Mazzone Stuart B, Bautista Tara G, Verberne Anthony J M, Trewella Matthew W, Farrell Michael J, McGovern Alice E
Department of Anatomy and Neuroscience, The University of Melbourne, Parkville 3010, Victoria, Australia.
Clinical Pharmacology and Therapeutics Unit, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg 3084, Victoria, Australia.
J Neurosci. 2020 Dec 2;40(49):9426-9439. doi: 10.1523/JNEUROSCI.2430-20.2020. Epub 2020 Oct 28.
The nodose and jugular vagal ganglia supply sensory innervation to the airways and lungs. Jugular vagal airway sensory neurons wire into a brainstem circuit with ascending projections into the submedius thalamic nucleus (SubM) and ventrolateral orbital cortex (VLO), regions known to regulate the endogenous analgesia system. Here we investigate whether the SubM-VLO circuit exerts descending regulation over airway vagal reflexes in male and female rats using a range of neuroanatomical tracing, reflex physiology, and chemogenetic techniques. Anterograde and retrograde neuroanatomical tracing confirmed the connectivity of the SubM and VLO. Laryngeal stimulation in anesthetized rats reduced respiration, a reflex that was potently inhibited by activation of SubM. Conversely, inhibition of SubM potentiated laryngeal reflex responses, while prior lesions of VLO abolished the effects of SubM stimulation. In conscious rats, selective chemogenetic activation of SubM neurons specifically projecting to VLO significantly inhibited respiratory responses evoked by inhalation of the nociceptor stimulant capsaicin. Jugular vagal inputs to SubM via the medullary paratrigeminal nucleus were confirmed using anterograde transsynaptic conditional herpes viral tracing. Respiratory responses evoked by microinjections of capsaicin into the paratrigeminal nucleus were significantly attenuated by SubM stimulation, whereas those evoked via the nucleus of the solitary tract were unaltered. These data suggest that jugular vagal sensory pathways input to a nociceptive thalamocortical circuit capable of regulating jugular sensory processing in the medulla. This circuit organization suggests an intersection between vagal sensory pathways and the endogenous analgesia system, potentially important for understanding vagal sensory processing in health and mechanisms of hypersensitivity in disease. Jugular vagal sensory pathways are increasingly recognized for their important role in defensive respiratory responses evoked from the airways. Jugular ganglia neurons wire into a central circuit that is notable for overlapping with somatosensory processing networks in the brain rather than the viscerosensory circuits in receipt of inputs from the nodose vagal ganglia. Here we demonstrate a novel and functionally relevant example of intersection between vagal and somatosensory processing in the brain. The findings of the study offer new insights into interactions between vagal and spinal sensory processing, including the medullary targets of the endogenous analgesia system, and offer new insights into the central processes involved in airway defense in health and disease.
结状神经节和颈静脉迷走神经节为气道和肺部提供感觉神经支配。颈静脉迷走神经气道感觉神经元与一个脑干回路相连,该回路向上投射到丘脑下正中核(SubM)和腹外侧眶皮质(VLO),这两个区域已知可调节内源性镇痛系统。在这里,我们使用一系列神经解剖示踪、反射生理学和化学遗传学技术,研究SubM-VLO回路是否对雄性和雌性大鼠的气道迷走反射发挥下行调节作用。顺行和逆行神经解剖示踪证实了SubM和VLO之间的连接性。在麻醉大鼠中进行喉部刺激会降低呼吸,而激活SubM可有效抑制这种反射。相反,抑制SubM会增强喉部反射反应,而预先损毁VLO则会消除SubM刺激的效果。在清醒大鼠中,选择性化学遗传学激活特异性投射到VLO的SubM神经元可显著抑制吸入伤害性感受器刺激物辣椒素所诱发的呼吸反应。使用顺行跨突触条件性疱疹病毒示踪证实了颈静脉迷走神经通过延髓三叉旁核向SubM的输入。向三叉旁核微量注射辣椒素所诱发的呼吸反应会因SubM刺激而显著减弱,而通过孤束核诱发的呼吸反应则未改变。这些数据表明,颈静脉迷走神经感觉通路输入到一个伤害性丘脑皮质回路,该回路能够调节延髓中的颈静脉感觉处理。这种回路组织表明迷走神经感觉通路与内源性镇痛系统之间存在交集,这对于理解健康状态下的迷走神经感觉处理以及疾病中超敏反应机制可能具有重要意义。颈静脉迷走神经感觉通路在气道引发的防御性呼吸反应中的重要作用越来越受到认可。颈静脉神经节神经元与一个中枢回路相连,该回路的显著特点是与大脑中的躯体感觉处理网络重叠,而不是与接收结状迷走神经节输入的内脏感觉回路重叠。在这里,我们展示了大脑中迷走神经和躯体感觉处理之间一个新的且功能相关的交集示例。该研究结果为迷走神经和脊髓感觉处理之间的相互作用提供了新见解,包括内源性镇痛系统的延髓靶点,也为健康和疾病状态下气道防御所涉及的中枢过程提供了新见解。