PLASTICITY IN RESPIRATORY MOTOR CONTROL

描述(改编自申请人的摘要)：本提案假设 间歇性低氧诱导独特的5-羟色胺依赖机制 中枢神经控制呼吸的可塑性。这些形式的 可塑性是独一无二的，因为它们是由间歇性低氧引起的，但不是 在相同的持续缺氧时间内。私家侦探提议调查 诱发两种特殊形式可塑性的细胞和分子机制 间歇性缺氧：1)膈神经运动的长时程易化(LTF) 三次短暂低氧后的输出量；和2)增强大鼠的LTF 先前暴露于慢性间歇性低氧。一个工作模式已经被 发展表明，尽管这些形式的可塑性在时间上有所不同 在它们对基因转录的要求中，它们是由 同样的事件。PI假定共同的启动事件重复发生 5-羟色胺能5-HT2a受体在膈运动神经元上的激活 增加细胞内的激酶活性。因此，谷氨酸能受体 与下行呼吸驱动和基因转录因子相关 环磷酸腺苷反应元件结合蛋白(CREB)被磷酸化，导致 分别为LTF和增强型LTF。提出了五个具体的测试目标 假设：1)膈LTF需要脊髓5-HT2A型受体的激活； 2)慢性间歇性低氧(但不是持续性低氧)增强LTF；3)增强 LTF与CREB调控的基因转录有关；4)5-羟色胺能 5)5-HT7受体的诱导是增强LTF所必需的；5)脑源性 神经营养因子(BDNF)的诱导是增强LTF所必需的。一个 将使用多学科方法来测试该模型的关键要素。

DESCRIPTION (Adapted from the applicant's abstract):This proposal hypothesizes that intermittent hypoxia elicits unique, serotonin-dependent mechanisms of plasticity in the central neural control of breathing. These forms of plasticity are unique since they are elicited by intermittent hypoxia, but not by an equivalent duration of sustained hypoxia. The PI proposes to investigate cellular and molecular mechanisms of two specific forms of plasticity elicited by intermittent hypoxia: 1) long term facilitation (LTF) of phrenic motor output following three brief hypoxic episodes; and 2) enhanced LTF in rats previously exposed to chronic intermittent hypoxia. A working model has been developed suggesting that, although these forms of plasticity differ in time course and in their requirement for gene transcription, they are initiated by the same events. The PI postulates that the common initiating event is repeated activation of serotonergic 5-HT2A receptors on phrenic motoneurons that increases intracellular kinase activity. As a result, glutamatergic receptors associated with descending respiratory drive and the gene transcription factor cyclic AMP response element binding protein (CREB) are phosphorylated, leading to LTF and enhanced LTF, respectively. Five specific aims are proposed to test the hypotheses that: 1) phrenic LTF requires spinal 5-HT2A receptor activation; 2) chronic intermittent (but not sustained) hypoxia enhances LTF; 3) enhanced LTF is associated with gene transcription regulated by CREB; 4) serotonergic 5-HT7 receptor induction is necessary for enhanced LTF; and 5) brain derived neurotrophic factor (BDNF) induction is necessary for enhanced LTF. A multidisciplinary approach will be used to test key elements of the model.