Neural Plasticity During Acclimatization to Hypoxia

适应缺氧过程中的神经可塑性

• 批准号: 7268951
• 负责人: Frank L. Powell
• 金额: $ 32.85万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7268951
• 关键词: AMPA Receptors; Acclimatization; Acute; Adopted; Agonist; Alkalosis; Binding; Brain; Brain Stem; Carotid Body; Cell Nucleus; Cell physiology; Cells; Chemoreceptors; Chromosome Pairing; Chronic; Chronic lung disease; Environmental air flow; Excitatory Amino Acid Antagonists; Funding; Gene Deletion; Gene Expression; Genes; Genetic Transcription; Glutamate Receptor; Glutamates; Hypocapnia; Hypoxemia; Hypoxia; Immunohistochemistry; In Vitro; Lead; Lesion; Life; Link; Literature; Lung diseases; Measures; Messenger RNA; Methods; Molecular; Molecular Biology; Motor output; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neuronal Plasticity; Nucleus solitarius; Patients; Physiological; Physiology; Play; Preparation; Principal Investigator; Program Research Project Grants; Property; Proteins; Rattus; Reactive Oxygen Species; Relative (related person); Research; Research Personnel; Respiratory Center; Role; Sensory; Signal Transduction; Site; Slice; Substance P; Synapses; System; Techniques; Testing; Tissues; Title; Transgenic Mice; Transgenic Organisms; Translations; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; amino 3 hydroxy 5 methylisoxazole 4 propionate; awake; base; design; mouse model; neural stimulation; novel; novel strategies; programs; receptor; receptor expression; receptor function; research study; respiratory; response

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.

描述（由申请人提供）： 项目名称：适应缺氧过程中的神经可塑性。慢性缺氧通过增加颈动脉体化学感受器的CV敏感性和CNS呼吸中枢对颈动脉体感觉输入的敏感性来增加缺氧通气反应（HVR）。 HVR 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。慢性缺氧也会增加常氧条件下的通气驱动，但其机制尚不清楚。然而，中枢化学感受器可能参与其中，因为适应环境后动脉 PCO2 被调节到较低水平。最近，我们发现慢性缺氧后 HVR 的增加和常氧通气驱动的增加可以通过向孤束核（NTS）微量注射谷氨酸受体拮抗剂来阻断。 NTS 对于呼吸控制非常重要，因为它是颈动脉体化学感受器的初级突触部位，也是许多 CO2 敏感的中枢化学感受器部位之一。我们假设（1）慢性缺氧会增加颈动脉体感觉输入的敏感性，并通过 NTS 中 NMDA 和非 NMDA 谷氨酸受体的变化增加常氧通气驱动，（2）这种神经可塑性是由 O2 敏感（例如 HIF-1a、活性 O2 物质）和 O2 独立机制（例如谷氨酸增加）引起的，以及 (3) 与脑干其他部位的 CO2 敏感化学感受器相比，NTS 中的中枢化学感受器在通气适应缺氧方面发挥着独特的作用。我们将通过以下方式测试这些假设：(1) 在清醒和麻醉的大鼠中显微注射 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 和蛋白质水平的影响，(3) 在体外研究大鼠髓质切片中的中枢化学感受器，以及 (4) 使用 CNS 条件性 HIF-1a 缺失的转基因小鼠模型。实验旨在阐明大脑慢性缺氧适应性变化信号传导的一般原理，以及最终通气控制的变化如何导致慢性肺病患者的低氧血症。