The coupled vascular hypothesis for transcranial direct current stimulation (tDCS)

项目总结 经颅直流电刺激(Tdcs)被研究用于治疗广泛的脑部疾病和 改变健康个体的认知。Tdcs人体试验的规模和广度已经超过了 对细胞机制的理解。Tdcs的灵活性来自与培训相结合的使用。 任务，目标是增强在特定任务上的可塑性(学习)的“神经元能力”。Tdcs是这样的 在一项任务中或之前应用，以使神经能力发生剧烈或持续的变化。理性的人 TDC作为临床/神经科学工具的发展需要了解刺激的细胞靶点，并且 将它们的激活与tdcs期间和术后神经元容量的变化联系起来。神经元，以及一个较小的 已被作为tDCs细胞靶点进行了研究。血脑屏障内皮细胞 直到最近才被我们的团队解决。然而，众所周知，血脑屏障功能对其他形式的 电刺激，血脑屏障的变化会改变大脑功能。事实上，血脑屏障的刺激是一致的 TDCs的概念通常起到启动大脑的作用(例如，改变兴奋性或代谢能力)。 这一建议提出了一种新的假设和科学前提，即BBB调制如何增强 TDCS术中或术后神经容量。我们认为穿过大脑的传导血管网络分流 电流并在这个过程中在血脑屏障上产生比神经元周围更高的电场。我们相信 TDCs引起的血脑屏障极化改变了水和溶质在血脑屏障上的运输(在刺激期间)和 通过激活导致神经活性化学物质(包括一氧化氮)产生的基因的表达 血脑屏障的血管(刺激后)，所有这些都调节神经元和 神经元容量。 给出了一种自然的偏向，倾向于将任何tdcs动作解释为反映了神经元的直接激活(从而反映了血脑屏障 反应作为次要/副现象)我们需要最先进的建模和实验工具来量化 TDCs对血脑屏障的直接刺激。我们提供了大量来自硅胶、体外和体内的初步数据。 支持我们总体假设的活体研究。这一数据反映了我们团队成功的R21协作； 在展示了一种新的细胞靶点的可行性后，这一RO1建立了 TDCs直接激活血脑屏障。目标1：我们将开发一个多尺度(从头部解剖到微血管) 多物理(电场与电扩散过滤输运耦合)模型。目标2：我们将验证 使用特别设计的体外血脑屏障模型研究水和分子渗透性的急性变化(在分散控制系统期间) 一种系统，在没有神经元的情况下，建立了电流对血脑屏障的直接作用，并测试了 在没有神经元的情况下，由DC激活一氧化氮(NO)和其他神经活性基因(神经营养素)。 目的3：利用多光子脑成像技术测定大鼠血脑屏障通透性，分析大鼠血脑屏障通透性 TDCs诱导的持续性(分钟)血脑屏障通透性改变及其对NO的依赖。

PROJECT SUMMARY Transcranial Direct Current Stimulation (tDCS) is investigated to treat a broad range of brain disorders and to change cognition in healthy individuals. The scale and breadth of tDCS human trials has outpaced understanding of cellular mechanisms. The flexibility of tDCS derives from use in combination with a training task, with the goal to enhance “neuronal capacity” for plasticity (learning) on the specific task. tDCS is thus applied either during or before a task, to produce an acute or persistent change in neural capacity. The rational advancement of tDCS as a clinical/neuroscience tool requires knowing the cellular targets of stimulation, and linking their activation with changes in neuronal capacity during and after tDCS. Neurons, and to a lesser extent glia, have been studied as tDCS cellular targets. Endothelial cells of the blood-brain barrier (BBB) have been unaddressed until recently by our team. Yet BBB function is well known to be sensitive to other forms of electrical stimulation, and that changes in BBB will alter brain function. Indeed BBB stimulation is consistent with the concept of tDCS acting to generally prime the brain (e.g. changing excitability or metabolic capacity). This proposal addresses a novel hypothesis and scientific premise for how BBB modulation may enhance neural capacity during or after tDCS. We propose that the conductive vascular network across the brain shunts current and in the process generates electric fields across the BBB higher than around neurons. We believe that BBB polarization by tDCS alters the transport of water and solutes across the BBB (during stimulation) and activates the expression of genes leading to the production of neuroactive chemicals (including NO) by the blood vessels of the BBB (after stimulation), all of which modulate the microenvironment of neurons and neuronal capacity. Given a natural bias toward interpreting any tDCS actions as reflecting direct neuron activation (and thus BBB response as secondary/epiphenomena) we require state-of-the-art modeling and experimental tools to quantify the direct stimulation of BBB by tDCS. We present substantial preliminary data from in silico, in vitro, and in vivo studies that support our overall premise. This data reflects a successful R21 collaboration by our team; having shown feasibly of a novel cellular target, this RO1 establishes the mechanism and potential impact of direct BBB activation by tDCS. Aim 1: We will develop a multi-scale (from head anatomy to micro-vasculature) multi-physics (coupling electric fields with electro-diffusion filtration transport) model. Aim 2: We will validate acute (during DCS) changes in water and molecule permeability using a specially designed in vitro BBB model system where the absence of neurons establishes a direct action of current on the BBB, as well as test the activation of nitric oxide (NO) and other neuro-active genes (neurotrophins) by DCS in the absence of neurons. Aim 3: Using multi-photon brain imaging for determining BBB permeability in a rat model, we will analyze the persistent (minutes) BBB permeability changes induced by tDCS and their dependence on NO.