Neural Plasticity During Acclimatization to Hypoxia

描述(申请人提供)：项目名称：低氧适应过程中的神经可塑性。慢性低氧通过增加颈动脉小体化学感受器的CV敏感性和增加中枢呼吸中枢对颈动脉小体感觉输入的敏感性来增加缺氧性呼吸系统反应(HVR)。HVR的这些变化涉及颈动脉小体和中枢神经系统中O2敏感基因的表达和其他分子信号。慢性缺氧也会增加常氧状态下的通气性驱动力，但其机制尚不清楚。然而，中枢化学感受器可能参与其中，因为习服后动脉血二氧化碳分压被调节在较低的水平。最近，我们发现在慢性低氧状态下，通过向孤束核(NTS)内微量注射谷氨酸受体拮抗剂，可以阻断慢性低氧后HVR的增加和常氧呼吸驱动的增加。作为颈动脉小体化学感受器初级突触的位置，以及许多对二氧化碳敏感的中枢性化学感受器位置之一，NTS对于呼吸控制是重要的。我们假设(1)慢性缺氧增加了对颈动脉躯体感觉输入的敏感性，并通过改变NTS中的NMDA和非NMDA谷氨酸受体来增加常氧呼吸驱动；(2)这种神经可塑性是由O2敏感(如HIF-1a，反应性O2物种)和O2非依赖性机制(如谷氨酸增加)引起的；(3)与脑干其他部位的CO2敏感化学受体相比，NTS中的中枢化学受体在呼吸适应低氧中发挥着独特的作用。我们将通过以下方式验证这些假说：(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mRNA和蛋白水平的影响；(3)体外研究大鼠延髓切片中的中枢化学受体；以及(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递的一般原理，以及最终呼吸机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.