Mechanisms and sites of ventilatory neurogenesis

描述(申请人提供)：在脑干的桥脑和延髓部分产生“自动”呼吸运动，不需要有意识的努力。真呼吸暂停是正常的呼吸。在Eupnea中，向身体提供足够的氧气，并清除二氧化碳以满足新陈代谢需求。如果真呼吸停止，就会出现缺氧。严重的缺氧会招致喘息，这是一种“自动复苏”的机制。我们提出了根本不同的产生呼吸暂停和喘息的机制。Eupnea反映的是桥延髓神经元回路的输出，而喘息则是由延髓起搏器放电产生的。在真呼吸暂停期间，这些起搏机制被抑制。研究将评估有关呼吸节律产生的神经生理机制的多种假说。将包括一项评估，即具有与产生喘息一致的放电特征的延髓神经元，将在突触传递被阻断后继续有节奏的爆发。因此，这些脉冲波被认为是“起搏器放电”。这项研究需要从真呼吸到喘息的可逆变化。神经元活动的细胞外和细胞内记录都将被连续获得。代理将被应用于阻断突触传递。“新生”和“幼年”大鼠的原位制备特别适合于这些研究。低氧诱导的喘息可以被可逆地诱导，在给予药物阻断突触传递后保持存活，脑干的最小运动使神经元活动的细胞外和细胞内记录成为可能。这些研究的结果将为正常呼吸产生的机制提供重要而独特的信息。这些信息可能会为人类的通风控制功能障碍提供洞察力，例如“睡眠呼吸暂停症”或“婴儿猝死综合症”。

DESCRIPTION (provided by applicant): "Automatic" breathing movements, which occur without conscious effort, are generated within the pontile and medullary portions of the brainstem. Eupnea is normal breathing. In eupnea, sufficient oxygen is supplied to the body and carbon dioxide is removed to meet the metabolic demands. If eupnea ceases, hypoxia will develop. Severe hypoxia recruits gasping, which is a mechanism for "autoresuscitation." We have proposed that fundamentally different mechanisms generate eupnea and gasping. Eupnea reflects the output of a pontomedullary neuronal circuit whereas gasping is generated by the discharge of medullary pacemakers. During eupnea, these pacemaker mechanisms are suppressed. Studies will evaluate multiple hypotheses concerning the neurophysiological mechanisms by which respiratory rhythms are generated. Included will be an evaluation that medullary neurons, with discharge characteristics consonant with generating the gasp, will continue rhythmic bursts following a blockade of synaptic transmission. Hence, these bursts are considered to represent a "pacemaker discharge." The studies require the reversible alteration from eupnea to gasping. Both extracellular and intracellular recordings of neuronal activities will be obtained continuously. Agents will be applied to block synaptic transmission. The in situ preparations of the "neonatal" and "juvenile" rats are uniquely suited for these studies. Hypoxia-induced gasping can be reversibly induced, viability is maintained following administration of pharmacological agents to block synaptic transmission, and the minimal movements of the brainstem make possible the extracellular and intracellular recordings of neuronal activities. Results of these studies will provide significant and unique information as to the mechanisms by which normal breathing is generated. Such information might provide insights into dysfunctions of the control of ventilation in humans, such as in "sleep apnea" or the "sudden infant death syndrome."