PLASTICITY IN RESPIRATORY MOTOR CONTROL

描述（改编自申请人摘要）：本提案假设 间歇性缺氧激发了独特的，依赖于降钙素的机制， 中枢神经控制呼吸的可塑性。这些形式的 可塑性是独特的，因为它们是由间歇性缺氧引起的，但不是 持续缺氧的时间相当。PI建议调查 两种特定形式的可塑性的细胞和分子机制引起 间歇性低氧：1）膈运动的长时程易化（LTF） 三次短暂缺氧后的输出; 2）大鼠LTF增强 之前暴露于慢性间歇性缺氧一个工作模型已经被 发展表明，虽然这些形式的可塑性在时间上不同， 在基因转录的过程中，它们是由 同样的事件。PI假设共同起始事件重复 膈运动神经元上的肾上腺素能5-HT 2A受体的激活， 增加细胞内激酶活性。因此，多巴胺能受体 与下行呼吸驱动和基因转录因子相关 cAMP反应元件结合蛋白（CREB）被磷酸化，导致 LTF和增强型LTF。提出了五个具体目标，以测试 1）膈LTF需要脊髓5-HT_（2A）受体激活; 2)慢性间歇性（但非持续性）缺氧增强LTF; 3）增强 LTF与CREB调控的基因转录有关; 4） 5-HT 7受体诱导对于增强的LTF是必需的;和5）脑源性 神经营养因子（BDNF）诱导对于增强的LTF是必需的。一 将采用多学科方法来测试模型的关键要素。

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.