Mechanisms underlying neuromodulation-induced breathing instability

描述（由申请人提供）：许多神经系统疾病与神经调节障碍有关。临床表型通常归因于神经调质丰度的病理变化。这项拟议中的研究测试了一个替代假设：某些疾病状态是由神经调节反应的变化引起的。我们将专门测试的假设，呼吸网络，这是正常的神经调节剂，如去甲肾上腺素（NE）稳定，成为NE中断后暴露于间歇性缺氧，这是典型的阻塞性睡眠呼吸暂停的条件。该研究计划提出，去甲肾上腺素能反应会因网络结构的细微变化而发生显著变化。基于我们的初步数据，我们假设，这些不规则性是由抑制性、甘氨酸能和GABA能突触机制引起的，这些机制导致神经元集合的解离。这种去同步的网络激活将导致呼吸节律生成网络中的低幅度爆发。低振幅爆发又导致呼吸运动活动的不完全和不稳定激活，从而导致膈核水平的频率不规则。我们将在前Botzinger复合体（一个重要的呼吸节律产生区域）以及自由呼吸动物的运动输出水平上描述这些效应。我们的研究可能具有重要的临床意义，因为它将提出新的治疗策略，而不仅仅是为了补充缺乏的神经调质。但是，相反，考虑疾病进展过程中调节反应的动态变化。

DESCRIPTION (provided by applicant): Many neurological disorders are associated with disturbances in neuromodulation. The clinical phenotype is generally attributed to pathological changes in the abundance of neuromodulators. The proposed research tests an alternative hypothesis: Certain disease states result from changes in the neuromodulatory response. We will specifically test the hypothesis that the respiratory network, which is normally stabilized by neuromodulators such as norepinephrine (NE), becomes disrupted by NE following exposure to intermittent hypoxia a condition which is typical for obstructive sleep apnea. The research plan proposes that the noradrenergic response is dramatically altered by subtle changes in the network configuration. Based on our preliminary data we hypothesize that the irregularities are caused by inhibitory, glycinergic and GABAergic synaptic mechanisms that lead to the dissociation neuronal ensembles. Such a de-synchronized network activation will result in low amplitude bursts in the respiratory rhythm generating network. Low amplitude bursts in turn lead to incomplete and erratic activation of respiratory motor activity thus resulting in frequency irregularities at the level of the phrenic nucleus. We will characterize these effects in the pre-Botzinger complex, an important respiratory rhythm generating area and also at the level of the motor output in freely breathing animals. Our study may have important clinical implications as it will suggest novel therapeutic strategies that do not simply aim at supplementing a deficient neuromodulator. But, instead consider dynamic changes in the modulatory response during the progression of a disease.