EtOH Modulation of Synaptic Plasticity in Nucleus Accumbens

伏核突触可塑性的乙醇调节

基本信息

批准号：
8297335
负责人：
Gilles E MARTIN
金额：
$ 28.96万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8297335
关键词：
Action Potentials Acute Alcohol dependence Alcohols Amygdaloid structure Animals Area Attention Behavior Brain Brain region Calcium Calcium Signaling Cells Data Drug effect disorder Ethanol Excitatory Postsynaptic Potentials Fire - disasters Foundations Frequencies Goals Heart Ion Channel Knockout Mice Light Long-Term Effects Long-Term Potentiation Mediating Mental Depression Modality Modeling Molecular Mus N-Methyl-D-Aspartate Receptors Neuronal Plasticity Neurons Nucleus Accumbens Pathway interactions Pharmaceutical Preparations Physiological Property Prosencephalon Recruitment Activity Regulation Reporting Research Role Shapes Signal Pathway Slice Synaptic plasticity Testing Time Vision Work alcohol effect alcohol exposure alcohol seeking behavior base hippocampal pyramidal neuron in vivo insight novel novel strategies patch clamp preference receptor research study stem tool

项目摘要

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.

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）中型多刺神经元突触可塑性影响的分子和细胞机制。我们相信，尽管过去做出了努力，但这种理解仍然难以捉摸，因为通常用于研究神经元可塑性的经典 Bliss 和 Lomo 长时程增强 (LTP) 模型对 NAcc 提出了一个主要限制。具体来说，该模型基于高频刺激（HFS；100 Hz）范例，不反映 NAcc 体内生理条件。事实上，在自由活动的动物中，NAcc 中型多棘神经元 (MSN) 的放电频率为 1 至 10 Hz。此外，MSN 接收来自杏仁核和皮质锥体神经元的输入，这些神经元以相似的低频放电。更好的方法是使用更生理相关的刺激范例。因此，我们建议通过使用一种称为尖峰时间依赖性可塑性的新可塑性模型来重新检查酒精对伏隔核突触可塑性的调节 (STDP) 依赖于体内频率 (~ 1Hz) 的动作电位 (AP) 和兴奋性突触后电位 (EPSP) 的配对。我们的初步数据表明伏核经历长时程增强 (tLTP) 和抑制 ( tLTD）在类似的实验条件下。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。我们的数据还支持 NMDA 受体和动作电位招募不同的细胞内钙信号传导的观点途径。引人注目的是，我们发现乙醇显着抑制 tLTP，但仅微弱地增强 tLTD。因此，我们的总体假设是，乙醇对伏核可塑性的具体影响是由 tLTP 和 tLTD 基础钙信号通路对该药物的不同敏感性引起的。该项目应揭示伏隔突触可塑性的新细胞和分子机制，以及它们在接近体内条件下对乙醇暴露的反应。