Neuroplasticity and the carotid body

描述（由申请人提供）：颈动脉体中的外周动脉化学感受器在应对氧张力变化时调节通气方面至关重要，它们在早期发育过程中提供必要的感觉输入，以稳定和维持生命中的呼吸。在出生后早期发育期间暴露于慢性缺氧和高氧（氧应激）显著抑制新生动物和早产儿对急性缺氧的通气反应。在暴露于慢性高氧的动物中，这种通气抑制可能是终身的，而在出生后早期发育期间暴露于慢性低氧的动物中，这种通气抑制只能部分逆转。早产儿特别容易受到高氧的影响，因为抗氧化防御能力降低了。此外，这些婴儿发生持续性呼吸暂停和心动过缓、睡眠时觉醒反应降低和猝死的风险很高，这些都是与化学受体功能紊乱有关的不良生理事件。腺苷调节化学受体活性，并已在其他模型系统中显示，在介导细胞保护免受氧化应激至关重要。本研究将验证出生后早期发育过程中的氧应激（缺氧和高氧）依赖于颈动脉体1型细胞和感觉神经元上功能性腺苷A1和A2a受体的存在，而氧应激的长期反应会扰乱兴奋性和抑制性腺苷机制的平衡，导致一级感觉神经元的兴奋性降低，从而减弱化学受体反应。我们将以3个具体目标来质疑这一假设，以确定发育对以下方面的影响：1)颈动脉体中腺苷系统的功能神经解剖学；2)缺氧诱导的腺苷和ATP释放（用新型生物传感器测量）与单个感觉神经活动之间的相关性；3)慢性缺氧和高氧暴露（体内）对颈动脉体超微结构和腺苷神经调节系统的影响；4)活性氧、核因子- kB和腺苷受体在颈动脉体和感觉神经元中介导高氧诱导的细胞毒性（体外）中的作用。

DESCRIPTION (provided by applicant): The peripheral arterial chemoreceptors in the carotid body are critical in regulating ventilation in response to changes in oxygen tension, and they provide essential sensory input during early development to stabilize and maintain breathing throughout life. Exposure to chronic hypoxia and hyperoxia (oxygen stress) during early postnatal development significantly depresses ventilatory responses to acute hypoxia in both newborn animals and human infants born prematurely. This ventilatory depression can be life-long in animals exposed to chronic hyperoxia and only partially reversible in animals exposed to chronic hypoxia during early postnatal development. Premature infants are particularly vulnerable to the effects of hyperoxia since antioxidant defenses are reduced. Furthermore, these infants are at high risk for persistent apnea and bradycardia, reduced arousal responses during sleep, and sudden death which are all adverse physiological events related to perturbations in chemoreceptor function. Adenosine modulates chemoreceptor activity and has been shown in other model systems to be critically important in mediating cytoprotection from oxidative stress. This proposal will test the overall hypothesis that oxygen stress (hypoxia and hyperoxia) during early postnatal development depends on the presence of functional adenosine A1 and A2a receptors on type 1 cells and sensory neurons in the carotid body, and the long term response of oxygen stress perturbs the balance of excitatory and inhibitory adenosine mechanisms resulting in decreased excitability of first order sensory neurons thereby blunting chemoreceptor responses. We will interrogate this hypothesis with 3 specific aims that will determine the effect of development on 1) the functional neuoranatomy of the adenosine system in the carotid body, 2) the correlation between hypoxic induced adenosine and ATP release (measured with novel biosensors) with single-unit sensory nerve activity, 3) the perturbations induced by chronic hypoxic and hyperoxic exposure (in vivo) on both the ultrastructure of carotid body and alterations in the adenosine neuromodulator system, 4) the role of reactive oxygen species, nuclear factor - kB, and adenosine receptors in mediating hyperoxic induced cytotoxicity (ex vivo) in the carotid body and sensory neurons.