Reflex Hypolossal Responses to Negative Pressure

阻塞性睡眠呼吸暂停（OSA）是一种以睡眠期间上呼吸道反复塌陷为特征的疾病。阻塞性睡眠呼吸暂停的最终原因被广泛认为是解剖学上的咽气道小。与正常人相比，较小的口咽通道具有增加的阻力，这导致吸气期间产生的负压增加。这些情况不会导致清醒期间的气道塌陷，因为气道扩张肌响应负压的反射激活（负压反射; NPR）保持气道通畅。然而，NPR在从清醒到睡眠的过渡期减少，并在REM睡眠期间逆转，从而导致肌肉激活和气道功能丧失。 易受影响的个体的崩溃。相反，NPR的这种状态依赖性下降对正常个体几乎没有影响，因为他们不依赖于它来保持他们的气道通畅。因此，OSA的合理治疗目标是确定一种减轻或防止睡眠期间NPR下降的方法。 不幸的是，人们对介导NPR的中央通路知之甚少，因此对这种反射的状态依赖机制也知之甚少。在动物模型中，传入信号由迷走神经（sin）的上级喉分支携带，其终止于孤束核（NTSis）的间质亚核。在动物和人类中，颏舌肌（gg）是舌头的主要肌肉，是由这种反射激活的肌肉之一。目前尚不清楚NTSIS中的神经元是否直接投射到支配gg的舌下神经运动神经元（ggHMNs）或信息通过前运动神经元传递。如果是后者，定位这些神经元是很重要的，因为它们可能是NPR睡眠状态调节的关键底物。本项目的具体目标旨在解决我们知识中的这些差距。我们打算首先发现大脑中传递负压的区域 上气道肌肉组织的传入信号;第二，可以介导NPR的状态依赖性下降的神经递质，最终的长期目标是发现一种全身药理学干预，以改善上气道通畅性的状态依赖性下降。

Obstructive sleep apnea (OSA) is a disorder characterized by recurrent collapse of the upper airway during sleep. The ultimate cause of OSA is widely believed to be an anatomically small pharyngeal airway. Smaller oropharyngeal passages have increased resistance compared to normals, which results in increased negative pressures generated during inspiration. These conditions do not result in airway collapse during waking because reflex activation of airway dilator muscles in response to negative pressure (the negative pressure reflex; NPR) maintains airway patency. However, the NPR is diminished at the transition from wake to sleep, and reversed during REM sleep, with consequential loss of muscle activation and airway collapse in susceptible individuals. In contrast, this state-dependence decline in NPR has little consequence to normal individuals because they are not dependent upon it to keep their airways patenL Thus a rational therapeutic goal for OSA is to identify a means to attenuate or prevent decreases in the NPR during sleep. Unfortunately little is known of the central pathways that mediate the NPR and consequently little of the mechanisms of state dependence of this reflex. In animal models the afferent signal is carried by the superior laryngeal branch of the vagus nerve (sin), which terminates in the interstitial subnucleus of the nucleus of the solitary tract (NTSis). In both animals and humans the genioglossus (gg), the primary protruder muscle of the tongue, is one of the muscles activated by this reflex. It is unknown whether neurons in the NTSis project directly to the hypoglossal motoneurons that innervate the gg (ggHMNs) or information is relayed via premotoneurons. If the latter, it is important to locate these neurons as they may be key substrates for sleep-state modulation of the NPR. The Specific Aims of this project are designed to address these gaps in our knowledge. We intend to discover first, the brain regions that convey negative pressure afferent signals to the upper airway musculature; second, the neurotransmitters that could mediate the statedependent decline in the NPR with an ultimate long term goal of discovering a systemic pharmacological intervention to ameliorate state-dependent decrements in upper airway patency.