Mons Nicole, Beracochea Daniel
CNRS UMR 5287, Institut des Neurosciences cognitives et intégratives d'Aquitaine, Nouvelle Université de Bordeaux , Pessac , France.
Front Psychiatry. 2016 Oct 6;7:165. doi: 10.3389/fpsyt.2016.00165. eCollection 2016.
A prime mechanism that contributes to the development and maintenance of alcoholism is the dysregulation of the hypothalamic-pituitary-adrenal axis activity and the release of glucocorticoids (cortisol in humans and primates, corticosterone in rodents) from the adrenal glands. In the brain, sustained, local elevation of glucocorticoid concentration even long after cessation of chronic alcohol consumption compromises functional integrity of a circuit, including the prefrontal cortex (PFC), the hippocampus (HPC), and the amygdala (AMG). These structures are implicated in learning and memory processes as well as in orchestrating neuroadaptive responses to stress and anxiety responses. Thus, potentiation of anxiety-related neuroadaptation by alcohol is characterized by an abnormally AMG hyperactivity coupled with a hypofunction of the PFC and the HPC. This review describes research on molecular and epigenetic mechanisms by which alcohol causes distinct region-specific adaptive changes in gene expression patterns and ultimately leads to a variety of cognitive and behavioral impairments on prefrontal- and hippocampal-based tasks. Alcohol-induced neuroadaptations involve the dysregulation of numerous signaling cascades, leading to long-term changes in transcriptional profiles of genes, through the actions of transcription factors such as [cAMP response element-binding protein (CREB)] and chromatin remodeling due to posttranslational modifications of histone proteins. We describe the role of prefrontal-HPC-AMG circuit in mediating the effects of acute and chronic alcohol on learning and memory, and region-specific molecular and epigenetic mechanisms involved in this process. This review first discusses the importance of brain region-specific dysregulation of glucocorticoid concentration in the development of alcohol dependence and describes how persistently increased glucocorticoid levels in PFC may be involved in mediating working memory impairments and neuroadaptive changes during withdrawal from chronic alcohol intake. It then highlights the role of cAMP-PKA-CREB signaling cascade and histone acetylation within the PFC and limbic structures in alcohol-induced anxiety and behavioral impairments, and how an understanding of functional alterations of these pathways might lead to better treatments for neuropsychiatric disorders.
导致酒精中毒发生和维持的一个主要机制是下丘脑 - 垂体 - 肾上腺轴活动失调以及肾上腺释放糖皮质激素（人类和灵长类动物中的皮质醇，啮齿动物中的皮质酮）。在大脑中，即使在长期饮酒停止后很长时间，糖皮质激素浓度的持续局部升高也会损害包括前额叶皮质（PFC）、海马体（HPC）和杏仁核（AMG）在内的神经回路的功能完整性。这些结构与学习和记忆过程以及协调对压力和焦虑反应的神经适应性反应有关。因此，酒精对焦虑相关神经适应性的增强表现为杏仁核异常过度活跃，同时前额叶皮质和海马体功能减退。本综述描述了关于分子和表观遗传机制的研究，酒精通过这些机制在基因表达模式中引起不同区域特异性的适应性变化，并最终导致基于前额叶和海马体的任务出现各种认知和行为障碍。酒精诱导的神经适应性涉及众多信号级联的失调，通过诸如[cAMP反应元件结合蛋白（CREB）]等转录因子的作用以及组蛋白蛋白质翻译后修饰导致的染色质重塑作用，导致基因转录谱的长期变化。我们描述了前额叶 - 海马体 - 杏仁核神经回路在介导急性和慢性酒精对学习和记忆的影响中的作用，以及参与这一过程的区域特异性分子和表观遗传机制。本综述首先讨论了糖皮质激素浓度在大脑区域特异性失调在酒精依赖发展中的重要性，并描述了前额叶皮质中持续升高的糖皮质激素水平如何可能参与介导慢性酒精摄入戒断期间的工作记忆障碍和神经适应性变化。然后，它强调了cAMP - PKA - CREB信号级联以及前额叶皮质和边缘结构内的组蛋白乙酰化在酒精诱导的焦虑和行为障碍中的作用，以及对这些途径功能改变的理解如何可能导致对神经精神疾病的更好治疗。
