Effects of direct-current stimulation on synaptic plasticity

 描述（由申请人提供）：经颅直流电刺激（tDCS）是一种向头部施加弱电流的神经调节技术。tDCS被提议调节认知功能，几乎没有已知的副作用，并且正在研究用于治疗各种神经或精神疾病，如疼痛、抑郁和中风。对tDCS作用机制的传统假设是，带正电荷的电极增加皮层的“兴奋性”，并且这“增强”了归因于靶向的神经元的功能。 皮质区然而，这种简单化的兴奋性假设并不能解释研究的多样性和研究中报告的认知效应的特异性，并且在预测临床试验结果方面并不可靠。为了指导和加速新的治疗方案的发展，阐明直流电刺激（DCS）的细胞机制是重要的。我们认为DCS通过调节内源性突触可塑性机制发挥作用。对这一点的支持来自人类的药理学实验以及DCS可以增强大脑切片中突触可塑性的直接证据。这个建议的目标是确定DCS调节长期突触可塑性的细胞机制。我们最近已经证明了DCS对长时程增强（LTP）和长时程抑制（LTD）的强大作用，使用标准的可塑性诱导方案，如破伤风和θ爆发刺激。我们将在海马切片中探索这些诱导方案的成熟细胞机制，这些机制为刺激对不同细胞区室的影响提供独特的控制。在目的1中，我们探讨了DCS通过电压依赖性钙通道极化树突直接影响钙动力学来调节LTP/LTD的具体假设。在目标2中，我们测试的具体假设，DCS调制LTP极化细胞胞体，从而调制突触后放电率。将使用双光子钙成像、来自多个通路的刺激和记录、膜片钳记录和药物干预来测试从这些特定假设产生的一系列预测，以确定钙和钠通道以及神经调节剂如脑源性神经营养因子（BDNF）的参与。最后，所有的实验结果将在生物物理学现实的计算模型合成。我们的基本建议提供了一个机制的解释观察到的功能特异性，因为只有网络进行可塑性的DCS提升。重要的是，如果得到证实，我们的特定假设将DCS的机制与LTD/LTP的成熟机制联系起来，而LTD/LTP又与学习和疾病有关。这具有重要的临床意义。例如，它表明tDCS作为促进可塑性的行为干预的辅助手段将是最有效的， 提供了临床相关问题的答案，如tDCS的影响持续多久。该项目的结果将提供一个精确和定量的框架来理解DCS的细胞机制，这是为了推进tDCS的科学和治疗所必需的。

 DESCRIPTION (provided by applicant): Transcranial direct current stimulation (tDCS) is a neuromodulatory technique that applies weak electric currents to the head. tDCS is proposed to modulate cognitive function with few known side effects and is under investigation for the treatment of diverse neurological or psychiatric conditions such as pain, depression, and stroke. The conventional assumption for the mechanism of action of tDCS is that a positively charged electrode increases cortical 'excitability' and this 'enhances' function attributed to the targeted cortical area. However, this simplistic excitability assumption does not explain the diversity across studies and specificity within studies of reported cognitive effects, and has not been reliable at predicting outcomes of clinical trials. To guide and accelerate the development of new treatment protocols, it is important to clarify the cellular mechanisms of direct current stimulatin (DCS). We propose that DCS acts via a modulation of endogenous synaptic plasticity mechanisms. Support for this comes from pharmacological experiments in humans as well as direct evidence that DCS can boost synaptic plasticity in brain slices. The goal of this proposal is to determine the cellular mechanisms by which DCS modulates long-term synaptic plasticity. We have recently demonstrated robust effects of DCS on long-term potentiation (LTP) and long-term depression (LTD) using standard plasticity induction protocols such as tetanus and theta burst stimulation. We will probe well-established cellular mechanisms of these induction protocols in hippocampal slices, which provide unique control of the effects of stimulation on different cellular compartments. In Aim 1 we explore the specific hypothesis that DCS modulates LTP/LTD by polarizing dendrites directly affecting calcium dynamics through voltage dependent calcium channels. In Aim 2 we test the specific hypothesis that DCS modulates LTP by polarizing cell somata, thus modulating post-synaptic firing rate. A series of predictions that result from these specific hypotheses will be tested using two-photon calcium imaging, stimulation and recordings from multiple pathways, patch-clamp recordings, and pharmacological interventions to determine involvement of calcium and sodium channels as well as neuro-modulators such as brain-derived neurotropic factor (BDNF). Finally, all experimental results will be synthesized in biophysically realistic computational models. Our basic proposal provides a mechanistic explanation for observed functional specificity, because only networks undergoing plasticity are boosted by DCS. Importantly, if confirmed, our specific hypotheses link the mechanisms of DCS with well-established mechanisms of LTD/LTP, which are in turn linked to learning and disease. This has important clinical implications. For instance, it suggests that tDCS will be most effective as an adjunct to behavioral interventions that foster plasticity and it provides answers for clinically relevant questions such as how long the effects of tDCS persist. The results of this project will provide a precise and quantitative framework to understand the cellular mechanistic of DCS, which is required in order to advance the science and treatment of tDCS.