Department of Biomedical Sciences, University of Missouri, Columbia, MO, USA.
Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA.
J Physiol. 2024 Jul;602(14):3375-3400. doi: 10.1113/JP286069. Epub 2024 May 3.
Chronic intermittent hypoxia (CIH) in rodents mimics the hypoxia-induced elevation of blood pressure seen in individuals experiencing episodic breathing. The brainstem nucleus tractus solitarii (nTS) is the first site of visceral sensory afferent integration, and thus is critical for cardiorespiratory homeostasis and its adaptation during a variety of stressors. In addition, the paraventricular nucleus of the hypothalamus (PVN), in part through its nTS projections that contain oxytocin (OT) and/or corticotropin-releasing hormone (CRH), contributes to cardiorespiratory regulation. Within the nTS, these PVN-derived neuropeptides alter nTS activity and the cardiorespiratory response to hypoxia. Nevertheless, their contribution to nTS activity after CIH is not fully understood. We hypothesized that OT and CRH would increase nTS activity to a greater extent following CIH, and co-activation of OT+CRH receptors would further magnify nTS activity. Our data show that compared to their normoxic controls, 10 days' CIH exaggerated nTS discharge, excitatory synaptic currents and Ca influx in response to CRH, which were further enhanced by the addition of OT. CIH increased the tonic functional contribution of CRH receptors, which occurred with elevation of mRNA and protein. Together, our data demonstrate that intermittent hypoxia exaggerates the expression and function of neuropeptides on nTS activity. KEY POINTS: Episodic breathing and chronic intermittent hypoxia (CIH) are associated with autonomic dysregulation, including elevated sympathetic nervous system activity. Altered nucleus tractus solitarii (nTS) activity contributes to this response. Neurons originating in the paraventricular nucleus (PVN), including those containing oxytocin (OT) and corticotropin-releasing hormone (CRH), project to the nTS, and modulate the cardiorespiratory system. Their role in CIH is unknown. In this study, we focused on OT and CRH individually and together on nTS activity from rats exposed to either CIH or normoxia control. We show that after CIH, CRH alone and with OT increased to a greater extent overall nTS discharge, neuronal calcium influx, synaptic transmission to second-order nTS neurons, and OT and CRH receptor expression. These results provide insights into the underlying circuits and mechanisms contributing to autonomic dysfunction during periods of episodic breathing.
慢性间歇性低氧（CIH）在啮齿动物中模拟了在经历间歇性呼吸的个体中观察到的缺氧诱导的血压升高。脑干孤束核（nTS）是内脏感觉传入整合的第一部位，因此对心肺稳态及其在各种应激源下的适应至关重要。此外，下丘脑室旁核（PVN）部分通过其包含催产素（OT）和/或促肾上腺皮质激素释放激素（CRH）的 nTS 投射，有助于心肺调节。在 nTS 内，这些源自 PVN 的神经肽改变 nTS 活性和对缺氧的心肺反应。然而，它们对 CIH 后 nTS 活性的贡献尚不完全清楚。我们假设，OT 和 CRH 在 CIH 后会更大程度地增加 nTS 活性，而 OT+CRH 受体的共同激活将进一步放大 nTS 活性。我们的数据表明，与正常氧对照相比，10 天 CIH 加重了 nTS 放电、对 CRH 的兴奋性突触电流和 Ca2+ 内流，OT 的加入进一步增强了这一作用。CIH 增加了 CRH 受体的紧张功能贡献，这伴随着 mRNA 和蛋白质的升高。总之，我们的数据表明，间歇性低氧会夸大神经肽对 nTS 活性的表达和功能。关键点：间歇性呼吸和慢性间歇性低氧（CIH）与自主神经失调有关，包括交感神经系统活动升高。nTS 活性的改变有助于这种反应。源自室旁核（PVN）的神经元，包括那些包含催产素（OT）和促肾上腺皮质激素释放激素（CRH）的神经元，投射到 nTS，并调节心肺系统。它们在 CIH 中的作用尚不清楚。在这项研究中，我们专注于 OT 和 CRH 个体，以及暴露于 CIH 或正常氧对照的大鼠的 nTS 活性。我们表明，在 CIH 后，CRH 单独和与 OT 一起增加到更大的程度，整体上增加了 nTS 放电、神经元钙内流、第二级 nTS 神经元的突触传递，以及 OT 和 CRH 受体的表达。这些结果为理解在间歇性呼吸期间导致自主功能障碍的潜在电路和机制提供了线索。
