慢性束缚应激对大鼠脑内Fas、FasL含量的影响

为探讨慢性束缚应激对大鼠脑内不同部位Fas/FasL系统表达的不同影响。将24只雄性SD大鼠随机分为束缚应激组、装置对照组和正常对照组（n=8）。分别对三组大鼠给予相应的干预14天,用Western-blotting方法测定应激后大鼠大脑前脑皮质、内嗅皮质以及海马区域Fas、FasL蛋白含量。结果表明,应激后各脑区三组大鼠Fas含量差异具有统计学意义（p < 0.01）,束缚应激组明显高于正常对照组或装置对照组（p < 0.01）。在海马区域,三组大鼠FasL含量差异具有统计学意义（p < 0.01）,束缚应激组大鼠FasL蛋白水平显著高于正常对照组或装置对照组(p < 0.01)。三组大鼠自身大脑前脑皮质、内嗅皮质以及海马Fas含量的差异比较均无统计学意义( p > 0.05) 。束缚应激组大鼠海马的FasL含量高于前脑皮质和内嗅皮质(p < 0.05);正常对照组或装置对照组自身不同脑区间FasL含量的变化无统计学意义。提示慢性束缚应激能诱导大鼠脑内Fas/FasL系统表达水平的改变,对不同的脑区,其影响程度明显不同     

不同应激范式对大鼠行为和脑神经颗粒素含量的影响

为探讨慢性情绪应激、生理应激对大鼠旷场行为和脑神经颗粒素（Neurogranin,NG）含量的不同作用,以及NG含量变化与应激性行为效应之间的相互关系。分别以不确定性空瓶刺激和饮水剥夺,建立情绪应激和生理应激动物模型。将40只雄性SD大鼠随机分为情绪应激组（ES）、生理应激组（PS）、定时饮水组（C1）和正常对照组（C2）（n=10）。以旷场行为任务来评定大鼠应激后的行为变化,Western blotting方法测定海马和前脑皮层中的NG含量。结果表明：应激后四组大鼠海马的NG含量差异无显著性;ES组前脑皮层的NG含量低于C2组,差异具有显著性,p<0.01;PS组的前脑皮层NG含量也下降,但与C2组相比差异无显著性; 应激后ES组、PS组修饰行为多于C2组,差异具有显著性,分别为p<0.01,p<0.05;前脑皮层NG含量与修饰行为之间的相关达显著水平。提示慢性情绪和生理应激均能导致前脑皮层NG含量下降,修饰行为增加,情绪应激作用更显著。修饰行为可能是反映情绪状态的较敏感行为指标,前脑皮层NG水平可能是预测情绪应激所致焦虑或抑郁行为的较敏感生物学指标。     

慢性应激对大鼠海马Akt/FKHRL1信号通路活性的影响

探讨慢性应激对大鼠海马Akt/FKHRL1信号通路活性的影响,及其应激源特异性。将24只雄性SD大鼠随机分为心理应激组、束缚应激组和正常对照组（n=8）。用Western-blotting方法测定28天应激后海马Akt、FKHRL1蛋白含量及其磷酸化水平。结果表明,应激后三组大鼠海马磷酸化Akt、FKHRL1含量差异有统计学意义（p < 0.01;p < 0.001）,束缚应激组低于正常对照组（p < 0.01）。提示慢性应激能导致海马磷酸化Akt、FKHRL1表达水平降低,但其影响程度与应激源特异性有关     

慢性应激损害大鼠学习记忆且抑制海马及额叶FGF2蛋白表达

慢性应激能够影响学习和记忆等认知功能。海马和额叶是与学习和记忆联系密切的脑区, 参与信息的获得、保持及提取。碱性成纤维生长因子(FGF2)对神经元发生、存活以及损伤修复具有重要促进作用, 目前成为神经系统退行性疾病相关研究的热点。本研究旨在探索慢性应激如何影响大鼠学习和记忆能力, 以及这一过程中FGF2蛋白在海马和额叶中表达的改变。实验中将16只雄性SD大鼠随机分为对照组和慢性应激组, 采用慢性不可预见温和刺激建立大鼠慢性应激模型, 通过Morris水迷宫实验及Y迷宫实验检测学习与记忆功能的改变, 并对海马及额叶中FGF2蛋白的表达情况进行Western blot及免疫组织化学检测。结果发现, 5周慢性应激导致大鼠学习和记忆能力受损, 海马及额叶FGF2蛋白表达下调。因此认为, FGF2蛋白可能参与慢性应激损害学习记忆能力的机制, 提示FGF2可能是诊断和治疗神经系统退行性病变的分子靶目标。     

急性生理应激对大鼠的行为及脑神经颗粒素磷酸化水平的影响

突触特异性蛋白质在应激所致行为效应的中枢机制中的可能角色日益受到关注。神经颗粒素（Neurogranin,NG）是一种新发现的突触特异性蛋白质,主要分布在前额叶、杏仁核和海马区域,参与突触结构和功能可塑性机制,可能涉及到应激所致行为效应中枢机制。但是,关于NG、应激和行为之间的关系国内外尚缺乏系统的研究报道。本研究主要是探讨急性生理应激对大鼠行为和NG的作用,以及NG的变化与应激性行为效应之间的相互关系。以急性强迫性冷水游泳应激,建立生理应激动物模型。将40只雄性SD大鼠随机分为游泳应激组1（SS1,接受游泳应激和行为测试）、游泳应激组2（SS2,接受游泳应激而不接受行为测试）、正常对照组1（C1,接受行为测试）和正常对照组（C2,不给予任何处理）（n=10）。以旷场行为和高架十字迷宫任务来评定大鼠应激后的行为变化,Western blotting方法测定海马和前脑皮层中的NG含量和磷酸化水平。结果表明：应激后SS1组的呆滞行为增加,与C1组比较,差异有显著性, P<0.01; SS1组海马的NG含量和NG磷酸化水平增高,与C1和C2组相比,差异有显著性,均为P<0.05; SS1组皮层的NG含量增高,与C1和C2组相比,差异有显著性,均为P<0.01;SS1组皮层的NG磷酸化水平增高,与C1组相比,差异具有显著性,P<0.01;前脑皮层的NG磷酸化水平与呆滞行为之间的相关达显著水平。提示该应激源能诱发动物明显的恐惧反应,呆滞行为是反映急性生理应激导致行为障碍的敏感的行为学指标,海马和前脑皮层均是对急性生理应激反应敏感的脑区。NG的磷酸化水平可能是反映急性生理应激所致行为障碍的一项新的生物学指标     

急性情绪应激对大鼠行为和脑神经颗粒素磷酸化水平的影响

为探讨急性情绪应激对大鼠旷场行为的影响,以及脑神经颗粒素（Neuroganin,NG）变化与应激性行为效应之间的相互关系。以急性不确定性空瓶刺激,建立情绪应激动物模型。将40只雄性SD大鼠随机分为情绪应激组1（ES1,接受情绪应激和旷场测试）、情绪应激组2（ES2,只接受情绪应激）、正常对照组1（C1,无情绪应激,但接受旷场测试）和正常对照组（C2,无情绪应激,也无旷场测试）（n=10）。以旷场行为和高架十字迷宫任务来评定大鼠应激后的行为变化,Western印迹杂交法（Western blotting）测定海马和前脑皮层中的NG含量和磷酸化水平。结果表明：（1） 应激后ES1组的水平活动增加,与C1组比较,差异有显著性, p<0.01;（2）ES1组海马和前脑皮层的NG磷酸化水平高于C1和C2组,差异有显著性, 均为p<0.05; ES2组的前脑皮层NG的磷酸化水平高于C1组,差异有显著性,为p<0.05;（3） 海马的NG磷酸化水平与水平活动之间的相关达显著水平。提示急性情绪应激能导致动物明显的行为改变如焦虑,这种行为改变可能与脑内NG磷酸化水平的变化有关。水平活动可能是反映急性情绪应激的较敏感行为指标,海马NG磷酸化水平可能是预测急性情绪应激所致焦虑或抑郁行为的较敏感生物学指标     

丰富环境对脑缺血大鼠突触界面结构修饰和PSD-95基因表达的影响

探讨丰富环境干预对局部脑缺血大鼠突触界面结构修饰和突触后致密物-95 (postsynaptic density-95,PSD-95 ) mRNA表达的影响。栓塞健康雄性Sprague-Dawley大鼠的右侧大脑中动脉,建立脑中动脉栓塞(middle cerebral artery occlusion,MCAO)模型后,分为丰富环境缺血组(IE)、标准环境缺血组(IS),同时分别设丰富环境假手术组(SE)、标准环境假手术组(SS)。以Morris水迷宫检测大鼠的空间学习记忆能力,应用透射电镜、图像分析和细胞形态计量学技术,观察海马CA1区和额叶皮层突触界面结构变化,采用RT-PCR检测突触后脚手架蛋白PSD-95 mRNA的表达。结果表明：丰富环境干预能有效改善脑缺血导致的空间学习记忆能力下降,并对正常大鼠的空间学习记忆能力也有改善作用。同时,丰富环境干预能抑制局部脑缺血导致的突触数密度减少,该作用对额叶皮层特别明显;丰富环境干预不同程度地逆转脑缺血造成的突触界面参数变化,特别使突触间隙宽度显著减小、PSD厚度明显增加;并有效抑制因脑缺血诱导的PSD-95 mRNA表达下调。以上结果提示,丰富环境改善脑缺血大鼠的空间学习记忆能力可能与其促进缺血区边缘组织突触界面结构修饰,提高PSD-95 mRNA表达有关     

催产素调控心理韧性:基于对海马的作用机制

心理韧性指个体面对逆境、挫折或重大威胁等应激情境下的有效且灵活适应的能力, 促进机体恢复正常的生理和心理功能。研究表明海马是调控心理韧性的重要脑区, 且催产素可能通过作用于海马增强心理韧性。海马内部环路内嗅皮层-齿状回-CA3可能调节恐惧记忆的泛化和消退以增强心理韧性; 海马外部环路齿状回-杏仁核-伏隔核及海马-伏隔核环路调节情绪, 可能分别通过促进奖赏和带来厌恶进而增强或降低心理韧性。催产素作用于海马增强心理韧性的可能途径有:催产素促进海马神经发生, 降低海马腹侧成熟神经元对应激的敏感性, 提高海马“模式分离”功能, 降低应激记忆泛化; 催产素恢复海马谢弗侧枝-CA1突触长时程增强, 促进机体适应应激; 催产素降低海马糖皮质激素受体水平, 重新建立机体稳态。     

成年期双酚A暴露对小鼠行为的影响

探究成年期环境雌激素双酚A(bisphenol A, BPA)暴露对不同性别小鼠行为的影响。出生5周的小鼠灌胃染毒BPA (40、400 µg/kg/d), 同时设对照组。染毒8周后, 以开场行为检测小鼠的自发活动及探究行为, 以高架十字迷宫检测小鼠的焦虑和探究行为, 以水迷宫检测小鼠的空间学习记忆行为, 以跳台检测小鼠的被动回避记忆行为。结果显示, BPA暴露不影响同性别小鼠在开场中的各种行为, 但消除了悬空站立和扶壁站立频率的性别差异。高架十字迷宫行为测试中, BPA暴露显著减少雄鼠进入开放臂的次数和停留时间(p<0.05和p<0.01), 却显著增加雌鼠进入开放臂的次数和停留时间(p<0.05和p<0.01); 同时, BPA暴露显著减少雄鼠(p<0.05和p<0.01)却增加雌鼠在中央区的探头次数(p<0.01), 消除甚至反向诱导成年小鼠焦虑行为和探究行为的性别分化。BPA (40 µg/kg/d)暴露显著延长成年雄鼠在水迷宫中搜寻平台的平均距离(p<0.05), 但对雌鼠没有影响, BPA因此消除了正常成年小鼠空间记忆行为的性别差异。BPA(40 µg/kg/d)暴露显著缩短了雄鼠在遭电击24h后跳下平台的潜伏期(p<0.05), 但对雌鼠没有明显影响, 并因此诱导成年小鼠被动回避行为的性别差异。以上结果表明, 成年期BPA 暴露可性别特异性地影响小鼠的多种行为, 干扰成年小鼠行为的性别差异。     

慢性强迫游泳应激对大鼠情绪和脑细胞外信号调节激酶的影响

为探讨慢性强迫游泳应激对动物情绪和脑组织细胞外信号调节激酶（extracellular signal-regulated kinase, ERK1/2）的影响,动物情绪和脑组织ERK1/2之间的关系,将动物随机分为游泳应激组、装置对照组和控制组。分别对三组大鼠给予相应的干预14天, 然后进行行为观察,免疫印记法测定海马和前脑皮质ERK1/2水平。结果表明强迫游泳应激组和装置对照组都出现明显的情绪障碍。两组大鼠ERK1/2在前脑皮质的表达水平均显著升高,海马无显著变化。前脑皮质ERK2与糖精水摄入量呈显著负相关。提示慢性强迫游泳应激能够诱导大鼠的情绪障碍,提高ERK1/2在前脑皮质的表达水平,ERK1/2与情绪关系密切,可能是脑组织应激性情绪调节的重要生理机制。强迫游泳应激能够导致动物明显的抑郁反应,是比较理想的抑郁动物模型     

Endocannabinoids and stress

Endogenous cannabinoids play an important role in the physiology and behavioral expression of stress responses. Activation of the hypothalamic-pituitary-adrenal (HPA) axis, including the release of glucocorticoids, is the fundamental hormonal response to stress. Endocannabinoid (eCB) signaling serves to maintain HPA-axis homeostasis, by buffering basal activity as well as by mediating glucocorticoid fast feedback mechanisms. Following chronic stressor exposure, eCBs are also involved in physiological and behavioral habituation processes. Behavioral consequences of stress include fear and stress-induced anxiety as well as memory formation in the context of stress, involving contextual fear conditioning and inhibitory avoidance learning. Chronic stress can also lead to depression-like symptoms. Prominent in these behavioral stress responses is the interaction between eCBs and the HPA-axis. Future directions may differentiate among eCB signaling within various brain structures/neuronal subpopulations as well as between the distinct roles of the endogenous cannabinoid ligands. Investigation into the role of the eCB system in allostatic states and recovery processes may give insight into possible therapeutic manipulations of the system in treating chronic stress-related conditions in humans.     

Learning under stress: A role for the neural cell adhesion molecule NCAM

Stress is known to be a potent modulator of brain function and cognition. While prolonged and/or excessive stress generally exerts negative effects on learning and memory processes, acute stress can have differential effects on memory function depending on a number of factors (such as stress duration, stress intensity, timing and the source of the stress, as well as the learning type under study). Here, we have focused on the effects of ‘acute’ stress, and examined the literature attending to whether the “source of stress” is ‘intrinsic’ (i.e., when stress is originated by the cognitive task) or ‘extrinsic’ (i.e., when stress is induced by elements not related to the cognitive task). We have questioned here whether the neural cell adhesion molecule of the immunoglobulin superfamily (NCAM) contributes to the neurobiological mechanisms that translate the effects of these two different stress sources into the different behavioral and cognitive outcomes. NCAM is a cell adhesion macromolecule known to play a critical role in development and plasticity of the nervous system. NCAM and its post-translational modified form PSA-NCAM are critically involved in mechanisms of learning and memory and their expression levels are known to be highly susceptible to modulation by stress. Whereas available data are insufficient to conclude as to whether NCAM mediates extrinsic stress effects on learning and memory processes, we present systematic evidence supporting a key mediating role for both NCAM and PSA-NCAM in the facilitation of memory consolidation induced by intrinsic stress. Furthermore, NCAM is suggested to participate in some of the bidirectional effects of stress on memory processes, with its enhanced synaptic expression involved in facilitating stress actions while its reduced expression being related to impairing effects of stress on memory function.     

Acute predator stress impairs the consolidation and retrieval of hippocampus-dependent memory in male and female rats

We have studied the effects of an acute predator stress experience on spatial learning and memory in adult male and female Sprague-Dawley rats. All rats were trained to learn the location of a hidden escape platform in the radial-arm water maze (RAWM), a hippocampus-dependent spatial memory task. In the control (non-stress) condition, female rats were superior to the males in the accuracy and consistency of their spatial memory performance tested over multiple days of training. In the stress condition, rats were exposed to the cat for 30 min immediately before or after learning, or before the 24-h memory test. Predator stress dramatically increased corticosterone levels in males and females, with females exhibiting greater baseline and stress-evoked responses than males. Despite these sex differences in the overall magnitudes of corticosterone levels, there were significant sex-independent correlations involving basal and stress-evoked corticosterone levels, and memory performance. Most importantly, predator stress impaired short-term memory, as well as processes involved in memory consolidation and retrieval, in male and female rats. Overall, we have found that an intense, ethologically relevant stressor produced a largely equivalent impairment of memory in male and female rats, and sex-independent corticosterone-memory correlations. These findings may provide insight into commonalities in how traumatic stress affects the brain and memory in men and women.     

Biopsychology research in China

The early studies on biopsychology in China were classified under the name of physiological psychology and comparative psychology. In 1979 the Division of Physiological Psychology of the Chinese Psychological Society was founded. Fifteen years later, the Brain‐Behavior Research Center was founded at the Institute of Psychology, Chinese Academy of Sciences. The objective of the Center was to establish a multidisciplinary scientific environment for conducting experimental research on the relationship between brain and behaviour as well as the interactions of the mind and body. A wide range of studies in biopsychology has been conducted in China. The most major research areas are: (1) Behavioural and physiological studies of stress: Research work includes the effect of early environment on stressful responses, interactions of behavioural and endocrine responses under stress, effects of emotional stress on immune function, stress and hypertension and the related role of interleukin‐1. (2) Conditioning and immunity: Studies focus on the effects of conditioning in the modulation of bidirectional immune function. Data from different experiments demonstrate that psychological processes are capable of influencing immune function. The neural substrates are also explored. (3) Memory and learning: Studies mostly concentrate on types of memory formation and training stimulus, effect of light exposure and corticosterone on learning and memory, and the role of the hippocampus in learning and memory. (4) Drug addiction: Work mainly focuses on long‐term aspects of addiction, including memory, novelty seeking, motivation‐related models, and the brain mechanisms underlying morphine psychological dependence.     

Enduring deficits in contextual and auditory fear conditioning after adolescent, not adult, social instability stress in male rats

Adolescence is a time of developmental changes and reorganization in the brain and stress systems, thus, adolescents may be more vulnerable than adults to the effects of chronic mild stressors. Most studies, however, have not directly compared stress experienced in adolescence to the same stress experience in adulthood. In the present study, adolescent (n=46) and adult (n=48) male rats underwent 16 days of social instability stress (daily 1h isolation and change of cage partners) or were non-stress controls. Rats were then tested on the strength of acquired contextual and cued fear conditioning, as well as extinction learning, beginning either the day after the stress procedure or 3 weeks later. No difference was found among the groups during the Training Phase of conditioning. Irrespective of the time between the social stress experience and fear conditioning, rats stressed in adolescence had decreased context and cue memory, and cue generalization compared to control rats, as measured by the percentage of time spent freezing in tests. Social instability stress in adulthood had no effect on any measure of fear conditioning. The results support the hypothesis that adolescence is a time of heightened vulnerability to stressors.     

Environmental enrichment protects against the effects of chronic stress on cognitive and morphological measures of hippocampal integrity

Chronic stress has detrimental effects on hippocampal integrity, while environmental enrichment (EE) has beneficial effects when initiated early in development. In this study, we investigated whether EE initiated in adulthood would mitigate chronic stress effects on cognitive function and hippocampal neuronal architecture, when EE started one week before chronic stress began, or two weeks after chronic stress onset. Adult male Sprague Dawley rats were chronically restrained (6h/d) or assigned as non-stressed controls and subdivided into EE or non-EE housing. After restraint ended, rats were tested on a radial arm water maze (RAWM) for 2-d to assess spatial learning and memory. The first study showed that when EE began prior to 3-weeks of chronic stress, EE attenuated chronic stress-induced impairments in acquisition, which corresponded with the prevention of chronic stress-induced reductions in CA3 apical dendritic length. A second study showed that when EE began 2-weeks after the onset of a 5-week stress regimen, EE blocked chronic stress-induced impairments in acquisition and retention at 1-h and 24-h delays. RAWM performance corresponded with CA3 apical dendritic complexity. Moreover, rats in EE housing (control or stress) exhibited similar corticosterone profiles across weeks, which differed from the muted corticosterone response to restraint by the chronically stressed pair-housed rats. These data support the interpretation that chronic stress and EE may act on similar mechanisms within the hippocampus, and that manipulation of these factors may yield new directions for optimizing brain integrity and resilience under chronic stress or stress related neuropsychological disorders in the adult.     

Chronically stressed female rats show increased anxiety but no behavioral alterations in object recognition or placement memory: a preliminary examination

Stress, depending on intensity and duration, elicits adaptive or maladaptive physiological effects. Increasing evidence shows those patterns of advantageous versus deleterious physiologic stress effects also exist for some brain functions, including learning and memory. For example, short stress enhances, while chronic stress impairs, performance on numerous cognitive tasks in male rats. In contrast, performance of female rats is enhanced, or not altered, following both short-term and long-term stress exposure on the same behavioral tasks. The current study was designed to better characterize the behavioral effects of sustained chronic restraint stress in female rats. Female Sprague Dawley rats were assigned to a stress (restraint, 6 h/day, 35 days) or control (no stress) condition, weighed weekly, and then tested on open field (OF), object recognition (OR) and object placement (OP) tasks. Stressed females gained less weight during stress than controls. On the OF, there were no group differences in locomotor activity, but stressed females made fewer inner visits than controls, indicating increased anxiety. Both groups successfully performed the OP and OR tasks across all inter-trial delays, indicating intact non-spatial and spatial memory in both control and stress females. The current results provide preliminary evidence that the commonly used chronic restraint stress model may not be an efficient stressor to female rats.     

Histidine-decarboxylase knockout mice show deficient nonreinforced episodic object memory, improved negatively reinforced water-maze performance, and increased neo- and ventro-striatal dopamine turnover

The brain's histaminergic system has been implicated in hippocampal synaptic plasticity, learning, and memory, as well as brain reward and reinforcement. Our past pharmacological and lesion studies indicated that the brain's histamine system exerts inhibitory effects on the brain's reinforcement respective reward system reciprocal to mesolimbic dopamine systems, thereby modulating learning and memory performance. Given the close functional relationship between brain reinforcement and memory processes, the total disruption of brain histamine synthesis via genetic disruption of its synthesizing enzyme, histidine decarboxylase (HDC), in the mouse might have differential effects on learning dependent on the task-inherent reinforcement contingencies. Here, we investigated the effects of an HDC gene disruption in the mouse in a nonreinforced object exploration task and a negatively reinforced water-maze task as well as on neo- and ventro-striatal dopamine systems known to be involved in brain reward and reinforcement. Histidine decarboxylase knockout (HDC-KO) mice had higher dihydrophenylacetic acid concentrations and a higher dihydrophenylacetic acid/dopamine ratio in the neostriatum. In the ventral striatum, dihydrophenylacetic acid/dopamine and 3-methoxytyramine/dopamine ratios were higher in HDC-KO mice. Furthermore, the HDC-KO mice showed improved water-maze performance during both hidden and cued platform tasks, but deficient object discrimination based on temporal relationships. Our data imply that disruption of brain histamine synthesis can have both memory promoting and suppressive effects via distinct and independent mechanisms and further indicate that these opposed effects are related to the task-inherent reinforcement contingencies.     

Chronic stress modulates the use of spatial and stimulus-response learning strategies in mice and man

Acute stress modulates multiple memory systems in favor of caudate nucleus-dependent stimulus-response and at the expense of hippocampus-dependent spatial learning and memory. We examined in mice and humans whether chronic stress has similar consequences. Male C57BL/6J mice that had been repeatedly exposed to rats ("rat stress") used in a circular hole board task significantly more often a stimulus-response strategy (33%) than control mice (0%). While velocity was increased, differences in latency to exit hole, distance moved or number of holes visited were not observed. Increased velocity and performance during retention trials one day later indicates altered emotionality and motivation to explore in rat stressed mice. Forty healthy young men and women were split into "high chronic stress" and "low chronic stress" groups based on their answers in a chronic stress questionnaire ("Trier Inventory of Chronic Stress"-TICS) and trained in a 2D task. A test trial immediately after training revealed that participants of the "high chronic stress" group used the S-R strategy significantly more often (94%) than participants of the "low chronic stress" group (52%). Verbal self-reports confirmed the strategy derived from participants' choice in the test trial. Learning performance was unaffected by the chronic stress level. We conclude that one consequence of chronic stress is the shift to more rigid stimulus-response learning, that is accompanied by changes in motivational factors in mice.