Mechanisms underlying respiratory motor plasticity

背景：呼吸控制系统不仅是反射性的--它很聪明，它会学习，而且实际上它有工作记忆。呼吸系统倾听并仔细记住以前的刺激是如何影响呼吸的。呼吸记忆是通过调节呼吸神经元之间的突触强度来建立的。反复的呼吸刺激(如呼吸暂停)会诱发一种记忆形式，这种记忆会增强呼吸运动神经元触发呼吸肌肉收缩的能力。这种类型的呼吸运动可塑性被称为长期促进(LTF)，它可能有助于加深呼吸和改善有效的肺通气量。 理论基础：虽然引发呼吸性LTF的生理因素是已知的(例如，呼吸暂停)，但导致LTF的实际大脑回路和递质通路在很大程度上仍不清楚。这笔赠款将：1)识别并绘制出诱发LTF的神经回路。2)确定这些回路如何与呼吸系统通信，从而引发呼吸的LTF。 研究方法和目标：我之前的NSERC Discovery Grant的工作发现了一种由反复呼吸暂停引起的新型呼吸性LTF(Tadjalli等人，《神经科学杂志》，30(50)：16886-95,2010年)。在麻醉和自主呼吸的大鼠中，我们发现反复的呼吸道阻塞--类似于阻塞性睡眠呼吸暂停的情况--导致上呼吸道肌肉(例如膝舌肌)呼吸活动的LTF。呼吸暂停诱导LTF激活的生理因素是反复呼吸道阻塞引起的肺传入反馈。重要的是，去甲肾上腺素能系统的激活是引发LTF所必需的。这个发射机系统如何启动LTF尚不清楚。这项拨款提案是我们先前工作的直接延伸。它的总体目标是确定和定义负责呼吸性LTF的去甲肾上腺素能机制和途径。

Context: The respiratory control system is not just reflexive - it is smart, it learns and in fact it has a working memory. The respiratory system listens to and carefully remembers how previous stimuli affect breathing. Respiratory memory is laid down by adjusting synaptic strength between respiratory neurons. Repeated respiratory stimuli (e.g. apnea) induce a form of memory that strengthens the ability of respiratory motoneurons to trigger contraction of breathing muscles. This type of respiratory motor plasticity is called long-term facilitation (LTF) and it may serve to deepen breathing and improve effective lung ventilation. Rationale: Although the physiological factors that trigger respiratory LTF are known (e.g., apneas), the actual brain circuitry and transmitter pathways that cause LTF remain largely unidentified. This grant will: 1) identify and map-out the neuro-circuits that induce LTF. 2) determine how these circuits communicate with the respiratory system to elicit LTF of breathing. Research Approach and Aims: Work from my previous NSERC Discovery Grant identified a novel type of respiratory LTF that is caused by repeated apneas (Tadjalli et al, J. Neuroscience, 30(50):16886-95, 2010). In anesthetized and spontaneously breathing rats, we found that repeated airway occlusions - similar to those in obstructive sleep apnea - caused LTF of respiratory activity in upper airway muscles, e.g., genioglossus. The physiological factor responsible for apnea-induced LTF activation was the lung afferent feedback caused by repeated airway obstructions. Importantly, activation of the noradrenergic system was required to elicit LTF. How this transmitter system initiates LTF is unknown. This grant proposal is a direct extension of our previous work. Its overall aim is to identify and define the noradrenergic mechanisms and pathways responsible for respiratory LTF.