EtOH Modulation of Synaptic Plasticity in Nucleus Accumbens

描述（由申请人提供）：该项目的目标是进一步了解酒精对伏隔核（NAcc）中棘神经元突触可塑性影响的分子和细胞机制。我们认为，尽管过去的努力，这种理解仍然难以捉摸，因为经典的Bliss和Lomo长期增强模型（LTP）通常用于研究神经元可塑性，在NAcc方面存在一个主要限制。具体来说，该模型基于高频刺激（HFS; 100 Hz）模式，不反映NAcc在体内的生理状况。事实上，在自由运动的动物中，NAcc中棘神经元（msn）的放电频率在1到10赫兹之间。此外，msn接收来自杏仁核和皮质锥体神经元的输入，它们以相似的低频放电。更好的方法是使用与生理更相关的刺激模式。因此，我们建议使用一种新的可塑性模型，即spike - time - dependent plasticity，来重新研究酒精对伏隔核突触可塑性的调节

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.