Neuropharmacological aspects of adaptive pain inhibition in murine “victims” of aggression

This review outlines recent research on a subset of physiological responses in murine “victims” or aggression. In a typical resident-intruder paradigm, the detailed study of intruders has revealed that exposure to conspecific attack (and related stimuli) is associated with two forms of analgesia which appear to be integral components of the murine defensive repertoire. In response to intense/enduring attack, intruder mice display a profound, long-lasting and opioid-mediated analgesia. This reaction is highly correlated with defensive immobility and may function to reduce involuntary cues to further attack. In contrast, the inhibition of pain reactivity in mice tested immediately upon the display of defeat is less intense, shorter-lasting, non-opioid in nature and may function to facilitate active defenses such as escape. As this form of pain inhibition is also evident in intruders exposed to the scent of an aggressive male conspecific, a possible anticipatory defensive function linked to mechanisms of anxiety has been proposed. This hypothesis is supported by 1) the prevention of defeat analgesia by a range of antianxiety drugs (benzodiazepines, 5-hydroxytryptamine_1A [5-HT_1A] receptor agonists, and 5-HT₃ receptor antagonists) and 2) the effects of social defeat on behavior in the elevated plusmaze model of anxiety. These findings are discussed in relation to coping mechanisms in murine “victims” of aggression. © 1995 Wiley-Liss, Inc.     

Regulation of glutamate synapses by nicotinic acetylcholine receptors in auditory cortex

Acetylcholine plays an important role in regulating the processing of sensory stimuli, and understanding its specific cellular actions is critical to understanding how sensory cortex develops and functions in different behavioral states. Here we review recent work on the cellular effects of nicotinic receptor activation in auditory cortex and describe how these actions could affect systems-level auditory function. In particular, we describe a novel function of nicotinic acetylcholine receptors to regulate glutamate synapses containing N-methyl-D-aspartate receptors during early postnatal development. The transient regulation of developing glutamate synapses also defines a window of vulnerability during which exposure to exogenous nicotine disrupts synapse development. Thus, it appears that nicotinic regulation of glutamate synapses is a critical feature of auditory cortex development.     

CXCR4和CXCR7在甲状腺癌中的表达及病理意义

研究甲状腺癌组织中趋化因子4受体（CXCR4）和趋化因子7受体（CXCR7）的表达情况及临床病理意义。应用免疫组织化学PV-6000法及Westernblot法检测CXCR4与CXCR7在甲状腺癌中的表达。二者在甲状腺癌与甲状腺良性疾病组织的差异均具有统计学意义（P〈0．05）,在甲状腺癌中表达仅与淋巴结转移有关（P〈0．05）,CXCR4与CXCR7之间呈正相关。Westernblot结果提示二者在甲状腺癌中的表达率高于癌旁及甲状腺腺瘤。CXCR4和CXCR7的表达水平与淋巴结转移相关,可作为甲状腺癌预后的判断指标。     

非小细胞肺癌 EG FR 基因突变检测与临床意义

采用荧光PCR法对199例晚期非小细胞肺癌（NSCLC ）组织进行表皮生长因子受体（EGFR ）基因突变检测,分析EGFR基因突变的分布特征及其与临床病理特征的相关性。结果显示56例（28．1％）存在EGFR基因突变,其中27例（13．6％）为外显子19突变,25例（12．6％）为外显子21突变,2例为外显子18突变,1例外显子20突变,1例外显子18和20的共突变。另外,除广东及安徽省铜陵市外,辽宁地区NSCLC患者EGFR基因突变率及主要突变类型与其他地区相符,常见于外显子19、21突变,其中腺癌、不吸烟患者突变率更高,更适宜EGFR-TKI靶向治疗。     

EGFR突变NSCLC二线TKIs治疗优化选择

恶性肿瘤的治疗已经进入驱动基因指导下的个体治疗时代,肺癌患者应该进行多基因检测,特别是表皮生长因子受体（EGFR）基因突变。EGFR基因突变的非小细胞肺癌（NSCLC）患者,如果一线接受了化疗,二线应该选择表皮生长因子受体一酪氨酸酶抑制剂（EGFR—TKIs）。EGFR基因突变的NSCLC患者一线EGFR—TKIs治疗失败后,二线治疗应该是个体化合理选择,包括局部放疗、化疗和继续EGFR—TKIs。目前一代和二代EGFR—TKIs药物之间未见到显著疗效差别。第三代EGFR—TKIs是目前的EGFR—TKIs耐药后的最有希望的选择,特别是针对T790M突变耐药。     

环境雌激素双酚A对成年小鼠学习记忆和突触结构的影响*

双酚A (bisphenol, BPA)是一种广泛存在的环境内分泌干扰物,它可与雌激素受体结合干扰内源性雌激素对中枢神经系统的调控作用。本研究通过将10周龄小鼠灌胃染毒BPA (0.4、4、40 mg/kg/day)3个月,研究长期BPA暴露对成年小鼠记忆行为和突触可塑性的影响。开场行为测试结果表明, BPA (0.4、4、40 mg/kg/day)增加雄性的站立次数和理毛频率, BPA (4 mg/kg/day)却显著减少雌鼠的站立次数。水迷宫和被动回避行为模型检测显示, BPA主要损伤雄鼠的空间学习记忆和被动回避记忆。通过制备海马CA1区超薄切片后,电镜观测发现, BPA (0.4、40 mg/kg/day)暴露降低雄鼠海马CA1区突触数密度,缩短雄鼠突触前活性带长度,减小雄鼠突触后致密体(PSD)厚度,增加雄鼠突触间隙宽度。进一步用Western blot方法检测突触前、后的标志性蛋白Synapsin I和PSD95以及兴奋性氨基酸NMDA受体NR1亚基和AMPA受体GluR1亚基蛋白的表达,发现BPA暴露致雄鼠Synapsin I、PSD95、NR1蛋白表达水平下调。而BPA对雌鼠的记忆行为、突触形态、突触蛋白和受体蛋白均没有明显作用。以上结果提示长期B PA暴露性别特异性地影响成年小鼠的活动性和探究行为,损伤雄鼠的学习记忆,这些作用可能通过下调突触蛋白和NMDA受体的表达而负性影响突触结构可塑性,最终影响雄鼠的学习记忆功能。     

Because difficulty is not the same for everyone: the impact of complexity in working memory is associated with cannabinoid 1 receptor genetic variation in young adults

Individual differences in working memory ability are mainly revealed when a demanding challenge is imposed. Here, we have associated cannabinoid 1 (CB1) receptor genetic variation rs2180619 (AA, AG, GG), which is located in a potential CNR1 regulatory sequence, with performance in working memory. Two-hundred and nine Mexican-mestizo healthy young participants (89 women, 120 men, mean age: 23.26 years, SD?=?2.85) were challenged to solve a medium (2-back) vs. a high (3-back) difficulty N-back tasks. All subjects responded as expected, performance was better with the medium than the high demand task version, but no differences were found among genotypes while performing each working memory (WM) task. However, the cost of the level of complexity in N-back paradigm was double for GG subjects than for AA subjects. It is noteworthy that an additive-dosage allele relation was found for G allele in terms of cost of level of complexity. These genetic variation results support that the endocannabinoid system, evaluated by rs2180619 polymorphism, is involved in WM ability in humans.     

干预胆碱M受体对药物成瘾的影响及其与多巴胺的关系

药物成瘾是一类精神及行为障碍, 涉及到中枢神经系统的病变。毒蕈碱受体(Muscarinic receptor, M受体)属于胆碱能受体, 分5种亚型。行为学研究表明, 干预M受体能有效影响药物成瘾行为, 但其神经机制还亟待探索。阿片类药物与精神活性药物均能激活中枢多巴胺系统, 而M受体与多巴胺系统在多个脑区产生了交互作用。其中激动M2及M4受体抑制了多巴胺系统功能, 而激动M5受体增强了多巴胺系统功能, 与干预M2、M4、M5受体对药物成瘾行为的影响相对应。以上证据提示, 干预M受体可能通过影响多巴胺系统对药物成瘾起作用。     

Examining the sex- and circadian dependency of a learning phenotype in mice with glycine transporter 1 deletion in two Pavlovian conditioning paradigms

Behavioural characterisation of transgenic mice has been instrumental in search of therapeutic targets for the modulation of cognitive function. However, little effort has been devoted to phenotypic characterisation across environmental conditions and genomic differences such as sex and strain, which is essential to translational research. The present study is an effort in this direction. It scrutinised the stability and robustness of the phenotype of enhanced Pavlovian conditioning reported in mice with forebrain neuronal deletion of glycine transporter 1 by evaluating the possible presence of sex and circadian dependency, and its consistency across aversive and appetitive conditioning paradigms. The Pavlovian phenotype was essentially unaffected by the time of testing between the two circadian phases, but it was modified by sex in both conditioning paradigms. We observed that the effect size of the phenotype was strongest in female mice tested during the dark phase in the aversive paradigm. Critically, the presence of the phenotype in female mutants was accompanied by an increase in resistance to extinction. Similarly, enhanced conditioned responding once again emerged solely in female mutants in the appetitive conditioning experiment, which was again associated with an increased resistance to extinction across days, but male mutants exhibited an opposite trend towards facilitation of extinction. The present study has thus added hitherto unknown qualifications and specifications of a previously reported memory enhancing phenotype in this mouse line by identifying the determinants of the magnitude and direction of the expressed phenotype. This in-depth comparative approach is of value to the interpretation of behavioural findings in general.