Mechanisms of respiratory long-term facilitation

描述（由申请人提供）：急性间歇性缺氧在呼吸的神经控制、呼吸长期促进（LTF）中引发独特形式的可塑性。由此产生的可塑性是独特的，因为持续缺氧的相同累积持续时间不会引发相同的潜在机制。我们建议研究体内膈神经活动（pLTF）中产生LTF的细胞机制，并确定区分持续性和间歇性缺氧的一些机制。我们的工作模型是间歇性（但不是持续性）缺氧会增加膈运动神经元内脑源性神经营养因子（BDNF）的合成。我们认为 BDNF 激活膈运动神经元内的细胞外调节激酶 (ERK 1/2)，即 MAP 激酶家族的成员。 ERK 1/2 随后增强脑干前运动神经元和膈神经元之间的突触，从而建立 pLTF。我们认为持续缺氧的独特之处在于它还会激活蛋白磷酸酶，从而阻止导致 BDNF 合成增加的机制。因此，pLTF 是在间歇性但非持续性缺氧后观察到的，主要是通过磷酸酶活性的差异调节。我们将追求四个具体目标来检验以下假设：1）间歇性（但非持续性）缺氧会增加呼吸运动神经元附近的 BDNF 合成； 2) 膈运动神经元内 BDNF 合成的增加对于 pLTF 是必要的； 3) 间歇性缺氧后 ERK 1/2 MAP 激酶激活增加对于 pLTF 是必要的； 4) 持续（但不是间歇性）缺氧会激活膈运动神经元内的蛋白磷酸酶，并停止导致 BDNF 合成、ERK 1/2 激活和 pLTF 增加的机制。该提案的优势在于采用多学科方法，包括应用 RNA 干扰等现代分子生物学技术，以了解体内呼吸神经可塑性。彻底了解导致呼吸可塑性的机制可能为治疗破坏性呼吸控制疾病（例如阻塞性睡眠呼吸暂停、脊髓损伤后呼吸功能不全、瑞特综合症和婴儿猝死综合症）的新治疗方法提供理论依据。

DESCRIPTION (provided by applicant): Acute intermittent hypoxia elicits a unique form of plasticity in the neural control of breathing, respiratory long-term facilitation (LTF). The resulting plasticity is unique in the sense that an equal cumulative duration of sustained hypoxia does not elicit the same underlying mechanisms. We propose to investigate cellular mechanisms giving rise to LTF in phrenic nerve activity (pLTF) in vivo, and to determine some of the mechanisms that distinguish sustained and intermittent hypoxia. Our working model is that intermittent (but not sustained) hypoxia increases synthesis of brain-derived neurotrophic factor (BDNF) within phrenic motoneurons. We propose that BDNF activates extracellular regulated kinases (ERK 1/2), members of the MAP kinase family, within phrenic motoneurons. ERK 1/2 subsequently strengthens the synapse between brainstem premotor neurons and phrenic neurons, thereby establishing pLTF. We suggest that sustained hypoxia is unique in that it also activates protein phosphatases, which halt the mechanisms leading to increased BDNF synthesis. Thus, pLTF is observed following intermittent, but not sustained, hypoxia, largely through the differential regulation of phosphatase activity. We will pursue four specific aims to test the hypotheses that: 1) Intermittent (but not sustained) hypoxia increases BDNF synthesis near respiratory motoneurons; 2) Increased BDNF synthesis within phrenic motoneurons is necessary for pLTF; 3) Increased ERK 1/2 MAP kinase activation following intermittent hypoxia is necessary for pLTF; and 4) Sustained (but not intermittent) hypoxia activates protein phosphatases within phrenic motoneurons and halts the mechanisms leading to increased BDNF synthesis, ERK 1/2 activation and pLTF. A strength of this proposal is the multidisciplinary approach, including the application of modern molecular biological techniques such as RNA interference, towards an understanding of respiratory neuroplasticity in vivo. A thorough understanding of mechanisms leading to respiratory plasticity may provide the rationale for new therapeutic approaches to the treatment of devastating respiratory control disorders such as obstructive sleep apnea, respiratory insufficiency following spinal cord injury, Rhett Syndrome and Sudden Infant Death Syndrome.