EtOH Modulation of Synaptic Plasticity in Nucleus Accumbens

描述(申请人提供)：本项目的目标是加深我们对酒精对伏核(NAcc)中棘神经元突触可塑性影响的分子和细胞机制的理解。我们认为，尽管过去的努力，这样的理解仍然是难以捉摸的，因为经典的Bliss和Lomo模型的长时程增强(LTP)通常用于研究神经元的可塑性，提出了一个关于NAcc的主要限制。具体地说，这个模型基于高频刺激(HFS；100赫兹)范式，不能反映NAcc在体内的生理条件。事实上，在自由活动的动物中，NAcc中棘神经元(MSN)在1至10赫兹之间放电。此外，MSN接受杏仁核和皮质锥体神经元的输入，这两个神经元的放电频率相似。一个更好的方法是使用更具生理学相关性的刺激模式。因此，我们建议使用一种新的可塑性模型，即峰时依赖可塑性，重新研究酒精对伏隔神经突触可塑性的调节。 (STDP)依赖于动作电位(AP)和兴奋性突触后电位(EPSP)在类活体频率(~1 Hz)的配对。我们的初步数据表明，在类似的实验条件下，伏核既经历长时程增强(TLTP)，又经历长时程增强(TLTD)。这两种形式的突触可塑性依赖于不同的途径：TLTP依赖于NMDA受体，而TLTD需要动作电位。我们的数据也支持NMDA受体和动作电位招募不同的细胞内钙信号的想法 小路。值得注意的是，我们发现乙醇显著抑制TLTP，但仅微弱地增强TLTD。因此，我们的主要假设是，乙醇对伏隔核可塑性的特异性影响是由于TLTP和TLTD背后的钙信号通路对该药物的不同敏感性所致。该项目应该揭示伏隔神经突触可塑性的新的细胞和分子机制，以及它们在接近体内发现的条件下对酒精暴露的反应。

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.