Ethanol Driven Neuroadaptation/Cholinergic Interneurons

乙醇驱动的神经适应/胆碱能中间神经元

• 批准号: 6449676
• 负责人: ADRIANA A ALCANTARA
• 金额: $ 17.09万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-27 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6449676
• 关键词: AMPA receptors; acetylcholine; alcoholism /alcohol abuse; amygdala; behavioral /social science research tag; behavioral genetics; cooperative study; dopamine receptor; drug withdrawal; ethanol; gene expression; genetically modified animals; glutamate receptor; interneurons; laboratory rat; nucleus accumbens; preference; regulatory gene; synapses; tegmentum; transfection

The shell nucleus accumbens (Nacc) comprises a critical component of the extended amygdala that receives a dopaminergic (DA) projection from the ventral tegmental area a glutamatergic (GLU) projection from the basolateral amygdala. Historically, the GABAergic projection neurons of the Nacc have been the focus of efforts to understand the alterations in neurochemical and synaptic structure and function that may underlie drug dependence and reinforcement phenomena. However, it is becoming increasingly apparent the cholinergic interneurons of the nucleus accumbens (CHI-NAccs) have experienced a relative dearth of analysis in drug abuse. This lack of analysis of these cells is especially disconcerting since it is apparent that these neurons are (1) critical neuronal integrators and modulators (2) possess key receptors and receptor-activated intracellular pathways important for plasticity and drug abuse, (3) express LTP and learning (4) exert powerful influences onto output projection neurons and (5) are compromised in clinical disorders such as schizophrenia, which can be induced by drug abuse. This accumulating evidence has led the P1 to hypothesize that these CHI-NAss may play a critical role in excessive ethanol consumption since these neurons share similar cellular, molecular and behavioral mechanisms with those involved in addiction for preliminary data examining the expression of immediate early genes (IEGs) in cholinergic interneurons following the self-administration of cocaine in rats). This project will test the hypothesis that ethanol induced neuroadaptation (i.e. changes in IEGs and receptors) and synaptic rewiring occurs on CHI-NAccs via "Hebbian- like" associative convergence of the activity of VTA and amygdaloid afferents. The following 4 specific aims are designed as a comprehensive test of this hypothesis. We seek to characterized ethanol induced IEG expression, dynamic trafficking of key DA/GLU synaptic components and synaptic rewiring within shell nucleus accumbens cholinergic neuronal networks in animal models of excessive ethanol consumption. We will also seek to determine the alterations of key DA/GLU components in relation to ethanol mice genetic models and ethanol exposure. The findings from this work should contribute to a better understanding of the neuronal mechanisms that cause or predict excessive ethanol consumption and toward the development of improved behavioral and pharmacological prevention treatments for alcoholism and alcohol abuse.

壳核伏隔（NACC）包括延长的杏仁核的关键成分，该成分从腹侧侧边缘区域接收多巴胺能（DA）投影，来自基底外侧杏仁核。 从历史上看，NACC的GABA能投射神经元一直是了解神经化学和突触结构和功能改变的努力，这可能是药物依赖性和增强现象的基础。 但是，越来越明显的是，伏隔核的胆碱能中间神经元（CHI-NACC）在药物滥用方面的分析相对缺乏。 对这些细胞的这种缺乏分析尤其令人不安，因为显然是（1）关键的神经元积分剂和调节剂（2）具有关键的受体和受体激活的细胞内途径对可塑性和药物滥用的重要性，（3）Express LTP和学习（4）对输出型神经元（5）的影响（5）构成临床的影响（5），构成了临床的影响（5），这是临床的综合症状。由药物滥用引起。 这种积累的证据使P1假设这些chi纳斯在过度乙醇消耗中可能起关键作用，因为这些神经元具有相似的细胞，分子和行为机制，而这些神经元与成瘾的人相似，从而在胆碱性肠媒介素中涉及早期基因（IEG）的直接早期基因表达（IEG）的表达。 该项目将检验乙醇诱导的神经适应（即IEG和受体的变化）和突触重新布线的假设发生在Chi-NACC上，这是通过“ Hebbian-like”相关性融合VTA和杏仁糖连接体的活动的关联融合。 以下4个特定目标被设计为对该假设的全面检验。 我们试图表征乙醇诱导的IEG表达，关键DA/GLU突触成分的动态运输以及在过度乙醇消耗的动物模型中，壳核振隔内壳核内壳核内的突触重新布线。 我们还将寻求确定与乙醇小鼠遗传模型和乙醇暴露有关的关键DA/GLU成分的改变。 这项工作的发现应有助于更好地理解导致或预测过度乙醇消耗的神经元机制，并为改善酒精中毒和酒精滥用的行为和药理预防治疗的改善发展。