Mechanisms underlying neuromodulation-induced breathing instability

描述(申请人提供)：许多神经紊乱与神经调节障碍有关。临床表型一般归因于丰富的神经调节剂的病理变化。这项拟议的研究测试了另一种假设：某些疾病状态是神经调节反应变化的结果。我们将专门测试这一假设，即呼吸网络通常由去甲肾上腺素(NE)等神经调节剂稳定，在间歇性低氧暴露后被NE扰乱，这是阻塞性睡眠呼吸暂停的典型情况。该研究计划提出，网络配置的细微变化会显著改变去甲肾上腺素的反应。根据我们的初步数据，我们假设这些异常是由抑制性、甘氨酸能和GABA能突触机制引起的，这些突触机制导致了神经元团的解离。这种不同步的网络激活将导致呼吸节律产生网络中的低幅度突发。低幅度的脉冲串反过来导致呼吸运动活动的不完全和不稳定的激活，从而导致膈核水平的频率不规律。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影响。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节剂。但是，取而代之的是考虑疾病发展过程中调节反应的动态变化。 公共卫生相关性：神经调节障碍是许多神经疾病背景下的一个主要健康问题。这项拟议的研究将检验这样一个假设，即对神经调节的反应不是固定的，而是可以在疾病的发展过程中改变的。我们将专门研究神经调节在呼吸网络中的作用，因为该网络中的调节障碍与许多呼吸障碍和婴儿猝死综合征有关。

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. PUBLIC HEALTH RELEVANCE: Disturbed neuromodulation is a major health problem in the context of numerous neurological disorders. The proposed research will test the hypothesis that the response to neuromodulation is not fixed, but can be altered during the progression of a disease. We will specifically study the role of neuromodulation in the respiratory network, because modulatory disturbances in this network have been associated with a number of breathing disorders and Sudden Infant Death Syndrome.