DEVELOPMENTAL REGULATION OF HYPERCAPNIC RESPONSES

早产儿呼吸暂停是一个主要的临床问题， 是很难理解的。 对于早产儿，尤其是呼吸暂停的早产儿， 对高碳酸血症的缓解反应受损：初步数据 揭示了高碳酸血症导致呼气持续时间延长， 与出生后早期缺氧暴露期间观察到的相似 生活 高碳酸血症引起的呼气延长被逆转， 在我们的新生动物模型中阻断GABAA受体，而缺氧 肾上腺素能受体可减弱α 2诱导的频率降低 应用于脑干的拮抗剂。 我们已经证明 新生儿球脊髓神经元受儿茶酚胺神经元支配 大鼠脑干和球脊髓吸气神经元亚群 神经元表达GABAA受体。 这一提议验证了 高碳酸血症调节呼吸时间和 生后早期吸气和呼气肌行为 发展我们进一步假设，CO2诱导了细胞的活化。 中枢抑制系统，如GABA能和α 2肾上腺素能 pathways途径is responsible负责for maturational成熟changes变化in these responses反应. 我们将在脑池内注射GABA AA和α 2肾上腺素能阻滞剂 为了表征神经抑制通路在CO2诱导的脑缺血中的作用， 成熟大鼠幼崽的呼气延长。 我们将利用新生儿 以表征CO2诱导的胸壁和喉的作用 肌肉反应在调节喉阻力的变化， 呼吸计时 微量注射GABAA和α 2肾上腺素能 脑干球脊髓神经元部位的阻滞剂 将使我们能够描述这些神经抑制通路的作用， 调节小猪的呼吸时间。 跨神经标记 技术将与免疫组织化学相结合， 成熟大鼠幼仔髓质中神经元的连通性。 我们 将描述GABAA和α 2的表达和激动剂亲和力 脑干吸气球脊髓神经元肾上腺素能受体 检验受体过度表达或激动剂增加 亲和力有助于延长呼气诱导的 早期的高碳酸血症 中央表征 导致受损的高碳酸血症的神经化学途径 阐明这些反应可能会促进我们对发病机制的理解 的新生儿呼吸暂停，并有助于新的药理学干预。

Apnea of prematurity is a major clinical problem whose pathophysiology is poorly understood. In preterm infants, especially those with apnea, ventilatory responses to hypercapnia are impaired: preliminary data reveal that hypercapnia causes prolongation of expiratory duration, similar to that observed during hypoxic exposure in early postnatal life. Hypercapnia induced prolongation of expiration is reversed by blockade of GABAA receptors in our neonatal animal models, while hypoxia induced frequency decrease is attenuated alpha2 by adrenergic receptor antagonists applied to the brainstem. We have demonstrated that catecholamine containing cells innervate bulbospinal neurons in newborn rat brainstem and that a subpopulation of bulbospinal inspiratory neurons express GABAA receptors. This proposal tests the hypothesis that hypercapnia modulates respiratory timing and the balance of inspiratory and expiratory muscle behavior during early postnatal development. We further hypothesize that C02 induced activation of central inhibitory systems such as GABAergic and alpha2 adrenergic pathways is responsible for maturational changes in these responses. We will administer intracisternal GABAA and alpha2 adrenergic blockers to characterize the role of neuroinhibitory pathways in C02 induced expiratory prolongation in maturing rat pups. We will utilize newborn piglets to characterize the role Of C02 induced chest wall and laryngeal muscle responses in modulating laryngeal resistance during changes in respiratory timing. Microinjection of GABAA and alpha2 adrenergic blockers at sites where brainstem bulbospinal neurons are identified will allow us to characterize the role of these neuroinhibitory pathways in mediating respiratory timing in piglets. Transneural labeling techniques will be combined with immunohistochemistry to characterize the connectivity of neurons in the medulla of maturing rat pups. We will describe expression and agonist affinity of GABAA and alpha2 adrenergic receptors on brainstem inspiratory bulbospinal neurons to test the hypothesis that receptor overexpression or increased agonist affinity contributes to the prolongation of expiration induced by hypercapnia during early life. Characterization of central neurochemical pathways that contribute to impaired hypercapnic ventilatory responses may advance our understanding of the pathogenesis of neonatal apnea and contribute to novel pharmacologic interventions.