毒品成瘾的分子基础

毒品成瘾的形成是一个循序渐进的、综合性的过程。在此过程,机体在分子、细胞学水平发生了代偿性变化,进而导致成瘾的一系列症状。中脑边缘系统多巴胺系统的激活是多种毒品成瘾的共同神经生物学特点。长期地施用毒品,可以导致机体的功能系统发生变化,即耐受性、依赖性、敏化性。上述不同的功能变化特点有其相应的分子细胞学基础。     

伏核内的△FosB——吗啡成瘾中的重要调节因子

众所周知，药物滥用能引起神经细胞特定的适应性反应，从而导致成瘾。基因表达的调节可能是导致这种适应性反应的重要机制之一。△FosB是一种转录因子，表达后能在脑内维持数周甚至几个月。长期药物滥用能引起伏核内△FosB表达稳定地增加，表明△FosB的表达可能是药物成瘾的分子转换机制，成为药物成瘾研究中最受重视的转录因子。     

植物基因表达中的倍性效应：研究进展、问题与展望

多（单）倍体在遗传与进化研究中极为活跃并取得了巨大成就,激发了科学家对基因表达倍性效应探讨的兴趣．本文综述了多（单）倍体特别是同源倍性系列基因表达及其调控机理研究进展;分析了前人研究,特别是研究材料的局限;提出利用双胚苗创造同源倍性系列,利用高通量测序分析转录组表达与倍性调控机制的设想．     

Hi-C技术在三维基因组学和疾病致病机理研究中的应用

三维基因组学在基因组序列、基因结构及其调控元件的基础上对细胞核内的染色质的三维空间结构进行研究。染色体的空间交互作用是基因表达调控的重要因素,随着高通量染色体构象捕获(high-throughput chromosome conformation capture,Hi-C)技术及其衍生技术的出现和快速发展,借助Hi-C技术获取高通量三维基因组学数据,对基因表达调控等生物过程进行研究,已成为揭示细胞深层机制、阐明疾病致病机理的重要手段。本文在介绍三维基因组的发展历程和研究技术的基础上,重点总结了近年来Hi-C技术在多种疾病研究、特别是致病机理阐释方面的应用和成果,为深入理解三维基因组学在构建全局基因调控图谱、挖掘疾病致病机理方面的应用提供参考和借鉴。     

基于遗传数据的机器学习在阿尔茨海默病研究中的应用

阿尔茨海默病(Alzheimer disease,AD)是一种神经退行性疾病,其发病与遗传和环境因素相关,约70%由遗传因素引起,但其发病机制尚不清楚.随着高通量测序技术的出现,利用机器学习(machine learning,ML)技术处理遗传数据的研究成为了当前热点.本文综述ML在AD中的应用研究,主要包括:遗传数据与影像、临床、组学等多模数据结合的AD诊断和预后;对单核苷酸多态性(single nucleotide polymorphism,SNP)数据挖掘发现与AD风险相关基因的遗传变异分析;与AD发病机制密切相关的基因表达谱分析.最后,应用高质量、综合性、大样本量数据,建立多层次ML模型探究AD的发病机制将是未来研究的重点.     

毒品成瘾与自噬的研究进展

毒品成瘾是一种严重危害人类健康和社会安定的疾病,但目前还缺乏有效的治疗药物和治疗手段。大量研究表明,自噬与毒品成瘾有着密不可分的联系,在毒品成瘾中有着重要的作用。因此,了解毒品成瘾过程中自噬及其相关分子的变化规律,将有助于人们对毒品成瘾机制及戒断的理解。现将以自噬为关注点,重点介绍自噬与毒品成瘾之间的相互关系,对该领域的研究进展进行综述。     

基因表达系列性分析技术及其应用

基因表达系列性分析（SAGE）是一种高通量的基因表达模式的研究技术,能够对特定细胞或组织中的大量转录本同时进行定量分析。本综述了SAGE技术的基本原理和实验流程以及近年来SAGE方法上的改进,同时介绍了该技术的一些应用研究实例和Internet上可资利用的SAGE数据库资源。     

单细胞转录组测序在药物成瘾研究中的应用

药物成瘾是复杂的中枢神经系统疾病，相关基础与临床研究均证实药物成瘾的神经机制及神经环路在成瘾行为形成的不同阶段逐渐发生改变。利用全基因组关联研究、全基因组测序、全外显子测序或高通量转录组测序等技术的组学研究对包括药物成瘾在内的精神疾病遗传的脆弱性进行了深入研究。上述单核苷酸多态性检测技术或测序技术主要预测疾病的遗传风险位点。然而，许多中枢神经系统疾病的发生与环境因素密切相关，而且在疾病发展的不同阶段，相关基因的表达存在脑区特异性的细胞异质性信息。因此，传统研究对发病机制的解释存在一定的局限性。单细胞转录组测序技术是针对单个细胞进行转录水平的测定，规避了传统测序对细胞群体平均转录水平检测的缺点，可以定量描述细胞异质性。近年来，单细胞转录测序技术在神经精神科学研究中的应用逐渐受到关注，本文总结了该技术在神经科学研究中的重要应用，并以药物成瘾为例，重点阐述说明其在中枢神经系统疾病中的应用价值。     

甲基苯丙胺成瘾的表观遗传学机制

苯丙胺类兴奋剂是全世界第二大滥用程度的药物,甲基苯丙胺作为苯胺类兴奋剂中的主要药物,是中国滥用的“头号毒品”。而现有的研究对甲基苯丙胺成瘾机制尚不清晰,且临床上对药物成瘾的治疗依然存在无药可医的局面。因此,发现新的成瘾机制和治疗策略尤为迫切。甲基苯丙胺成瘾与额前叶皮质（mPFC）、中脑腹侧被盖区（VTA）和伏隔核（NAc）中的多巴胺（DA）、谷氨酸（Glu）、去甲肾上腺素（NE）和血清素（SNRIS）等神经递质的异常释放有关。研究表明,这些神经递质受到表观遗传机制中组蛋白乙酰化、甲基化、泛素化和非编码RNA等调节,某些基因的表达在甲基苯丙胺的诱导过程中增强或被抑制,导致甲基苯丙胺依赖性产生。本文将针对表观遗传学对甲基苯丙胺成瘾机制的影响进行着重论述,以期推进临床开发甲基苯丙胺戒断药物的研究。     

DNA甲基化异常与肿瘤耐药

肿瘤耐药是导致肿瘤化疗失败的主要原因, 其产生机制复杂多样, 是多种因素共同作用的结果。近年来, 表观遗传改变在肿瘤耐药中的作用日益受到关注。DNA甲基化是一种重要的表观遗传修饰, 在调节基因表达和维持基因组稳定性中扮演着重要角色。原发性或获得性耐药的肿瘤细胞大多伴随DNA异常甲基化, 越来越多的证据显示, DNA甲基化异常是肿瘤细胞耐药表型产生的重要机制。文章就DNA甲基化异常与肿瘤细胞耐药的关系及相关作用机制进行了综述。     

Epigenetic mechanisms in drug addiction

Changes in gene expression in brain reward regions are thought to contribute to the pathogenesis and persistence of drug addiction. Recent studies have begun to focus on the molecular mechanisms by which drugs of abuse and related environmental stimuli, such as drug-associated cues or stress, converge on the genome to alter specific gene programs. Increasing evidence suggests that these stable gene expression changes in neurons are mediated in part by epigenetic mechanisms that alter chromatin structure on specific gene promoters. This review discusses recent findings from behavioral, molecular and bioinformatic approaches being used to understand the complex epigenetic regulation of gene expression by drugs of abuse. This novel mechanistic insight might open new avenues for improved treatments of drug addiction.     

Gene expression profiling of the rewarding effect caused by methamphetamine in the mesolimbic dopamine system

Methamphetamine, a commonly used addictive drug, is a powerful addictive stimulant that dramatically affects the CNS. Repeated METH administration leads to a rewarding effect in a state of addiction that includes sensitization, dependence, and other phenomena. It is well known that susceptibility to the development of addiction is influenced by sources of reinforcement, variable neuroadaptive mechanisms, and neurochemical changes that together lead to altered homeostasis of the brain reward system. These behavioral abnormalities reflect neuroadaptive changes in signal transduction function and cellular gene expression produced by repeated drug exposure. To provide a better understanding of addiction and the mechanism of the rewarding effect, it is important to identify related genes. In the present study, we performed gene expression profiling using microarray analysis in a reward effect animal model. We also investigated gene expression in four important regions of the brain, the nucleus accumbens, striatum, hippocampus, and cingulated cortex, and analyzed the data by two clustering methods. Genes related to signaling pathways including G-protein-coupled receptor-related pathways predominated among the identified genes. The genes identified in our study may contribute to the development of a gene modeling network for methamphetamine addiction.     

miRNAs与药物成瘾

药物成瘾是一种慢性复发性脑病,主要表现为不可控制的对药物持续渴求和戒断后的高复吸。目前观点认为,成瘾是中脑腹侧被盖（ventral tegmental area,VTA）到伏隔核（nucleus accumbens,NAc）脑区多巴胺能奖赏通路中神经可塑性发生改变而导致的一种神经精神疾病。基因表达变化在神经可塑性中发挥着重要作用,但成瘾药物导致相关脑区结构和功能改变的机制还不甚清楚。微小RNAs（microRNAs,miRNAs）是一类非编码RNA,主要通过结合靶基因mRNA 3′非翻译区（3′untranslated region,3′UTR）,在转录后水平阻断其翻译成蛋白质或触发其不稳定而降解。越来越多的研究证实,miRNAs参与调节成瘾相关神经可塑性的变化。本文较系统地阐述miRNAs在药物成瘾中的作用研究进展,将为深入阐明药物成瘾的机制以及药物成瘾临床有效干预和诊治提供新思路。     

Glutamate and Brain Glutaminases in Drug Addiction

Glutamate is the principal excitatory neurotransmitter in the central nervous system and its actions are related to the behavioral effects of psychostimulant drugs. In the last two decades, basic neuroscience research and preclinical studies with animal models are suggesting a critical role for glutamate transmission in drug reward, reinforcement, and relapse. Although most of the interest has been centered in post-synaptic glutamate receptors, the presynaptic synthesis of glutamate through brain glutaminases may also contribute to imbalances in glutamate homeostasis, a key feature of the glutamatergic hypothesis of addiction. Glutaminases are the main glutamate-producing enzymes in brain and dysregulation of their function have been associated with neurodegenerative diseases and neurological disorders; however, the possible implication of these enzymes in drug addiction remains largely unknown. This mini-review focuses on brain glutaminase isozymes and their alterations by in vivo exposure to drugs of abuse, which are discussed in the context of the glutamate homeostasis theory of addiction. Recent findings from mouse models have shown that drugs induce changes in the expression profiles of key glutamatergic transmission genes, although the molecular mechanisms that regulate drug-induced neuronal sensitization and behavioral plasticity are not clear.     

GEDA: new knowledge base of gene expression in drug addiction

Abuse of drugs can elicit compulsive drug seeking behaviors upon repeated administration, and ultimately leads to the phenomenon of addiction. We developed a procedure for the standardization of microarray gene expression data of rat brain in drug addiction and stored them in a single integrated database system, focusing on more effective data processing and interpretation. Another characteristic of the present database is that it has a systematic flexibility for statistical analysis and linking with other databases. Basically, we adopt an intelligent SQL querying system, as the foundation of our DB, in order to set up an interactive module which can automatically read the raw gene expression data in the standardized format. We maximize the usability of this DB, helping users study significant gene expression and identify biological function of the genes through integrated up-to-date gene information such as GO annotation and metabolic pathway. For collecting the latest information of selected gene from the database, we also set up the local BLAST search engine and nonredundant sequence database updated by NCBI server on a daily basis. We find that the present database is a useful query interface and data-mining tool, specifically for finding out the genes related to drug addiction. We apply this system to the identification and characterization of methamphetamine-induced genes' behavior in rat brain.