Retrotrapezoid nucleus and central chemoreception

描述（由申请方提供）：中枢呼吸化学感受是CNS pCO 2激活呼吸的过程。这一过程对睡眠期间维持呼吸自主性至关重要。它的失调可能导致常见形式的睡眠呼吸障碍（例如阻塞性睡眠呼吸暂停，Cheyne-Stokes呼吸），并且是中枢性先天性低通气综合征（CCHS）的最可能原因，CCHS是一种罕见的遗传性疾病，由于同源框转录因子Phox 2b的突变。中枢呼吸化学感受的细胞和分子基础仍然知之甚少，虽然一些最重要的神经元被认为是居住在某处靠近延髓腹侧表面（VMS）。在过去的三年中，我们已经确定了一个区域内的VMS称为后斜方核（RTN）的一个集群的amatergic神经元，具有与中央化学感受器一致的属性。我们最近发现这些神经元表达Phox 2b，这是CCHS中突变的转录因子，这突出了这些神经元的潜在重要性。本项目旨在探索这些Phox 2b表达神经元在呼吸中的作用，特别是在呼吸化学感受中。研究围绕三个目标展开。在目的1中，我们寻求进一步的证据，这些RTN神经元调节呼吸节律和模式发生器。更具体地说，我们建议，以确定是否选择性病变的Phox 2b表达神经元产生预期的减少中枢化学反射，我们还试图确定哪些呼吸神经元的突触这些细胞的目标。在目标2中，我们询问这些表达Phox 2b的神经元是否在体外被酸化激活，这是这些细胞有资格成为中央化学感受器所需的特性。最后，在目标3中，我们建议研究一些大脑输入，调节活性和pH值的RTN的Phox 2b表达神经元的敏感性，重点是肺机械感受器和输入的神经元能系统。简而言之，这项研究有两个目标：第一，增加目前对负责中枢呼吸化学感受的细胞机制的理解，第二，帮助理解CCHS的原因。

DESCRIPTION (provided by applicant): Central respiratory chemoreception is the process by which CNS pCO2 activates respiration. This process is essential to maintain breathing automaticity during sleep. Its dysregulation probably contributes to common forms of sleep-disordered breathing (e.g. obstructive sleep apnea, Cheyne-Stokes breathing) and is the most probable cause of the central congenital hypoventilation syndrome (CCHS), a rare genetic disease due to a mutation of the homeobox transcription factor Phox2b. The cellular and molecular underpinning of central respiratory chemoreception is still poorly understood although some of the most important neurons are assumed to reside somewhere close to the ventral surface of the medulla oblongata (VMS). In the past three years, we have identified within a region of the VMS called retrotrapezoid nucleus (RTN) a cluster of glutamatergic neurons that have properties consistent with central chemoreceptors. The potential importance of these neurons was highlighted by our recent finding that they express Phox2b, the transcription factor that is mutated in CCHS. The present project is designed to explore the role of these Phox2b-expressing neurons in breathing in general and in respiratory chemoreception in particular. The research is organized around three Aims. In Aim 1 we seek further evidence that these RTN neurons regulate the respiratory rhythm and pattern generator. More specifically, we propose to determine whether selective lesions of the Phox2b-expressing neurons produce the expected reduction in central chemoreflexes and we also seek to identify which respiratory neurons are synaptic targets of these cells. In Aim 2 we ask whether these Phox2b- expressing neurons are activated by acidification in vitro, a property required for such cells to qualify as central chemoreceptors. Finally, in Aim 3 we propose to study some of the brain inputs that regulate the activity and pH-sensitivity of the Phox2b-expressing neurons of the RTN with a focus on lung mechanoreceptors and on inputs from the serotonergic system. In short, this research has two objectives: first to increase current understanding of the cellular mechanisms responsible for central respiratory chemoreception and second, to help understand the causes of CCHS.