇咳治疗方法的发展有影响。
在啮齿动物中，结状迷走感觉神经元优先支配远端气道，中枢投射到孤束核。相比之下，颈静脉迷走感觉神经元优先支配近端气道，在延髓背外侧的副三叉神经核终止。这种差异组织提示结状和颈静脉通路在呼吸感觉处理中具有不同的作用。然而，尚不清楚人类的支气管-肺传入通路是否也有类似的排列。我们使用健康人类参与者的高分辨率脑干和全脑功能磁共振成像来研究这一点，当他们吸入已知能分别激活结状和颈静脉通路的刺激物时。吸入辣椒素或 ATP 会引起呼吸感觉，描述为咳嗽冲动，但与辣椒素相比，ATP 诱发咳嗽的运动作用明显不那么有效。结状和颈静脉神经元刺激物辣椒素增加了延髓背侧和背外侧的血氧水平依赖（BOLD）信号，包括包含孤束核和副三叉神经核的区域。相比之下，在感知上可比的刺激强度下，结状选择性刺激物 ATP 引起的 BOLD 信号强度变化仅限于孤束核的区域。在全脑成像中，与 ATP 相比，辣椒素显示出更广泛的活性分布网络，与参与运动控制功能的区域的活性显著增加。这些数据表明，人类支气管-肺结状和颈静脉感觉通路组织的功能和神经解剖学差异是保守的，这也意味着这对理解咳嗽的神经生物学机制有影响。
