VOLATILE ANESTHETIC ACTION IN A COMPUTATIONAL MODEL OF THALAMOCORTICAL NETWORKS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。对该分项目和该分项目首席调查员的主要支持可能是由其他来源提供的，包括国家卫生研究院的其他来源。列出的子项目总成本可能代表子项目使用的中心基础设施的估计数量，而不是NCRR拨款提供给子项目或子项目工作人员的直接资金。 背景 麻醉剂调节许多电压门控和配基门控离子通道，但似乎并不是所有麻醉剂的作用部位都有特定的通道。即使当一种特定麻醉剂的作用部位已知时，麻醉剂对离子通道的调节导致麻醉状态的过程仍未确定。这项研究的总体目标是使用大规模的计算模型来阐明模型神经元对麻醉剂的集成系统水平的反应。本申请中请求的计算资源产生的数据将用于支持向NIH申请额外资源以继续这项工作。为了认识到在受体水平和系统水平的麻醉作用之间建立计算桥梁的重要性，有必要认识到每个领域对麻醉剂的根本不同的反应。单一麻醉剂可以调节一个或多个电压门控和/或配基门控离子通道的活性。通常，给定通道的浓度效应曲线相对较浅，中点出现在麻醉浓度远高于临床使用的浓度处。这种离子通道行为的分级调节与麻醉剂在系统水平上诱导的突然变化形成对比。脑电和功能成像研究显示，对于临床上有用的麻醉剂浓度，大脑远不是静止的。在一组受试者中，随着麻醉剂浓度的增加，麻醉状态的开始是相对突然的，并且发生这种情况的浓度远低于假定离子通道的浓度效应曲线的中点。系统水平对麻醉药的反应是额外复杂的，因为它包含了在不同的麻醉剂浓度下出现的许多不同的特征。最低限度的症状包括健忘症、意识丧失、疼痛刺激的阻断和行动不便。重要的是，这些效应可以由针对完全不同受体的麻醉剂产生。所描述的定性不同的行为表明，需要将受体水平的麻醉作用与大规模系统水平的行为联系起来。尽管没有明确与全身麻醉有关的特定网络行为，但越来越多的人认识到，全身麻醉至少在某些方面与大脑产生连贯振荡的能力有关。这些振荡被认为起源于丘脑回路，这些振荡的同步性取决于丘脑和皮质之间建立的相互作用。这些对丘脑和皮质的影响可能是麻醉状态的重要组成部分，这一假设是合理的，因为这一区域已经被证明与睡眠和意识密切相关。此外，我们的初步结果证明了麻醉药在丘脑中继神经元和网状核神经元模型中同步和减慢振荡的能力。这些变化对丘脑其余部分的可能影响及其与皮质的相互作用是尚未检验的重要考虑因素。到目前为止，我们已经检查了各种麻醉剂对丘脑网状核、丘脑皮质神经元、海马神经元、快速放电中间神经元网络和海绵体的单细胞和小网络模型的影响。我们现在寻求扩大这一努力，以整合在离子通道类型和形态方面更现实的神经元。在包含4种不同类型神经元的小网络(每种神经元类型2个细胞)上的初步结果表明，丘脑神经元和皮质神经元之间的反馈对于了解神经元在麻醉作用下的行为是重要的。能够创建大型复杂网络(每种神经元类型的100个细胞)对于辨别麻醉剂在整个系统水平、行为和细胞水平上的差异至关重要。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Background Anesthetic agents modulate a number of voltage gated and ligand gated ion channels, but there does not seem to be specific channels that are the site of action for all anesthetics. Even when the site of action of a specific anesthetic is known, the process whereby anesthetic modulation of ion channels leads to the anesthetic state has yet to be established. The overall goal of this research is to use large scale computational models to elucidate the integrated systems level response of model neurons to anesthetics. The data generated from computing resources requested in this application will be used to support an application to NIH for additional resources to continue this work. To appreciate the importance of building a computational bridge between anesthetic action at the receptor level and the systems level, it is necessary to realize the fundamentally different responses to anesthetics in each domain. A single anesthetic can modulate the activity of one or more voltage gated and/or ligand gated ion channels. Typically, the concentration effect curves for a given channel are relatively shallow with midpoints occurring at anesthetic concentrations that are well above those used clinically. This graded modulation of ion channel behavior contrasts the abrupt changes that anesthetics induce at the systems level. For clinically useful anesthetic concentrations the brain is far from quiescent, as revealed by electroencephalographic and functional imaging studies. Over a population of subjects, the onset of the anesthetic state is relatively abrupt as anesthetic concentration is increased, and the concentration at which this occurs is considerably below the midpoint of the concentration effect curve for the putative ion channels. The systems level response to anesthetics is additionally complex because it encompasses a number of distinct features that emerge at distinct anesthetic concentrations. Minimally these include amnesia, loss of consciousness, blockade of painful stimuli, and immobility. Importantly, these effects can be produced by anesthetics that target entirely different sets of receptors. The qualitatively disparate behaviors described demonstrate the need for approaches linking anesthetic action at the receptor level with large scale systems level behavior. Although there is no specific network behavior that is definitively linked to general anesthesia, there is a growing appreciation that at least some aspects of general anesthesia are linked to the ability of the brain to generate coherent oscillations. These oscillations are thought to originate in the thalamic circuitry and the synchronization of these oscillations are dependent on the interaction established between the thalamus and the cortex. It is reasonable to hypothesize that these effects on the thalamus and cortex could be an important component of the anesthetic state since this region has already been shown to be closely associated with both sleep and consciousness. Furthermore, our preliminary results have demonstrated the ability of anesthetics to both synchronize and slow oscillations in a model of the thalamic relay and reticular nucleus neurons. The possible impact of these alterations on the rest of the thalamus and its interaction with the cortex are important considerations which have yet to be examined. To date, we have examined the effects of a variety of anesthetics on single cell and small network models of the reticular nucleus of the thalamus, thalamocortical neurons, hippocampal neurons, a fast spiking interneuron network, and Aplysia. We now seek to expand this effort to incorporate neurons which are more realistic with respect to types of ion channels and morphology. Preliminary results in small networks (2 cells of each neuron type) incorporating 4 different types of neurons, pyramidal neurons (PY) and interneurons (IN) in the cortex and thalamic relay (TC) and reticular nucleus (RE) neurons in the thalamus, have shown that the feedback between the thalamic neurons and the cortical neurons are important in understanding the behavior of the neurons under anesthetic effects. Being able to create large complex networks (100 cells of each neuron type) is essential to discerning the differences in anesthetics on the overall system level behavior and at the cellular level.