Developmental disruption of brain tissue oxygen regulation and deficiency of learning after neonatal anesthesia exposure

项目总结 每年数以百万计的儿童接受全身麻醉，动物和人体研究 表明在幼年时接触麻醉剂会影响神经元的发育，导致 表现在儿童和青春期后期的行为和学习障碍。 然而，人们对可用于评估这些损伤的方法知之甚少。 我们的初步和公布的数据表明，区域静息状态的变化起作用 磁共振成像(Rsfmri)可以反映局部神经元网络的状态，并具有预测价值。 用于麻醉诱导的学习缺陷。区域性rsfMRI依赖于局部的调节 脑组织氧气。根据已公布的初步数据，我们假设脑组织 氧和局部rsfMRI调节由GABA能神经元(中间神经元)调节，但 新生儿麻醉扰乱了这种调节的发展，并产生了一种特定的 RsfMRI信号上的签名。在目标1中，我们将确定负责 正常和新生儿出生后局部rsfMRI与脑组织氧调节 麻醉暴露使用脑组织氧气，BOLD功能磁共振，电生理记录， 成人的局部药理学和光遗传学方法。在目标2中，我们将确定 新生儿对局部rsfMRI发育和脑组织氧波动的影响 麻醉暴露并找到rsfMRI可以预测未来行为的时间点 缺乏症。行为测试，局部rsfMRI，脑组织氧气和神经元活动将 记录新生儿麻醉暴露后的多个时间点和对照组 一群人。拟议工作的结果将提供一个清晰的图景，说明如何监管 脑组织氧气受到新生儿麻醉暴露的影响，并将提供强大的 静息功能磁共振对预测学习缺陷的翻译价值。

PROJECT SUMMARY Millions of children undergo general anesthesia each year, and animal and human studies have indicated that exposure to anesthesia at an early age can impact neuronal development, leading to behavioral and learning impairments that manifest later in childhood and adolescence. However, little is known about the methods which can be used to evaluate these impairments. Our preliminary and published data suggest that changes in regional resting state functional MRI (rsfMRI) can reflect the status of local neuronal networks and can have a predictive value for anesthesia-induced learning deficiency. Regional rsfMRI depends on the regulation of local brain tissue oxygen. Based on published and preliminary data we hypothesize that brain tissue oxygen and regional rsfMRI regulation are modulated by GABAergic neurons (interneurons) but neonatal anesthesia disrupts the development of this modulation and produces a specific signature on the rsfMRI signal. In Aim 1 we will determine the mechanisms responsible for regional rsfMRI and brain tissue oxygen regulation under normal conditions and after neonatal anesthesia exposure by using brain tissue oxygen, BOLD fMRI, electrophysiological recordings, local pharmacological and optogenetic approach in adults. In Aim 2 we will determine how the development of regional rsfMRI and brain tissue oxygen fluctuations is affected by neonatal anesthesia exposure and find time points when rsfMRI can predict the future behavioral deficiency. Behavioral tests, local rsfMRI, brain tissue oxygen, and neuronal activity will be recorded in across multiple time points after neonatal anesthesia exposure and in the control group. The results of the proposed work will provide a clear picture of how the regulation of brain tissue oxygen is affected by neonatal anesthesia exposure and will offer strong translational value of resting-state fMRI to predict learning deficiency.