Effects of direct-current stimulation on synaptic plasticity

 描述(申请人提供)：经颅直流电刺激(Tdcs)是一种对头部施加微弱电流的神经调节技术。TDCs被提出用来调节认知功能，几乎没有已知的副作用，目前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，带正电的电极增加了大脑皮层的兴奋性，这增强了靶点的功能。 皮质区。然而，这种简单化的兴奋性假设不能解释不同研究之间的多样性和已报道的认知效应研究中的特异性，并且在预测临床试验结果方面也不可靠。为了指导和加速新的治疗方案的开发，阐明直流电刺激(DC)的细胞机制非常重要。我们认为，DCs通过调节内源性突触可塑性机制发挥作用。这一点得到了人类药理学实验的支持，也有直接证据表明，DC可以提高脑片的突触可塑性。这项建议的目的是确定DC调节长期突触可塑性的细胞机制。最近，我们使用标准的可塑性诱导方案，如破伤风和theta猝发刺激，展示了DCs对长时程增强(LTP)和长时程增强(LTD)的强大影响。我们将在海马片中探索这些诱导方案的成熟的细胞机制，这些机制提供了对刺激对不同细胞间隔的影响的独特控制。在目标1中，我们探索了DCs通过极化树突直接通过电压依赖性钙通道影响钙动力学来调节LTP/LTD的具体假设。在目标2中，我们验证了特定的假设，即DCs通过极化细胞胞体来调节LTP，从而调节突触后的放电频率。根据这些特定假设得出的一系列预测将使用双光子钙成像、多路径刺激和记录、膜片钳记录和药物干预来验证，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)的参与。最后，所有的实验结果将在生物物理上真实的计算模型中综合。我们的基本建议为观察到的功能特异性提供了一个机械解释，因为只有经历可塑性的网络才会被DC增强。重要的是，如果得到证实，我们的特定假设将DC的机制与LTD/LTP的成熟机制联系起来，后者反过来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工具将是最有效的，而且它 为临床相关问题提供答案，例如tDCs的影响持续多长时间。本课题的研究结果将为进一步研究和研究弥漫性弥漫性轴索硬化的细胞机制提供一个准确、定量的框架，为进一步研究和治疗弥漫性弥漫性轴索硬化症提供理论依据。

 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.