Comparative Medicine, University of Missouri, Columbia, Missouri, USA.
Area Pathobiology, University of Missouri, Columbia, Missouri, USA.
J Physiol. 2024 Mar;602(6):1147-1174. doi: 10.1113/JP285854. Epub 2024 Feb 20.
Viscerosensory information travels to the brain via vagal afferents, where it is first integrated within the brainstem nucleus tractus solitarii (nTS), a critical contributor to cardiorespiratory function and site of neuroplasticity. We have shown that decreasing input to the nTS via unilateral vagus nerve transection (vagotomy) induces morphological changes in nTS glia and reduces sighs during hypoxia. The mechanisms behind post-vagotomy changes are not well understood. We hypothesized that chronic vagotomy alters cardiorespiratory responses to vagal afferent stimulation via blunted nTS neuronal activity. Male Sprague-Dawley rats (6 weeks old) underwent right cervical vagotomy caudal to the nodose ganglion, or sham surgery. After 1 week, rats were anaesthetized, ventilated and instrumented to measure mean arterial pressure (MAP), heart rate (HR), and splanchnic sympathetic and phrenic nerve activity (SSNA and PhrNA, respectively). Vagal afferent stimulation (2-50 Hz) decreased cardiorespiratory parameters and increased neuronal Ca measured by in vivo photometry and in vitro slice imaging of nTS GCaMP8m. Vagotomy attenuated both these reflex and neuronal Ca responses compared to shams. Vagotomy also reduced presynaptic Ca responses to stimulation (Cal-520 imaging) in the nTS slice. The decrease in HR, SSNA and PhrNA due to nTS nanoinjection of exogenous glutamate also was tempered following vagotomy. This effect was not restored by blocking excitatory amino acid transporters. However, the blunted responses were mimicked by NMDA, not AMPA, nanoinjection and were associated with reduced NR1 subunits in the nTS. Altogether, these results demonstrate that vagotomy induces multiple changes within the nTS tripartite synapse that influence cardiorespiratory reflex responses to afferent stimulation. KEY POINTS: Multiple mechanisms within the nucleus tractus solitarii (nTS) contribute to functional changes following vagal nerve transection. Vagotomy results in reduced cardiorespiratory reflex responses to vagal afferent stimulation and nTS glutamate nanoinjection. Blunted responses occur via reduced presynaptic Ca activation and attenuated NMDA receptor expression and function, leading to a reduction in nTS neuronal activation. These results provide insight into the control of autonomic and respiratory function, as well as the plasticity that can occur in response to nerve damage and cardiorespiratory disease.
内脏感觉信息通过迷走神经传入纤维传递到大脑，在脑干孤束核（nTS）中首先整合，nTS 是心肺功能的关键贡献者，也是神经可塑性的发生部位。我们已经表明，通过单侧迷走神经切断术（迷走神经切断术）减少对 nTS 的传入会导致 nTS 神经胶质的形态变化，并减少缺氧时的叹息。迷走神经切断术后变化的机制尚不清楚。我们假设慢性迷走神经切断术通过减弱 nTS 神经元活性来改变对迷走传入刺激的心肺反应。雄性 Sprague-Dawley 大鼠（6 周龄）在颈静脉结节下方进行右侧颈迷走神经切断术或假手术。1 周后，大鼠麻醉、通气并进行仪器测量平均动脉压（MAP）、心率（HR）和内脏交感神经和膈神经活动（SSNA 和 PhrNA，分别）。迷走神经传入刺激（2-50 Hz）降低心肺参数，并通过体内光度法和 nTS GCaMP8m 的体外切片成像增加神经元 Ca 测量值。与假手术相比，迷走神经切断术减弱了这些反射和神经元 Ca 反应。迷走神经切断术还降低了 nTS 切片中刺激的突触前 Ca 反应（Cal-520 成像）。nTS 纳米注射外源性谷氨酸引起的 HR、SSNA 和 PhrNA 减少也在迷走神经切断术后减弱。这种作用不能通过阻断兴奋性氨基酸转运体来恢复。然而，NMDA 而不是 AMPA 的纳米注射模拟了迟钝的反应，并且与 nTS 中 NR1 亚基减少有关。总之，这些结果表明，迷走神经切断术会在孤束核三联突触内引起多种变化，从而影响传入刺激的心肺反射反应。关键点：孤束核（nTS）内的多种机制有助于迷走神经切断术后的功能变化。迷走神经切断术导致对迷走传入刺激和 nTS 谷氨酸纳米注射的心肺反射反应减弱。迟钝的反应通过减少突触前 Ca 激活和减弱 NMDA 受体表达和功能来发生，导致 nTS 神经元激活减少。这些结果为自主和呼吸功能的控制以及神经损伤和心肺疾病反应中可能发生的可塑性提供了深入了解。
