钩体凋亡相关基因的特征分析

应用生物信息学方法预测钩体与凋亡相关基因 ,并对其编码蛋白的结构特征进行深入分析。结果发现问号钩体黄疸出血型赖株 3对凋亡相关基因 ,其编码蛋白一级结构 ,保守区域和结构域同大肠埃希菌凋亡基因同源性很高。这提示凋亡相关基因存在于钩体中 ,可能在钩体流行和生态方面具有重要意义 ,深入研究可望发现新型抗菌靶基因。     

Alcohol‐dependent molecular adaptations of the NMDA receptor system

Phenotypes such as motivation to consume alcohol, goal‐directed alcohol seeking and habit formation take part in mechanisms underlying heavy alcohol use. Learning and memory processes greatly contribute to the establishment and maintenance of these behavioral phenotypes. The N‐methyl‐d ‐aspartate receptor (NMDAR) is a driving force of synaptic plasticity, a key cellular hallmark of learning and memory. Here, we describe data in rodents and humans linking signaling molecules that center around the NMDARs, and behaviors associated with the development and/or maintenance of alcohol use disorder (AUD). Specifically, we show that enzymes that participate in the regulation of NMDAR function including Fyn kinase as well as signaling cascades downstream of NMDAR including calcium/calmodulin‐dependent protein kinase II (CamKII), the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR) and the mammalian target of rapamycin complex 1 (mTORC1) play a major role in mechanisms underlying alcohol drinking behaviors. Finally, we emphasize the brain region specificity of alcohol's actions on the above‐mentioned signaling pathways and attempt to bridge the gap between the molecular signaling that drive learning and memory processes and alcohol‐dependent behavioral phenotypes. Finally, we present data to suggest that genes related to NMDAR signaling may be AUD risk factors.     

Midkine in the mouse ventral tegmental area limits ethanol intake and Ccl2 gene expression

Midkine (MDK) is a cytokine and neurotrophic factor that is more highly expressed in the brains of alcoholics and in mice predisposed to drink large amounts of ethanol, suggesting that MDK may regulate ethanol consumption. Here we measured ethanol consumption in male and female Mdk knockout (?/?) mice using the two‐bottle choice and the drinking in the dark (DID) tests. We found that Mdk ?/? mice consumed significantly more ethanol than wild‐type controls in both tests. To determine if MDK acts in the ventral tegmental area (VTA) to regulate ethanol consumption, we delivered lentivirus expressing a Mdk shRNA into the VTA of male C57BL/6J mice to locally knockdown Mdk and performed the DID test. Mice expressing a Mdk shRNA in the VTA consumed more ethanol than mice expressing a control non‐targeting shRNA, demonstrating that the VTA is one site in the brain through which MDK acts to regulate ethanol consumption. Since MDK also controls the expression of inflammatory cytokines in other organs, we examined gene expression of interleukin‐1 beta (Il1b), tumor necrosis factor alpha (Tnfα ) and the chemokine (C‐C motif) ligand 2 (Ccl2) in the VTA of Mdk ?/? mice and in mice expressing Mdk shRNA in the VTA. Expression of Ccl2 was elevated in the VTA of Mdk ?/? mice and in mice expressing Mdk shRNA in the VTA. These results demonstrate that MDK functions in the VTA to limit ethanol consumption and levels of CCL2, a chemokine known to increase ethanol consumption.     

Neuronal cell adhesion molecule deletion induces a cognitive and behavioral phenotype reflective of impulsivity

Cell adhesion molecules, such as neuronal cell adhesion molecule (Nr-CAM), mediate cell–cell interactions in both the developing and mature nervous system. Neuronal cell adhesion molecule is believed to play a critical role in cell adhesion and migration, axonal growth, guidance, target recognition and synapse formation. Here, wild-type, heterozygous and Nr-CAM null mice were assessed on a battery of five learning tasks (Lashley maze, odor discrimination, passive avoidance, spatial water maze and fear conditioning) previously developed to characterize the general learning abilities of laboratory mice. Additionally, all animals were tested on 10 measures of sensory/motor function, emotionality and stress reactivity. We report that the Nr-CAM deletion had no impact on four of the learning tasks (fear conditioning, spatial water maze, Lashley maze and odor discrimination). However, Nr-CAM null mice exhibited impaired performance on a task that required animals to suppress movement (passive avoidance). Although Nr-CAM mutants expressed normal levels of general activity and body weights, they did exhibit an increased propensity to enter stressful areas of novel environments (the center of an open field and the lighted side of a dark/light box), exhibited higher sensitivity to pain (hot plate) and were more sensitive to the aversive effects of foot shock (shock-induced freezing). This behavioral phenotype suggests that Nr-CAM does not play a central role in the regulation of general cognitive abilities but may have a critical function in regulating impulsivity and possibly an animal's susceptibility to drug abuse and addiction.     

Self-perception and Experiential Schemata in the Addicted Brain

This study investigated neurophysiological differences between recovering substance abusers (RSA) and controls while electroencephalogram (EEG) was continuously recorded during completion of a new assessment instrument. The participants consisted of 56 total subjects; 28 RSA and 28 non-clinical controls (C). The participants completed the self-perception and experiential schemata assessment (SPESA) and source localization was compared utilizing standardized low-resolution electromagnetic tomography (sLORETA). The data show significant differences between groups during both the assessment condition and baselines. A pattern of alpha activity as estimated by sLORETA was shown in the right amygdala, uncus, hippocampus, BA37, insular cortex and orbitofrontal regions during the SPESA condition. This activity possibly reflects a circuit related to negative perceptions of self formed in specific neural pathways. These pathways may be responsive to the alpha activity induced by many substances by bringing the brain into synchrony if only for a short time. In effect this may represent the euphoria described by substance abusers.     

Target-specific glutamatergic regulation of dopamine neurons in the ventral tegmental area

Dopamine (DA) neurons in the ventral tegmental area (VTA) are thought to play a critical role in affective, motivational, and cognitive functioning. There are fundamental target-specific differences in the functional characteristics of subsets of these neurons. For example, DA afferents to the prefrontal cortex (PFC) have a higher firing and transmitter turnover rate and are more responsive to some pharmacological and environmental stimuli than DA projections to the nucleus accumbens (NAc). These functional differences may be attributed in part to differences in tonic regulation by glutamate. The present study provides evidence for this mechanism: In freely moving animals, blockade of basal glutamatergic activity in the VTA by the selective alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate antagonist LY293558 produced an increase in DA release in the NAc while significantly decreasing DA release in the PFC. These data support an AMPA receptor-mediated tonic inhibitory regulation of mesoaccumbens neurons and a tonic excitatory regulation of mesoprefrontal DA neurons. This differential regulation may result in target-specific effects on the basal output of DA neurons and on the regulatory influence of voltage-gated NMDA receptors in response to phasic activation by behaviorally relevant stimuli.     

Epigenetics and memory: causes,consequences and treatments for post‐traumatic stress disorder and addiction

Understanding the interaction between fear and reward at the circuit and molecular levels has implications for basic scientific approaches to memory and for understanding the etiology of psychiatric disorders. Both stress and exposure to drugs of abuse induce epigenetic changes that result in persistent behavioral changes, some of which may contribute to the formation of a drug addiction or a stress‐related psychiatric disorder. Converging evidence suggests that similar behavioral, neurobiological and molecular mechanisms control the extinction of learned fear and drug‐seeking responses. This may, in part, account for the fact that individuals with post‐traumatic stress disorder have a significantly elevated risk of developing a substance use disorder and have high rates of relapse to drugs of abuse, even after long periods of abstinence. At the behavioral level, a major challenge in treatments is that extinguished behavior is often not persistent, returning with changes in context, the passage of time or exposure to mild stressors. A common goal of treatments is therefore to weaken the ability of stressors to induce relapse. With the discovery of epigenetic mechanisms that create persistent molecular signals, recent work on extinction has focused on how modulating these epigenetic targets can create lasting extinction of fear or drug‐seeking behavior. Here, we review recent evidence pointing to common behavioral, systems and epigenetic mechanisms in the regulation of fear and drug seeking. We suggest that targeting these mechanisms in combination with behavioral therapy may promote treatment and weaken stress‐induced relapse.     

天然奖赏与药物奖赏

动物和人的中枢神经系统具有奖赏机制来加强和激励对机体有益的行为,以利个体生存和种族繁衍。但这一系统一旦被某些外源性物质反复地异常激活(如药物滥用),则引起神经系统的慢性适应性改变,将对机体造成严重损害。实现奖赏效应的神经结构主要位于中脑边缘系统,中脑腹侧被盖区(VTA)至伏核(NAc)的多巴胺通路是食物和性活动等天然奖赏和成瘾性药物引起奖赏效应的共同通路。本文概述天然奖赏和成瘾性药物奖赏的异同,旨在探讨阻断后者而不损及前者的途径。