Mechanisms of respiratory long-term facilitation

描述(申请人提供)：急性间歇性低氧引起呼吸神经控制的一种独特形式的可塑性，呼吸长期促进(LTF)。由此产生的可塑性是独特的，因为同等累积的持续缺氧时间不会引发相同的潜在机制。我们建议在体内研究在膈神经活动(PLTF)中产生LTF的细胞机制，并确定区分持续性和间歇性低氧的一些机制。我们的工作模型是间歇性(但不是持续的)低氧增加了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可以激活膈运动神经元中的细胞外调节蛋白激酶(ERK1/2)，ERK1/2是MAP激酶家族成员。ERK1/2随后加强了脑干运动前神经元和膈神经元之间的突触，从而建立了pLTF。我们认为，持续的低氧是独特的，因为它还激活了蛋白磷酸酶，从而阻止了导致BDNF合成增加的机制。因此，在间歇性低氧后观察到pLTF，但不是持续低氧，主要是通过磷酸酶活性的不同调节。我们将追求四个特定的目标来检验假设：1)间歇(但不是持续的)低氧增加呼吸运动神经元附近BDNF的合成；2)增加隔膜运动神经元内BDNF的合成是pLTF所必需的；3)间歇低氧后ERK 1/2 MAP激酶的激活是pLTF所必需的；以及4)持续(但不是间歇性的)低氧激活膈运动神经元内的蛋白磷酸酶并阻止导致BDNF合成、ERK 1/2激活和pLTF增加的机制。这一建议的一个优点是多学科方法，包括应用现代分子生物学技术，如RNA干扰，以了解体内呼吸神经可塑性。对导致呼吸可塑性的机制的透彻理解可能为治疗严重的呼吸控制疾病提供新的治疗方法的理论基础，如阻塞性睡眠呼吸暂停、脊髓损伤后的呼吸功能不全、瑞德综合征和婴儿猝死综合征。

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.