Carotid afferent and parafacial neuronal excitatory effects on breathing

颈动脉传入和面旁神经元对呼吸的兴奋作用

• 批准号: 8259079
• 负责人: HUBERT V FORSTER
• 金额: --
• 依托单位: CLEMENT J. ZABLOCKI VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8259079
• 关键词: Affect; Agonist; American; Apnea; Attenuated; Bilateral; Brain; Brain Injuries; Brain Part; Brain Stem; Breathing; Carbon Dioxide; Caring; Carotid Body; Cell Nucleus; Cerebrospinal Fluid; Chemoreceptors; Complex; Denervation; Disease; Drowsiness; Dysphasia; Environmental air flow; Equilibrium; Exercise; Functional disorder; Glutamate Receptor; Goat; Hypercapnia; Hypercapnic respiratory failure; Hypertension; Hypoxia; Immunohistochemistry; Injection of therapeutic agent; Injury; Lesion; Mediating; Mediation; Mental disorders; Military Personnel; Muscle; Myocardial Infarction; Neuromodulator; Neurons; Obstructive Sleep Apnea; Pathway interactions; Population; Pulmonary Ventilation; Pump; Quality of life; Recovery; Research; Sleep; Sleep Apnea Syndromes; Stroke; System; Testing; Time; Up-Regulation; Validation; Veterans; awake; brain cell; combat; improved; insight; neuroregulation; receptor; respiratory; response

DESCRIPTION (provided by applicant): Neurons within the respiratory network regulate and coordinate respiratory pump and airway muscle activation. As such, the level of pulmonary ventilation is determined by the balance of excitatory and inhibitory inputs to these neurons. It has long been assumed that the primary excitatory drive to breathe is from intracranial CO2- H+ chemoreceptors. However, severe hypoventilation and reduced central CO2-H+ chemosensitivity after carotid body denervation (CBD) suggest a major excitatory drive is provided by carotid chemoreceptor afferents. It is unknown how, despite the presence of the intact and highly-sensitive intracranial chemoreceptors, CBD leads to hypoventilation, and furthermore what mechanisms of plasticity govern the normalization of breathing two or more weeks after CBD. One proposed pathway (Res. Plan, Figure 1, page 1) for these excitatory carotid chemoreceptor effects is through second order solitary tract (NTS) neuronal projections to the parafacial respiratory group/retrotrapezoid nucleus (pFRG/RTN). Phox2b-expressing (Phox2b+) pFRG/RTN neurons are hypothesized to: 1) receive and integrate multiple excitatory inputs, including those from the carotid bodies, and 2) provide the critical excitatory drive to pre-Bvtzinger complex (preBvtzC) respiratory rhythmogenic neurons during sleep; hence, dysfunction of Phox2b+ neurons underlies central and obstructive sleep apnea, and abnormal chemoreceptor and exerciseventilatory responses. An alternative hypothesis is that the carotid excitatory effect is through changes in neuromodulator inputs to brainstem respiratory neurons. We will test these and other hypotheses with the following Specific Aims: 1) Determine the effects on breathing in awake and asleep goats of destruction of Phox2b+ pFRG/RTN neurons. Hypothesis: Bilateral destruction of Phox2b+ pFRG/RTN neurons will cause: a) hypoventilation while awake which will be accentuated during NREM sleep by prolonged apneas, and b) attenuated ventilatory responses to hypercapnia, hypoxia, and exercise. Validation of these hypotheses will support the concept that the pFRG/RTN neurons provide critical excitatory input for breathing, particularly during sleep. 2) Determine whether CBD in goats induces central shifts in the balance between excitatory and inhibitory neuromodulation of the brainstem respiratory network. Hypothesis: After CBD when goats hypoventilate and CO2 sensitivity is reduced, the concentration of excitatory and inhibitory neuromodulators in effluent mock cerebrospinal fluid (mCSF) dialyzed through the preBvtzC will be decreased and increased respectively from baseline. Also after CBD, the ventilatory response to an injection of a glutamate receptor agonist into the preBvtzC will be reduced. Validation of these hypotheses will support the concept that tonic excitatory carotid activity affects neuromodulator-mediated excitability of respiratory rhythmogenic neurons. 3) Determine whether the observed time-dependent plasticity (recovery) after CBD is through upregulation of excitatory neuromodulatory mechanisms. Hypothesis: Two weeks after CBD in goats when they are no longer hypoventilating, the concentrations of excitatory and inhibitory neuromodulators in effluent mCSF dialyzed through the preBvtzC and the ventilatory response to a glutamate receptor agonist injection into the preBvtzC will be at or above normal. Furthermore, post-mortem immunohistochemistry will show increased percentage of neurons with receptors for excitatory neuromodulators in the preBvtzC. Validation of these hypotheses will be consistent with the concept that plasticity after CBD is due to upregulation of brainstem excitatory neuromodulatory mechanisms within the respiratory network. 4) Determine the effects on breathing in awake and sleeping goats of CBD after pFRG/RTN lesions. Hypothesis: When goats undergo CBD a month after lesioning the pFRG/RTN, the effects on breathing will be less than what normally occurs after CBD. Validation of this hypothesis will indicate the major pathway (Res. Plan, Figure 1, page 1) for central mediation of carotid afferent excitatory effect is through the pFRG/RTN. PUBLIC HEALTH RELEVANCE: In millions of Americans during sleep, the cycling mechanism of breathing does not function properly or airways collapse resulting in central and obstructive sleep apnea respectively. The repeated apneas result in low O2 and high CO2 in the body which in many leads to arterial hypertension, strokes, heart attacks, daytime somnolence, dysphasia, and psychiatric disorders. These breathing disorders and the resultant diseases are prominent in the VA population leading to poor quality of life of many veterans. In the proposed studies on goats, we will eliminate part of the brain's system that regulates breathing which we hypothesize will result in disordered breathing during sleep. However, we expect that by a month later, breathing will have returned toward normal. Post mortem studies on brain cells will provide insight into how the brain recovers from major injury. Thus the present study will be another step toward improving care and management of veterans with sleep disordered breathing and also for military personal that had brain injury during combat.

描述（由申请人提供）： 呼吸网络内的神经元调节和协调呼吸泵和气道肌肉激活。因此，肺通气的水平由对这些神经元的兴奋性和抑制性输入的平衡决定。长期以来，人们一直认为呼吸的主要兴奋性驱动来自颅内CO2- H+化学感受器。然而，颈动脉体去神经支配（CBD）后严重的通气不足和中枢CO2-H+化学敏感性降低表明颈动脉化学感受器传入提供了主要的兴奋性驱动。目前尚不清楚，尽管存在完整和高度敏感的颅内化学感受器，CBD如何导致通气不足，以及CBD后两周或两周以上的呼吸正常化的可塑性机制。这些兴奋性颈动脉化学感受器效应的一种拟议途径（Res. Plan，图1，第1页）是通过二级孤束（NTS）神经元投射到面旁呼吸组/后斜方核（pFRG/RTN）。假设Phox 2b表达（Phox 2b+）pFRG/RTN神经元：1）接收和整合多个兴奋性输入，包括来自颈动脉体的那些，和2）在睡眠期间向前Bvtzinger复合体（preBvtzC）呼吸节律性神经元提供关键的兴奋性驱动;因此，Phox 2b+神经元的功能障碍是中枢性和阻塞性睡眠呼吸暂停以及异常化学感受器和运动性震颤反应的基础。另一种假设是颈动脉兴奋效应是通过脑干呼吸神经元的神经调质输入的变化。我们将测试这些和其他假设，具体目的如下：1）确定Phox 2b + pFRG/RTN神经元的破坏对清醒和睡眠山羊呼吸的影响。假设：Phox 2 B + pFRG/RTN神经元的双侧破坏将导致：a）清醒时通气不足，这将在NREM睡眠期间通过延长的呼吸暂停而加重，和B）减弱对高碳酸血症、缺氧和运动的呼吸反应。这些假设的验证将支持pFRG/RTN神经元为呼吸提供关键兴奋性输入的概念，特别是在睡眠期间。2)确定山羊中的CBD是否诱导脑干呼吸网络的兴奋性和抑制性神经调节之间的平衡的中枢转移。假设：CBD后，当山羊低氧和CO2敏感性降低时，通过preBvtzC透析的流出液模拟脑脊液（mCSF）中兴奋性和抑制性神经调质的浓度将分别从基线降低和升高。同样在CBD后，对将谷氨酸受体激动剂注射到preBvtzC中的兴奋性反应将降低。这些假设的验证将支持这一概念，紧张性兴奋性颈动脉活动影响神经调节剂介导的兴奋性的呼吸节律神经元。3)确定CBD后观察到的时间依赖性可塑性（恢复）是否是通过兴奋性神经调节机制的上调。假设：山羊CBD后两周，当它们不再换气不足时，通过preBvtzC透析的流出物mCSF中的兴奋性和抑制性神经调质的浓度以及对注射到preBvtzC中的谷氨酸受体激动剂的兴奋性反应将处于或高于正常。此外，死后免疫组织化学将显示在preBvtzC中具有兴奋性神经调质受体的神经元的百分比增加。这些假设的验证将与CBD后的可塑性是由于呼吸网络内脑干兴奋性神经调节机制上调的概念一致。4)确定pFRG/RTN损伤后CBD对清醒和睡眠山羊呼吸的影响。假设：当山羊在损伤pFRG/RTN一个月后接受CBD时，对呼吸的影响将小于CBD后通常发生的影响。该假设的验证将表明颈动脉传入兴奋效应的中枢介导的主要途径（研究计划，图1，第1页）是通过pFRG/RTN。 公共卫生相关性： 在数以百万计的美国人睡眠期间，呼吸的循环机制不能正常工作或气道塌陷，分别导致中枢性和阻塞性睡眠呼吸暂停。反复呼吸暂停导致体内低O2和高CO2，这在许多情况下导致动脉高血压、中风、心脏病发作、日间嗜睡、言语困难和精神疾病。这些呼吸障碍和由此产生的疾病在VA人群中很突出，导致许多退伍军人的生活质量很差。在对山羊的拟议研究中，我们将消除部分大脑调节呼吸的系统，我们假设这将导致睡眠期间的呼吸紊乱。然而，我们预计到一个月后，呼吸将恢复正常。对脑细胞的死后研究将有助于了解大脑如何从重大损伤中恢复。因此，本研究将是朝着改善睡眠呼吸障碍退伍军人的护理和管理迈出的又一步，也为在战斗中脑损伤的军人。