EtOH Modulation of Synaptic Plasticity in Nucleus Accumbens

描述（由申请人提供）：本项目的目标是进一步了解酒精对延髓核（NAcc）中棘神经元突触可塑性影响的分子和细胞机制。我们相信，尽管过去的努力，这样的理解仍然难以捉摸，因为经典的布利斯和Lomo模型的长时程增强（LTP）通常用于研究神经元的可塑性，提出了一个主要的限制方面的NAcc。具体而言，该模型基于高频刺激（HFS; 100 Hz）范例，其不反映NAcc体内生理条件。事实上，在自由移动的动物中，NAcc中等多刺神经元（MSN）在1和10 Hz之间放电。此外，MSN接收来自杏仁核和皮质锥体神经元的输入，这些神经元以类似的低频发射。更好的方法是使用更生理相关的刺激范例。因此，我们建议使用一种新的可塑性模型--尖峰时间依赖可塑性来重新研究酒精对突触可塑性的调节 我们的初步研究结果表明，在相似的实验条件下，伏隔核既发生长时程增强（tLTP），又发生抑制（tLTD）。这两种形式的突触可塑性依赖于不同的通路：tLTP依赖于NMDA受体，而tLTD需要动作电位。我们的数据也支持NMDA受体和动作电位募集不同的细胞内钙信号的观点 途径。引人注目的是，我们发现乙醇显著抑制tLTP，但仅微弱地增强tLTD。因此，我们的总体假设是，乙醇对延髓核可塑性的特定影响是由作为tLTP和tLTD基础的钙信号通路对该药物的不同敏感性引起的。该项目将揭示伏隔核突触可塑性的新的细胞和分子机制，以及它们如何在接近体内发现的条件下对乙醇暴露作出反应。

DESCRIPTION (provided by applicant): The goal of this project is to further our understanding of molecular and cellularmechanisms underlying alcohol's effects on synaptic plasticity in nucleus accumbens (NAcc) medium spiny neurons. We believe that, despite past efforts, such understanding remains elusive because the classical Bliss and Lomo model of long-term potentiation (LTP) typically used to study neuronal plasticity, presents one major limitation with regard to the NAcc. Specifically, this model is based on high-frequency stimulation (HFS; 100 Hz) paradigm that doesn't reflect NAcc in vivo physiological conditions. Indeed, NAcc medium spiny neurons (MSNs) fire between 1 and 10 Hz in freely moving animals. Moreover, MSNs receive inputs from amygdala and cortical pyramidal neurons that fire at similar low frequencies. A better approach would be to use a more physiologically relevant stimulation paradigm. Therefore, we propose to reexamine alcohol regulation of accumbens synaptic plasticity by using a new model of plasticity called Spike-Timing-Dependent Plasticity (STDP) that relies on pairing of action potentials (APs) and excitatory postsynaptic potentials (EPSP) at in vivo-like frequencies (~ 1Hz).Our preliminary data indicate that the Nucleus Accumbens undergoes both long term potentiation (tLTP) and depression (tLTD) in similar experimental conditions. These two forms of synaptic plasticity rely on separate pathways: tLTP is dependent on NMDA receptors, while tLTD requires Action Potentials. Our data also support the idea that NMDA receptors and action potentials recruit distinct intracellular calcium signaling pathways. Strikingly, we found that Ethanol dramatically inhibits tLTP, but only weakly potentiates tLTD. Our overarching hypothesis is therefore that the specific effects of Ethanol on Nucleus accumbens plasticity is caused by the differential sensitivity of calcium signaling pathways underlying tLTP and tLTD to this drug. This project should reveal new cellular and molecular mechanisms underlying synaptic plasticity in Accumbens and how they respond to ethanol exposure in conditions approaching those found in vivo.