DNA表观遗传修饰在药物成瘾记忆中的作用及机制

DNA表观遗传修饰主要包括DNA甲基转移酶介导的DNA甲基化和10-11易位酶介导的DNA去甲基化。这两种表观遗传修饰都可以响应环境刺激,调控基因表达,引起神经功能和行为的改变。已有大量研究表明DNA甲基化是调控成瘾记忆的重要机制之一,近年来也发现DNA去甲基化参与调控恐惧记忆及成瘾行为,提示DNA表观遗传修饰在成瘾记忆中的作用需要重新评估。本文将重点讨论DNA甲基化和去甲基化可能共同调控成瘾记忆,探讨其调控机制,并试图提出可深入的研究展望。     

药物成瘾诱导相关大脑核团功能和行为改变的DNA甲基化机制

药物成瘾会导致相关神经环路的结构和功能长期改变.大量新的研究证据表明,在DNA序列不变的情况下,药物成瘾可通过影响不同亚型DNA甲基转移酶(DNMTs)的表达,使脑内多个相关核团发生DNA甲基化以及基因表达的改变,进而导致神经元功能的可塑性变化.因此,DNA甲基化被视作导致成瘾行为长期存在的可能机制之一.结合近几年来的重要发现,本文将重点讨论相关脑区的DNA甲基化在成瘾行为发生发展过程中的作用,以及成瘾药物影响DNA甲基化水平的可能机制,并试图提出可深入的研究展望.     

非药物成瘾的遗传学和神经生物学机制研究述评

非药物成瘾又称“非物质相关性成瘾”或“行为成瘾”。特征性表现包括对成瘾对象的渴望、受损的冲动控制、对成瘾对象的耐受、撤退反应和高复发率等。目前发现的非药物成瘾类型包括病理性赌博、网络成瘾、购物成瘾、游戏成瘾、性瘾以及贪食等。非药物成瘾与药物成瘾在症状学上表现出很高的相似性且具有较高的共病率, 提示二者之间可能存在着共同的发病机制。从遗传学和神经生物学的角度探讨非药物成瘾的机制具有重要的理论价值和临床应用价值。家庭研究和双生子研究发现, 男性的病理性赌博和贪食障碍具有中度以上的遗传度。分子遗传学研究发现, 单胺能神经递质相关基因, 如5-羟色胺转运体基因、多巴胺受体基因和单胺氧化酶A基因等, 与非药物成瘾有关。神经影像学研究发现, 非药物成瘾者脑内负责奖赏,线索加工和冲动控制的神经通路活动性异于正常对照。未来研究需要进一步从多个角度入手, 探讨非药物成瘾与药物成瘾的共性和特性。     

基于“相关线索-自动化用药行为”联结的成瘾记忆消退

成瘾记忆消退致力于消除成瘾者相关线索与药物奖赏效应的联结,以达到消除心理渴求、戒断成瘾行为的目的,但其效果还十分有限。最近,大量的动物和人类实验研究发现:在相关线索下,成瘾者的激活脑区不仅包括中脑边缘皮层-背内侧纹状体,还延伸到感觉运动脑区-背外侧纹状体。这意味着成瘾记忆中存在相关线索与自动化(习惯性)用药行为的联结。所以,与成瘾相关的记忆可能包含两种不同的成分:一是与药物奖赏效应相关的情绪记忆,另一种是与用药动作、技能有关的动作记忆(程序记忆)。由于在成瘾阶段,药物奖赏效应对药物使用和复发的作用已经相对减少,因此,针对成瘾记忆的消退训练,以相关线索与自动化用药行为的联结为标靶,可能可以取得更好的效果,值得做进一步的深入探索。     

成瘾药物心理依赖及复发的脑机制研究

围绕学习、记忆、情绪及应激等心理因素与复发的关系,应用阿片类物质心理依赖研究条件性位置偏爱,条件性位置厌恶,Morris水迷宫量化觅药动机模型,行为及条件性行为敏感化等多种动物行为模型,从情绪相关学习、记忆在成瘾行为中的作用,不同神经核团与神经递质系统活动性的改变,应激相关因素易化的成瘾易感性,自然奖赏与成瘾药物奖赏相关记忆的比较研究等方面,对应激与记忆相关的吗啡心理依赖及复发的脑机制进行了系列研究     

亲代孕前成瘾药物暴露对子代行为的影响及其表观遗传机制

孕前成瘾药物暴露不仅危害使用者的身体健康,而且会对子代的生理行为造成影响,近年来研究发现表观遗传机制在其中发挥重要作用。孕前成瘾药物暴露会对子代的成瘾易感性和焦虑样行为造成影响,引起子代的抑郁样行为和认知受损。这些现象可能是成瘾药物通过引起亲代生殖细胞内表观遗传修饰变化所致,其中包括印记基因、神经递质系统、BDNF三个方面的表观遗传修饰变化。此外,未来除了加强以上三个方面基因的研究,也需要增加其他方面基因的研究,以及寻找能预测子代异常行为的表观遗传生物标志物。     

中枢胆碱能系统对吗啡成瘾的影响研究现状

介绍了中枢胆碱能系统对吗啡成瘾的影响及其机制。研究结果表明,吗啡成瘾过程中伏隔核等脑区细胞间乙酰胆碱水平发生了改变;去除伏隔核等脑区胆碱能细胞强化了吗啡成瘾行为;胆碱能激动剂和抑制剂都能干预吗啡成瘾、但机制可能不同——前者可能通过与多巴胺能交互作用来实现,后者可能通过干扰记忆或者加速吗啡代谢而发挥作用;胆碱能受体对吗啡成瘾也具有重要影响     

药物成瘾的易感性生物标记：从神经认知到分子遗传的证据

药物成瘾作为一种慢性复发性的脑疾病,具有从偶然性用药、规律性用药到强迫性用药的渐进式发展特征。研究提示,药物成瘾存在潜在的个体易感性机制,即在成瘾发生过程中不同个体接触药物后的成瘾风险并不相同,探索药物成瘾的神经生物标记是揭示成瘾易感性机制的重要途径。近十多年来,关于成瘾易感性标记的研究不断积聚。文章从神经认知、神经影像及脑电生理、分子遗传等层面梳理与药物成瘾生物标记有关的证据,试图在基因-大脑-心理-行为的理论框架下,对成瘾的发生发展机制进行综合阐释,期望为未来研究在探索药物成瘾的候选神经生物标记、寻找临床干预试验的精准靶点等方面提供更多理论参考。     

反社会行为的遗传基础:基因多态性和DNA甲基化

反社会行为是受遗传与环境共同影响的不良行为。分子遗传学和神经生物学的研究发现,基因以基因多态性和DNA甲基化的方式影响脑结构、功能及脑内神经递质的产生和释放,进而影响反社会行为的发生发展。本文从基因多态性和DNA甲基化两方面整理了5-HTT、MAOA、OXTR等8个候选基因与反社会行为的关联。并提出未来研究需进一步探讨基因、脑和神经递质对反社会行为的联合作用。同时,扩展多基因位点、基因多态性与DNA甲基化、积极环境与基因交互作用对反社会行为影响的研究,以全面探索反社会行为发生的遗传基础,进而更加有效的预防反社会行为。     

反社会行为的遗传基础:基因多态性和DNA甲基化

反社会行为是受遗传与环境共同影响的不良行为。分子遗传学和神经生物学的研究发现,基因以基因多态性和DNA甲基化的方式影响脑结构、功能及脑内神经递质的产生和释放,进而影响反社会行为的发生发展。本文从基因多态性和DNA甲基化两方面整理了5-HTT、MAOA、OXTR等8个候选基因与反社会行为的关联。并提出未来研究需进一步探讨基因、脑和神经递质对反社会行为的联合作用。同时,扩展多基因位点、基因多态性与DNA甲基化、积极环境与基因交互作用对反社会行为影响的研究,以全面探索反社会行为发生的遗传基础,进而更加有效的预防反社会行为。     

Post-training amphetamine administration enhances memory consolidation in appetitive Pavlovian conditioning: Implications for drug addiction

It has been suggested that some of the addictive potential of psychostimulant drugs of abuse such as amphetamine may result from their ability to enhance memory for drug-related experiences through actions on memory consolidation. This experiment examined whether amphetamine can specifically enhance consolidation of memory for a Pavlovian association between a neutral conditioned stimulus (CS-a light) and a rewarding unconditioned stimulus (US-food), as Pavlovian conditioning of this sort plays a major role in drug addiction. Male Long-Evans rats were given six training sessions consisting of 8 CS presentations followed by delivery of the food into a recessed food cup. After the 1st, 3rd, and 5th session, rats received subcutaneous injections of amphetamine (1.0 or 2.0 mg/kg) or saline vehicle immediately following training. Conditioned responding was assessed using the percentage of time rats spent in the food cup during the CS relative to a pre-CS baseline period. Both amphetamine-treated groups showed significantly more selective conditioned responding than saline controls. In a control experiment, there were no differences among groups given saline, 1.0 or 2.0 mg/kg amphetamine 2 h post-training, suggesting that immediate post-training amphetamine enhanced performance specifically through actions on memory consolidation rather than through non-mnemonic processes. This procedure modeled Pavlovian learning involved in drug addiction, in which the emotional valence of a drug reward is transferred to neutral drug-predictive stimuli such as drug paraphernalia. These data suggest that amphetamine may contribute to its addictive potential through actions specifically on memory consolidation.     

Aberrant learning and memory in addiction

Over the past several years, drug addiction has increasingly been accepted to be a disease of the brain as opposed to simply being due to a lack of willpower or personality flaw. Exposure to addictive substances has been shown to create enduring changes in brain structure and function that are thought to underlie the transition to addiction. Specific genetic and environmental vulnerability factors also influence the impact of drugs of abuse on the brain and can enhance the likelihood of becoming an addict. Long-lasting alterations in brain function have been found in neural circuits that are known to be responsible for normal appetitive learning and memory processes and it has been hypothesized that drugs of abuse enhance positive learning and memory about the drug while inhibiting learning about the negative consequences of drug use. Therefore, the addict's behavior becomes increasingly directed towards obtaining and using drugs of abuse, while at the same time developing a poorer ability to stop using, even when the drug is less rewarding or interferes with functioning in other facets of life. In this review we will discuss the clinical evidence that addicted individuals have altered learning and memory and describe the possible neural substrates of this dysfunction. In addition, we will explore the pre-clinical evidence that drugs of abuse cause a progressive disorder of learning and memory, review the molecular and neurobiological changes that may underlie this disorder, determine the genetic and environmental factors that may increase vulnerability to addiction, and suggest potential strategies for treating addiction through manipulations of learning and memory.     

冲动性对不同成瘾行为发展的调控及其神经机制

近年来越来越多的研究证据提示, 个体冲动性在成瘾疾患发生发展机制中具有关键作用, 可能成为成瘾行为的潜在易感标记以及早期识别和干预的重要靶点, 但冲动性对不同成瘾行为变化发展的调控机制尚不明确。项目拟综合跨成瘾谱系比较、纵向追踪设计、冲动行为干预等研究途径, 采用人格测量、神经认知、神经影像等技术, 首先比较尼古丁依赖者与网络游戏成瘾者的冲动性结构及其在前额叶–纹状体环路的结构功能改变; 然后采用混合分组设计筛选出具有高低冲动性的非成瘾青少年进行连续追踪研究, 考察冲动性对尼古丁依赖与网络游戏成瘾的预测效力; 并采用认知行为训练, 对吸烟成瘾者与网络游戏成瘾者进行冲动干预, 考察行为干预对冲动性水平及前额叶–纹状体环路功能的改变, 以及对不同成瘾行为发展的抑制后效。旨在探索冲动性作为成瘾的潜在易感标记及干预靶点的效力。     

慢性应激对大鼠空间学习记忆及海马和前脑皮层突触体膜流动性的影响

慢性应激对学习记忆功能的影响是神经科学的热点问题, 在脑内, 海马和前额叶是与学习记忆功能密切相关的重要脑区, 也是应激易累及损伤的主要靶区。膜流动性的改变在神经细胞功能活动中起重要作用。为探讨慢性应激对大鼠空间学习记忆功能的影响及前脑皮层和海马突触体膜流动性的作用。采用多因素慢性应激动物模型, 通过开场试验和Morris水迷宫测试大鼠行为及空间学习记忆能力; 并且测定大鼠前脑皮层和海马突触体膜流动性和突触体内游离Ca2+浓度的变化。研究结果显示, 与对照组相比, 应激组大鼠在应激后即刻, 在新异环境中的自发活动和探究行为显著降低(p<0.05, p<0.01), 空间学习记忆能力明显下降(p<0.05, p <0.01); 并且应激组大鼠前脑皮层和海马突触体膜流动性显著降低(p <0.05, p <0.01); 而突触体内游离Ca2+浓度的显著增加 (p <0.05, p <0.01)。停止应激后一周, 应激大鼠的各项指标有所恢复, 但仍未达到正常水平。研究结果提示, 慢性应激引起大鼠明显的开场行为改变和空间学习记忆功能障碍, 这些变化可能与突触体膜流动性和突触体内游离Ca2+浓度的变化密切相关。     

自传记忆的加工机制研究进展

自传记忆是关于个人生活经验的记忆,它有悖于Ehbinghaus的记忆研究传统。在国外．90年代以来自传记忆研究已成为继内隐记忆研究后．记忆领域的又一研究热点。自传记忆加工机制的研究是认知心理学对自传记忆研究的核心领域。本文主要评析了自传记忆的知识表征．自传记忆提取机制的研究进展。目前已有的研究结论是：（1）自传记忆是以个人生活片段知识、一般事件知识和具体事件知识三种方式表征的;（2）自传记忆的提取方式主要通过生成提取和直接提取方式来实现。     

The double-edged pen: Omnipotent fantasies in the creativity and addictions of Stephen King

The legendary debate over whether a connection between creativity and addictions exists is one that is shrouded in mystery and intrigue, but also one that continuously returns to the circuitous metaphor of the chicken and the egg. In an effort to better understand nuances in the relationship between creativity and addictions, this paper examines the life of Stephen King, and the omnipotent fantasies from which both his creative processes and addictive behaviours emerged. Since the early twentieth century, psychodynamic thinkers have highlighted omnipotent fantasies as a psychological force driving creative processes as efforts towards personal transformation. Similarly, numerous psychodynamic theories have highlighted omnipotent fantasies as playing a cardinal role in the psychological processes that propel substance abuse. And yet, the construct of omnipotence has yet to be examined as a theoretical bridge to bind such theories of creativity and substance abuse together. While fostering personal meaning and self-transformation when manifested in his creative writing processes, omnipotent fantasies have also lead Stephen King down a precarious path of addictive behaviours. Through a narrative analysis of the life of Stephen King, who has written in great depth about both his creativity and substance abuse, I will illustrate how omnipotent fantasies often shape and foster both healthy, creative processes towards growth and maladaptive, addictive impulses towards self-destruction.     

记忆再巩固现象及其生物学机制

已经巩固的长时记忆在激活后会经历一段易变而敏感的阶段后重新稳定下来,在此过程中,原有的记忆可以被修饰,加强,改变甚至消除,这个过程称为再巩固。记忆再巩固的研究意义在于它不仅扩展了人们对记忆本质的认识,而且对于临床治疗病理性记忆具有重大的现实意义。本文从行为学层面介绍了记忆的强度、记忆保持时间以及记忆激活方式对不同忆记忆再巩固模型的影响。并从蛋白质合成、基因水平、转录因子等方面简要介绍了再巩固的神经生物学机制的研究脉络。再巩固现象的研究不仅为治疗创伤性病理记忆提供了理论支持,并且为临床治疗药物成瘾相关病理记忆提供了新视角。     

Retrieval Inhibition and Memory Distortion: Negative Consequences of an Adaptive Process

ABSTRACT— Despite the fact that misinformation effects have long been studied by both applied researchers and modelers of human memory, there is little consensus as to the value of such endeavors. We argue that this may be due to a failure to identify the underlying mechanism responsible for such memory distortions. We consider novel evidence for a relationship between retrieval-induced forgetting and the reporting of misinformation. We also explore the extent to which retrieval inhibition underpins this relationship and the implications this has for the modeling of memory and finding potential solutions to real-world problems.     

Abstract recall of a happy memory to repair sad mood in dysphoria: A possible link to negative cognition

The capacity to repair sad mood through the deliberate recall of happy memories has been found to be impaired in dysphoric individuals. Rumination, or adopting an abstract processing mode, has been proposed as a possible mechanism underpinning this effect. In low and high dysphoric participants, we examined the relative consequences of adopting an abstract or concrete processing mode during happy memory recall or engaging in distraction for (1) mood repair and (2) cognitive content. Recalling a happy memory in either an abstract or concrete way resulted in greater happiness than distraction. Engaging in abstract recall of a happy memory resulted in high dysphoric participants generating negative evaluations and negative generalisations. These findings raise the interesting possibility that abstract processing of positive memories has the potential to generate negative cognition.