Interdependence among neuromodulators of ventilatory control

通气控制神经调节剂之间的相互依赖性

• 批准号: 8436946
• 负责人: HUBERT V FORSTER
• 金额: $ 36.77万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8436946
• 关键词: Adult; Agonist; Anesthesia procedures; Apnea; Attenuated; Blood gas; Brain Part; Breathing; Cell Nucleus; Cells; Cerebrospinal Fluid; Chemoreceptors; Complex; Depressed mood; Dialysis procedure; Equilibrium; Failure; Frequencies; Generations; Glycine; Goals; Goat; HTR2A gene; Homeostasis; Human; Implant; In Vitro; Lead; Measures; Microdialysis; Microtubules; Motor; Muscarinic Antagonists; Muscle; Neuromodulator; Neuromodulator Receptors; Neurons; Opiates; Opioid; Opioid Receptor; Overdose; Pain; Peripheral; Pharmaceutical Preparations; Pulmonary Ventilation; Pump; REM Sleep; Receptor Activation; Respiratory Diaphragm; Serotonin; Site; Sleep; Sleep Apnea Syndromes; Sleep Disorders; Substance P; Substance P Receptor; Synapses; Testing; Ventilatory Depression; Wakefulness; awake; cholinergic; in vivo; neurochemistry; neuroregulation; public health relevance; receptor; respiratory; response

DESCRIPTION (provided by applicant): Neurons within the respiratory network initiate and coordinate respiratory pump and airway muscle activation to adjust the level of pulmonary ventilation ( I) to maintain blood gas homeostasis. Chemoreceptors provide major excitatory drives to breathe (19, 22, 31, 65, 82), but it is the overall balance of excitatory and inhibitory neuromodulators that ultimately determine respiratory network excitability (15, 16, 28, 92). The contribution of endogenous neuromodulators to eupneic I while awake or asleep has not been determined, but in vitro evidence suggests "that a modulator's action is determined by the concurrent modulation and interaction with other neuromodulators" (16). The overall goal of our proposal is to test this hypothesis of neuromodulatory interdependence and test whether inadequate interdependence contributes to sleep disordered breathing (SDB) and/or opiate overdose-induced respiratory depression. In adult goats, microtubules will be chronically implanted for insertion into the preB¿tzinger Complex (preB¿tC) or hypoglossal motor nucleus (HMN) of probes for dialysis in mock cerebral spinal fluid (mCSF) of antagonists or agonist of excitatory or inhibitory neuromodulators during awake and asleep states. We will measure I, diaphragm and genioglossus (GG) muscle activity, and neurochemicals in effluent dialyzed mCSF. Specific Aim 1 determines whether there is interdependence among multiple excitatory neuromodulators within the preB¿tC. We hypothesize that: a) antagonists of muscarinic cholinergic, serotonin (5-HT2A), or neurokinin-1 receptors individually will have little or no effet on eupneic I and GG muscle activity but in combination will attenuate I and GG activity particularly during sleep and lead to SDB, b) antagonists of excitatory neuromodulatory inputs to the preB¿tC will produce compensatory changes in other neuromodulators at the site of antagonist dialysis. Specific Aim 2 determines whether there is interdependence within the preB¿tC between excitatory neuromodulators and the inhibitory neuromodulatory effects of ¿-opioid receptor activation. We hypothesize that: a) preB¿tC ¿-opioid receptor activation will depress I and GG activity while awake and to a greater extent during sleep, b) preB¿tC ¿-opioid receptor activation will not alter effluent neurochemical content and c) the ¿-opioid receptor activation-induced decreased I and GG activity will be attenuated by co-dialysis of the ¿-opioid agonist and agonists of 5-HT1A, or 5-HT4A receptors. Specific Aim 3 determines whether there is interdependence among neuromodulators of the HMN. We hypothesize that: a) unilateral dialysis of a ¿- opioid agonist within the HMN will decrease I and GG activity which during NREM and REM sleep will lead to SDB, b) there will be no compensatory changes in any of the measured local neurochemicals in the effluent mCSF during opioid dialysis, and c) the ¿-opioid receptor activation-induced decreased I and GG activity will be attenuated by co-dialysis of the ¿-opioid agonist and agonists of 5-HT1A, or 5-HT4A receptors.

描述（由申请人提供）：呼吸网络内的神经元启动并协调呼吸泵和气道肌肉激活，以调节肺通气水平（I），从而维持血气稳态。化学感受器提供呼吸的主要兴奋驱动（19，22，31，65，82），但它是兴奋性和抑制性神经调质的总体平衡，最终决定呼吸网络的兴奋性（15，16，28，92）。内源性神经调质在清醒或睡眠时对正常呼吸I的贡献尚未确定，但体外证据表明“调质的作用由同时调节和与其他神经调质的相互作用决定”（16）。我们的建议的总体目标是测试这一假设的神经调节的相互依赖性和测试是否相互依赖不足有助于睡眠呼吸障碍（SDB）和/或阿片类药物过量引起的呼吸抑制。在成年山羊中，将长期植入微管以插入探针的前B <$tzinger复合体（preB <$tC）或舌下神经运动核（HMN）中，用于在清醒和睡眠状态期间在兴奋性或抑制性神经调节剂的拮抗剂或激动剂的模拟脑脊液（mCSF）中透析。我们将测量I、膈肌和颏舌肌（GG）的肌肉活动，以及流出液透析mCSF中的神经化学物质。特异性目的1决定了前BtC内的多种兴奋性神经调质之间是否存在相互依赖性。我们假设：a）毒蕈碱胆碱能、5-羟色胺（5-HT 2A）或神经激肽-1受体的拮抗剂单独对正常呼吸的I和GG肌肉活性几乎没有影响或没有影响，但联合使用会减弱I和GG的活性，特别是在睡眠期间，并导致SDB。B）前B的兴奋性神经调节输入的拮抗剂将在拮抗剂透析部位产生其他神经调节剂的代偿性变化。具体目标2确定是否有相互依赖的前B <$tC之间的兴奋性神经调节剂和抑制性阿片受体激活的神经调节作用。我们假设：a）preB？TC？- 阿片受体激活将在清醒时抑制I和GG活性，并在睡眠期间更大程度地抑制I和GG活性，B）preB <$tC <$-阿片受体激活不会改变流出物神经化学物质含量，c）<$-阿片受体激活诱导的I和GG活性降低将通过<$-阿片激动剂和5-HT 1A或5-HT 4A受体激动剂的共透析而减弱。具体目标3确定HMN的神经调质之间是否存在相互依赖性。我们假设：a）单侧透析HMN内的<$阿片受体激动剂将降低I和GG活性，这在NREM和REM睡眠期间将导致SDB，B）在阿片透析期间流出液mCSF中任何测量的局部神经化学物质都不会发生代偿性变化，以及c）<$阿片受体激活诱导的I和GG活性降低将通过共同透析<$阿片受体而减弱。- 阿片激动剂和5-HT 1A或5-HT 4A受体的激动剂。