Neural Plasticity During Acclimatization to Hypoxia

描述（由申请人提供）：项目名称：缺氧适应期间的神经可塑性。慢性缺氧通过增加颈动脉体化学感受器的CV敏感性和CNS中呼吸中枢对来自颈动脉体的感觉输入的敏感性来增加缺氧性缓解反应（HVR）。HVR中的这些变化涉及颈动脉体和CNS中的O2敏感基因表达和其他分子信号。常氧通气驱动也增加慢性缺氧，但其机制尚不清楚。然而，中枢化学感受器可能参与，因为动脉PCO 2在适应后被调节在较低水平。近年来，我们发现慢性缺氧后HVR的增加和常氧兴奋性冲动的增强可被孤束核（NTS）内微量注射谷氨酸受体拮抗剂所阻断。NTS作为颈动脉体化学感受器的初级突触的位点，以及作为许多CO2敏感的中枢化学感受器位点之一，对于呼吸控制是重要的。我们推测：（1）慢性缺氧通过改变孤束核内NMDA和非NMDA谷氨酸受体，增加对颈动脉体感觉输入的敏感性和增加常氧兴奋性驱动;（2）这种神经可塑性是由O2敏感性引起的。（例如HIF-1a、活性O2物质）和O2非依赖性机制（例如谷氨酸盐增加），和（3）与脑干中其他部位的CO2敏感性化学感受器相比，NTS中的中枢化学感受器在低氧适应中发挥独特作用。我们将通过（1）在清醒和麻醉的大鼠中微量注射NMDA和AMPA受体激动剂和拮抗剂同时测量呼吸运动输出，（2）测量慢性缺氧和神经刺激对NTS中谷氨酸受体的mRNA和蛋白水平的影响，（3）在体外研究大鼠延髓切片中的中枢化学感受器，和（4）使用CNS中条件性HIF-1a缺失的转基因小鼠模型。实验旨在阐明大脑中慢性缺氧适应性变化的信号传导的一般原理，以及最终解释性控制的变化如何导致慢性肺病患者的低氧血症。

DESCRIPTION (provided by applicant): Title of project: Neural plasticity during acclimatization to hypoxia. Chronic hypoxia increases the hypoxic ventilatory response (HVR) by increasing the CV sensitivity of carotid body chemoreceptors and the sensitivity of respiratory centers in the CNS to sensory input from carotid bodies. These changes in the HVR involve O2-sensitive gene expression and other molecular signals in carotid bodies and the CNS. Ventilatory drive in normoxia is also increased by chronic hypoxia but the mechanisms for this are unknown. However, central chemoreceptors may be involved because arterial PCO2 is regulated at a lower level after acclimatization. Recently, we discovered that the increased HVR and increased normoxic ventilatory drive after chronic hypoxia could be blocked by microinjecting glutamate receptor antagonists into the nucleus tractus solitarius (NTS). The NTS is important for respiratory control as the site of the primary synapse from carotid body chemoreceptors, and as 1 of many CO2-sensitive central chemoreceptor sites. We hypothesize that (1) chronic hypoxia increases sensitivity to carotid body sensory input and increases normoxic ventilatory drive by changes in NMDA and non-NMDA glutamate receptors in the NTS, (2) such neural plasticity is caused by O2-sensitive (e.g. HIF-1a, reactive O2 species) and O2-independent mechanisms (e.g. increased glutamate), and (3) central chemoreceptors in the NTS play a unique role in ventilatory acclimatization to hypoxia compared to CO2-sensitive chemoreceptors at other sites in the brainstem. We will test these hypotheses by (1) microinjecting NMDA and AMPA receptor agonists and antagonists in awake and anesthetized rats while measuring respiratory motor output, (2) measuring effects of chronic hypoxia and neural stimulation on mRNA and protein levels for glutamate receptors in the NTS, (3) studying central chemoreceptors in rat medullary slices in vitro, and (4) using transgenic mouse models of conditional HIF-1a deletion in the CNS. Experiments are designed to elucidate general principles of signaling for adaptive changes to chronic hypoxia in the brain, and ultimately how changes in ventilatory control may contribute to hypoxemia in patients with chronic lung disease.