Retrotrapezoid nucleus and central chemoreception

描述（由申请人提供）：美国成年人群中有相当一部分（2- 4%，可能更多）患有睡眠呼吸障碍，其特征是呼吸频繁中断（呼吸暂停）和睡眠不佳。呼吸暂停，无论其原因，降低身体的氧气水平（缺氧）和增加二氧化碳（CO2，高碳酸血症）。这些血液气体的变化反过来会扰乱睡眠，影响记忆，并对健康产生不利影响，如血压和心率升高，慢性高血压和糖尿病恶化。这项研究的主要目的是了解维持呼吸自主性的机制，特别是在睡眠期间，以及这种自我平衡机制的失败如何反过来扰乱睡眠。无意识呼吸在很大程度上是由血液中的氧气和二氧化碳水平驱动的，这在很长一段时间内都是常识，但其机制仍然很不清楚。我们最近发现了一小群大脑神经元，称为后斜方核（RTN），编码二氧化碳的血液浓度。有多种理由假设这些神经元在睡眠期间维持呼吸中起着关键作用。一个特别有说服力的论点是，RTN神经元在人类遗传疾病的小鼠模型中未能发育，该疾病的特征是夜间无法呼吸和对二氧化碳不敏感（先天性中枢性通气不足综合征）。因此，我们设计了实验来测试RTN神经元在完全清醒的啮齿动物中的功能，以便结果尽可能与人类相关。我们还将探索RTN神经元如何对缺氧作出反应，试图解释由海拔引起的呼吸功能不全，我们认为这是由RTN神经元活动减少引起的。最后，将进行神经解剖学实验，以找出RTN神经元刺激呼吸的脑回路。本项目将采用先进的光遗传学和交叉遗传学方法以及设计成在突触间顺向或逆行方向传播的病毒载体进行。这项研究有望阐明在睡眠期间如何维持呼吸自主性，以及呼吸功能不全或呼吸衰竭如何反过来扰乱睡眠。如果RTN神经元像我们假设的那样重要，并且可以找到一种方法来激活它们，那么这项研究可能会产生有益于睡眠呼吸障碍的新的治疗干预措施。

DESCRIPTION (provided by applicant): A notable portion of the adult US population (2-4%, possibly more) suffers from sleep-disordered breathing, a condition characterized by frequent interruptions of breathing (apneas) and poor sleep. Apneas, whatever their cause, reduce the body's oxygen level (hypoxia) and increase carbon dioxide (CO2, hypercapnia). These changes in blood gases in turn disrupt sleep, affect memory and have adverse health consequences such as increased blood pressure and heart rate, chronic hypertension and exacerbation of diabetes. The main objective of the research is to understand the mechanisms that sustain breathing automaticity, especially during sleep and how failure of this homeostatic mechanism, in turn, disrupts sleep. That involuntary breathing is driven to a large extent by the level of oxygen and carbon dioxide in the blood has been common knowledge for a long time but the mechanisms are still far from clear. We have recently identified a small group of brain neurons, called retrotrapezoid nucleus (RTN), that encode the blood concentration of carbon dioxide. There are multiple reasons to hypothesize that these neurons play a critical role in sustaining breathing during sleep. One especially convincing argument is that RTN neurons fail to develop in a mouse model of a human genetic disease characterized both by the inability to breathe at night and by an insensitivity to carbon dioxide (congenital central hypoventilation syndrome). We have therefore designed experiments to test the function of RTN neurons in fully conscious rodents so that the results might be as relevant as possible to humans. We will also be exploring how RTN neurons respond to hypoxia in an attempt to explain the respiratory insufficiency caused by altitude, which we believe to be caused by a reduced activity of RTN neurons. Finally, neuroanatomical experiments will be conducted to find out the brain circuitry through which RTN neurons stimulate breathing. This project will be carried out using advanced optogenetic and intersectional genetic method and viral vectors designed to propagate in the anterograde or retrograde direction across synapses. This research is expected to clarify how breathing automaticity is maintained during sleep and how respiratory insufficiency or failure in turn disrupts sleep. Novel therapeutic interventions benefiting sleep disordered breathing could result from this research if RTN neurons prove to be as important as we postulate and a way can be found to activate them pharmacologically.