Review. Neural mechanisms underlying the vulnerability to develop compulsive drug-seeking habits and addiction

We hypothesize that drug addiction can be viewed as the endpoint of a series of transitions from initial voluntary drug use through the loss of control over this behaviour, such that it becomes habitual and ultimately compulsive. We describe evidence that the switch from controlled to compulsive drug seeking represents a transition at the neural level from prefrontal cortical to striatal control over drug-seeking and drug-taking behaviours as well as a progression from ventral to more dorsal domains of the striatum, mediated by its serially interconnecting dopaminergic circuitry. These neural transitions depend upon the neuroplasticity induced by chronic self-administration of drugs in both cortical and striatal structures, including long-lasting changes that are the consequence of toxic drug effects. We further summarize evidence showing that impulsivity, a spontaneously occurring behavioural tendency in outbred rats that is associated with low dopamine D2/3 receptors in the nucleus accumbens, predicts both the propensity to escalate cocaine intake and the switch to compulsive drug seeking and addiction.     

The CHAIN program: forging evolutionary links to underlying mechanisms

Proteins evolve new functions by modifying and extending the molecular machinery of an ancestral protein. Such changes show up as divergent sequence patterns, which are conserved in descendent proteins that maintain the divergent function. After multiply-aligning a set of input sequences, the CHAIN program partitions the sequences into two functionally divergent groups and then outputs an alignment that is annotated to reveal the selective pressures imposed on divergent residue positions. If atomic coordinates are also provided, hydrogen bonds and other atomic interactions associated with various categories of divergent residues are graphically displayed. Such analyses establish links between protein evolutionary divergence and functionally crucial atomic features and, as a result, can suggest plausible molecular mechanisms for experimental testing. This is illustrated here by its application to bacterial clamp-loader ATPases.     

Neural mechanisms and computations underlying stress effects on learning and memory

Stress has complex effects on memory function that can vary depending on the type of information that is learned and in relation to inter-individual characteristics. Recent work has also shown that stress can switch performance between memory systems, biasing it toward habit in detriment of spatial or goal-directed strategies. In addition, novel synaptic mechanisms have been implicated in the effects of stress in plasticity and memory. Computational modeling is emerging as a useful approach to integrate and to ascertain neural and cognitive computations underlying different effects of stress in memory. Having provided novel explanations for the inverted-U-shaped relationship between stress and cognitive performance, model-based analysis studies can improve our understanding of diverse effects of stress in cognition and psychopathology.     

Neural mechanisms underlying uninstructed orofacial movements during reward-based learning behaviors

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药物成瘾的神经生物学机制研究

药物滥用既是全球普遍存在的公共卫生问题,又是危害严重的社会问题。药物成瘾的本质是一种以药物引起的基因表达和神经突触可塑性改变为基础的病理性记忆。主要介绍国内外近年的重要研究成果。     

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.     

MicroRNAs regulate synaptic plasticity underlying drug addiction

Chronic use of drugs of abuse results in neurochemical, morphological and behavioral plasticity that underlies the emergence of compulsive drug seeking and vulnerability to relapse during periods of attempted abstinence. Identifying and reversing addiction‐relevant plasticity is seen as a potential point of pharmacotherapeutic intervention in drug‐addicted individuals. Despite considerable advances in our understanding of the actions of drugs of abuse in the brain, this information has thus far yielded few novel treatment options addicted individuals. MicroRNAs are small noncoding RNAs that can each regulate the translation of hundreds to thousands of messenger RNAs. The highly pleiotropic nature of miRNAs has focused attention on their contribution to addiction‐relevant structural and functional plasticity in the brain and their potential utility as targets for medications development. In this review, we discuss the roles of miRNAs in synaptic plasticity underlying the development of addiction and then briefly discuss the possibility of using circulating miRNA as biomarkers for addiction.     

Neural mechanisms underlying amblyopia.

The nature of the neural basis of amblyopia is a matter of some debate. Recent neurophysiological data show correlates of amblyopia in the spatial properties of neurons in primary visual cortex. These neuronal deficits are probably the initial manifestation of the visual loss, but there are almost certainly additional deficits at higher levels of the visual pathways.     

药物成瘾中的神经细胞骨架

神经细胞骨架对神经元功能有重要作用。药物成瘾会导致神经细胞病态发生,几乎在所有药物成瘾的蛋白质组学的研究中都能检测到细胞骨架蛋白的变化,细胞骨架蛋白在这个过程涉及神经细胞结构、突触可塑性、信号转导、功能蛋白的降解或修饰以及能量代谢等方面。本文综述了神经细胞骨架在药物成瘾中的研究。     

Genes and (common) pathways underlying drug addiction

Drug addiction is a serious worldwide problem with strong genetic and environmental influences. Different technologies have revealed a variety of genes and pathways underlying addiction; however, each individual technology can be biased and incomplete. We integrated 2,343 items of evidence from peer-reviewed publications between 1976 and 2006 linking genes and chromosome regions to addiction by single-gene strategies, microrray, proteomics, or genetic studies. We identified 1,500 human addiction-related genes and developed KARG (http://karg.cbi.pku.edu.cn), the first molecular database for addiction-related genes with extensive annotations and a friendly Web interface. We then performed a meta-analysis of 396 genes that were supported by two or more independent items of evidence to identify 18 molecular pathways that were statistically significantly enriched, covering both upstream signaling events and downstream effects. Five molecular pathways significantly enriched for all four different types of addictive drugs were identified as common pathways which may underlie shared rewarding and addictive actions, including two new ones, GnRH signaling pathway and gap junction. We connected the common pathways into a hypothetical common molecular network for addiction. We observed that fast and slow positive feedback loops were interlinked through CAMKII, which may provide clues to explain some of the irreversible features of addiction.     

条件性运动学习的神经基础

人和动物形成多样的、快速可变的刺激－反应联合关系的过程被称为条件性运动学习。条件性运动学习使得人和动物具有很强的适应优势。损毁或行为电生理研究表明：运动前区背外侧部、基底神经节以及前额叶皮层腹侧部在条件性运动学习中起至关重要的作用;海马在条件性运动学习中也起着一定的作用;而杏仁核等一些结构在条件性运动学习中不起作用。     

Neural mechanisms underlying the evolvability of behaviour

The complexity of nervous systems alters the evolvability of behaviour. Complex nervous systems are phylogenetically constrained; nevertheless particular species-specific behaviours have repeatedly evolved, suggesting a predisposition towards those behaviours. Independently evolved behaviours in animals that share a common neural architecture are generally produced by homologous neural structures, homologous neural pathways and even in the case of some invertebrates, homologous identified neurons. Such parallel evolution has been documented in the chromatic sensitivity of visual systems, motor behaviours and complex social behaviours such as pair-bonding. The appearance of homoplasious behaviours produced by homologous neural substrates suggests that there might be features of these nervous systems that favoured the repeated evolution of particular behaviours. Neuromodulation may be one such feature because it allows anatomically defined neural circuitry to be re-purposed. The developmental, genetic and physiological mechanisms that contribute to nervous system complexity may also bias the evolution of behaviour, thereby affecting the evolvability of species-specific behaviour.     

Neural mechanisms underlying sex-specific behaviors in vertebrates

From invertebrates to humans, males and females of a given species display identifiable differences in behaviors, mostly but not exclusively pertaining to sexual and social behaviors. Within a species, individuals preferentially exhibit the set of behaviors that is typical of their sex. These behaviors include a wide range of coordinated and genetically pre-programmed social and sexual displays that ensure successful reproductive strategies and the survival of the species. What are the mechanisms underlying sex-specific brain function? Although sexually dimorphic behaviors represent the most extreme examples of behavioral variability within a species, the basic principles underlying the sex specificity of brain activity are largely unknown. Moreover, with few exceptions, the quest for fundamental differences in male and female brain structures and circuits that would parallel that of sexual behaviors and peripheral organs has so far uncovered modest quantitative rather than the expected clear qualitative differences. As will be detailed in this review, recent advances have directly challenged the established notion of the unique role of steroid hormones in organizing and activating male- and female-specific brain circuits and have uncovered new mechanisms underlying the neural control of sex-specific behaviors.     

Neural mechanisms underlying hyperphagia in Prader-Willi syndrome

Objective: Prader‐Willi syndrome (PWS) is a genetic disorder associated with developmental delay, obesity, and obsessive behavior related to food consumption. The most striking symptom of PWS is hyperphagia; as such, PWS may provide important insights into factors leading to overeating and obesity in the general population. We used functional magnetic resonance imaging to study the neural mechanisms underlying responses to visual food stimuli, before and after eating, in individuals with PWS and a healthy weight control (HWC) group. Research Methods and Procedures: Participants were scanned once before (pre‐meal) and once after (post‐meal) eating a standardized meal. Pictures of food, animals, and blurred control images were presented in a block design format during acquisition of functional magnetic resonance imaging data. Results: Statistical contrasts in the HWC group showed greater activation to food pictures in the pre‐meal condition compared with the post‐meal condition in the amygdala, orbitofrontal cortex, medial prefrontal cortex (medial PFC), and frontal operculum. In comparison, the PWS group exhibited greater activation to food pictures in the post‐meal condition compared with the pre‐meal condition in the orbitofrontal cortex, medial PFC, insula, hippocampus, and parahippocampal gyrus. Between‐group contrasts in the pre‐ and post‐meal conditions confirmed group differences, with the PWS group showing greater activation than the HWC group after the meal in food motivation networks. Discussion: Results point to distinct neural mechanisms associated with hyperphagia in PWS. After eating a meal, the PWS group showed hyperfunction in limbic and paralimbic regions that drive eating behavior (e.g., the amygdala) and in regions that suppress food intake (e.g., the medial PFC).     

Cellular mechanisms of striatum-dependent behavioral plasticity and drug addiction

The striatum has long been known to be involved in the control of motor behavior, since disruption of dopamine-mediated function in this brain structure is directly linked to Parkinson's disease and other disorders of movement. However, it is now accepted that both dorsal and ventral striatal nuclei are also essential for a variety of cognitive processes, which depend on reward-based stimulus-response learning. Since the neuroanatomical and neurochemical organization of dorsal and ventral striatum is only partially overlapping, it is likely that both common and nucleus-specific cellular and molecular events contribute to synaptic plasticity, learning and memory processes mediated by these cerebral structures. Alterations in cell signaling in the striatum may be particularly important in the response to both acute and chronic administration of drugs of abuse, resulting in maladaptive changes in the reward-based associative learning involved in addiction, withdrawal and relapse.     

Neural network mechanisms underlying stimulus driven variability reduction

It is well established that the variability of the neural activity across trials, as measured by the Fano factor, is elevated. This fact poses limits on information encoding by the neural activity. However, a series of recent neurophysiological experiments have changed this traditional view. Single cell recordings across a variety of species, brain areas, brain states and stimulus conditions demonstrate a remarkable reduction of the neural variability when an external stimulation is applied and when attention is allocated towards a stimulus within a neuron's receptive field, suggesting an enhancement of information encoding. Using an heterogeneously connected neural network model whose dynamics exhibits multiple attractors, we demonstrate here how this variability reduction can arise from a network effect. In the spontaneous state, we show that the high degree of neural variability is mainly due to fluctuation-driven excursions from attractor to attractor. This occurs when, in the parameter space, the network working point is around the bifurcation allowing multistable attractors. The application of an external excitatory drive by stimulation or attention stabilizes one specific attractor, eliminating in this way the transitions between the different attractors and resulting in a net decrease in neural variability over trials. Importantly, non-responsive neurons also exhibit a reduction of variability. Finally, this reduced variability is found to arise from an increased regularity of the neural spike trains. In conclusion, these results suggest that the variability reduction under stimulation and attention is a property of neural circuits.