Long-term continuous, but not daily, environmental enrichment reduces spatial memory decline in aged male mice

Although environmental enrichment improves spatial memory and alters synaptic plasticity in aged rodents, it is unclear whether all types of enrichment treatments yield similar benefits. The present study examined the effects in aged male mice of three types of enrichment on spatial memory in Morris water maze and radial arm maze tasks, and on levels of the presynaptic protein synaptophysin in several brain regions. Non-enriched young and aged males were compared with males exposed to one of the following treatments for 10 weeks: 5 min of daily handling, 3 h of daily basic enrichment, or 24 h of continuous complex enrichment. Young controls outperformed aged controls in both tasks. Neither daily handling nor daily enrichment affected spatial memory or synaptophysin levels. In contrast, continuous enrichment significantly reduced age-related spatial memory decline in both tasks, such that this group was statistically indistinguishable from young controls in most measures of performance. Continuously enriched mice were also significantly better than other aged mice in several spatial memory measures. Despite these improvements, synaptophysin levels in the continuous enrichment group were significantly lower than those of young and aged controls in the frontoparietal cortex, hippocampus, and striatum, suggesting a negative relationship between synaptophysin levels and spatial memory in aged males. These data demonstrate that different types of enrichment in aged male mice have disparate effects on spatial memory, and that the relationship between enrichment-induced changes in synaptophysin levels and spatial memory in aged males differs from that we have previously reported in aged female mice.     

Environmental enrichment results in cortical and subcortical changes in levels of synaptophysin and PSD-95 proteins

Experience-dependent plasticity is thought to involve selective change in pre-existing brain circuits, involving synaptic plasticity. One model for looking at experience-dependent plasticity is environmental enrichment (EE), where animals are exposed to a complex novel environment. Previous studies using electron microscopy showed that EE resulted in synaptic plasticity in the visual cortex and hippocampus. However, the areas in the brain that have been examined following EE have been limited. The present study quantified potential synaptic plasticity throughout the brains of C57BL/6 mice using an enzyme-linked immunosorbent assay (ELISA) for two synaptic proteins, synaptophysin and PSD-95. EE resulted in increased synaptophysin and PSD-95 levels through major brain regions, including anterior and posterior areas of the forebrain, hippocampus, thalamus, and hypothalamus. However, no changes in synaptophysin were detected in the cerebellum. These results demonstrate that EE results in an increase in levels of both pre- and post-synaptic proteins in multiple regions of the brain, and it is possible that such changes represent the underlying synaptic plasticity occurring in EE.     

Training and transfer effects of long-term memory retrieval training

ABSTRACT

Long-term memory retrieval ability and working memory can share attention control ability. Based on cognitive plasticity, a hypothesis that cognitive training could improve long-term memory retrieval efficiency and that this could transfer to retrieval involving working memory was proposed. 60 undergraduates were randomly assigned to a group of training and an active control group; all the participants completed the same tasks in the same order before and after the training, the tasks included a long-term memory retrieval access task, a intelligence test, a switching task, a working memory updating task, a response inhibition task and an interference control task. The statistics results indicate that cognitive training can improve long-term memory retrieval efficiency and has a transfer effect on working memory updating, interference control and switching ability, but not on response inhibition or intelligence. This reveal the plasticity of long-term memory retrieval and its influence on working memory.     

Life-long environmental enrichment differentially affects the mnemonic response to estrogen in young, middle-aged, and aged female mice

The present study was designed to examine whether life-long exposure to standard or enriched housing affects the ability of estrogen to improve spatial and object memory throughout the lifespan. Three-week-old female mice were maintained in standard or enriched housing up to and through ovariectomy and behavioral testing at 5, 17, or 22 months of age. Spatial memory was tested in the Morris water maze and object memory was tested using an object recognition task. Immediately after training each day, mice were injected intraperitoneally with vehicle or 0.2 mg/kg 17beta-estradiol. Among young females, object recognition was enhanced by estradiol alone, an effect that was reduced by enrichment. In contrast, spatial water maze performance was impaired by estradiol alone, but improved by the combination of both estradiol and enrichment. At middle-age, object recognition was enhanced by estradiol or enrichment alone, and the combination of both treatments. Spatial memory in the water maze was also improved by both treatments at middle-age, but the beneficial effects of estradiol were limited to standard-housed females. Finally, whereas enrichment in aged females significantly enhanced performance in both tasks, estradiol had no effect at this age in either task. In total, the data indicate that life-long enrichment can significantly alter the extent to which estradiol affects memory in mice throughout the lifespan. Importantly, the interaction between these treatments is highly dependent on age and type of memory tested.     

工作记忆训练对认知功能和大脑神经系统的影响

工作记忆训练成为近年来提升个体认知绩效的一种有效方式。工作记忆训练主要是指采用工作记忆广度任务、刷新任务以及各种复杂工作记忆任务在计算机上以循序渐进的方式进行训练。近年来的研究发现, 工作记忆训练能提升工作记忆、流体智力、抑制、注意、阅读和数学等认知功能。神经机制的研究发现：工作记忆训练引起大脑额-顶区域激活减弱, 而皮层下结构包括纹状体和尾状核区域的激活增强; 工作记忆训练减少了大脑灰质的数量, 增强了大脑白质的功能连通性; 工作记忆训练引起尾状核上多巴胺受体的变化。未来的研究需要在研究设计、被试人群、研究手段上进一步确认和扩展工作记忆训练的有效性和内在认知神经机制。     

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     

基于中央执行功能的儿童工作记忆可塑性机制

近期的研究发现儿童的工作记忆能力具有一定的可塑性。研究者采用双盲对照实验设计, 通过改编的工作记忆广度、N-back、活动记忆和GO-NOGO等任务对15岁以下的正常儿童和特殊儿童(多动症、智力低下等)的工作记忆能力进行训练, 训练的周期一般为15~30天不等, 每天训练时长约15~25分钟。研究结果发现, 工作记忆训练不仅可以提高儿童的工作记忆能力, 而且还可以迁移至其它高级认知功能(流体智力、数学能力等), 甚至可以改善多动症儿童的临床症状。研究者还发现这种训练效应可以保持3~6个月。通过工作记忆中央执行功能的训练, 是否可以促进儿童认知功能的发展？儿童认知功能的可塑性表现为短暂的提高还是促进认知发展？中央执行功能的训练如何影响儿童认知加工过程的发展？这些问题的回答对于近一步探索认知活动和认知神经的可塑性具有一定的理论意义。可以为工作记忆缺陷儿童的临床干预和治疗提供有效的工具, 具有实践意义。     

工作记忆刷新功能的可塑性

从工作记忆刷新功能的训练入手, 以不同人群为研究对象, 采用活动记忆任务, 从行为层面和认知神经层面探讨工作记忆刷新功能的可塑性。结果发现, 工作记忆刷新功能具有可塑性。具体表现为, 通过刷新功能训练, 个体在工作记忆刷新任务上的成绩提高。工作记忆刷新功能训练使得个体对刺激的识别能力增强, 对无关信息的抑制能力提高, 进而促使工作记忆中的更新能力得到提升。通过工作记忆刷新训练可以提高个体其它认知功能, 但是, 相对于认知能力稳定以及衰退的个体, 这种迁移效应在工作记忆能力发展个体中的表现更为明显。     

Environmental enrichment modifies the PKA-dependence of hippocampal LTP and improves hippocampus-dependent memory

cAMP-dependent protein kinase (PKA) is critical for the expression of some forms of long-term potentiation (LTP) in area CA1 of the mouse hippocampus and for hippocampus-dependent memory. Exposure to spatially enriched environments can modify LTP and improve behavioral memory in rodents, but the molecular bases for the enhanced memory performance seen in enriched animals are undefined. We tested the hypothesis that exposure to a spatially enriched environment may alter the PKA dependence of hippocampal LTP. Hippocampal slices from enriched mice showed enhanced LTP following a single burst of 100-Hz stimulation in the Schaffer collateral pathway of area CA1. In slices from nonenriched mice, this single-burst form of LTP was less robust and was unaffected by Rp-cAMPS, an inhibitor of PKA. In contrast, the enhanced LTP in enriched mice was attenuated by Rp-cAMPS. Enriched slices expressed greater forskolin-induced, cAMP-dependent synaptic facilitation than did slices from nonenriched mice. Enriched mice showed improved memory for contextual fear conditioning, whereas memory for cued fear conditioning was unaffected following enrichment. Our data indicate that exposure of mice to spatial enrichment alters the PKA dependence of LTP and enhances one type of hippocampus-dependent memory. Environmental enrichment can transform the pharmacological profile of hippocampal LTP, possibly by altering the threshold for activity-dependent recruitment of the cAMP-PKA signaling pathway following electrical and chemical stimulation. We suggest that experience-dependent plasticity of the PKA dependence of hippocampal LTP may be important for regulating the efficacy of hippocampus-based memory.     

Effects of daily environmental enrichment on memory deficits and brain injury following neonatal hypoxia-ischemia in the rat

Environmental enrichment (EE) results in improved learning and spatial memory, as well as attenuates morphological changes resulting from cerebral ischemia in adult animals. This study examined the effects of daily EE on memory deficits in the water maze and cerebral damage, assessed in the hippocampus and cerebral cortex, caused by neonatal hypoxia-ischemia. Male Wistar rats in the 7th postnatal day were submitted to the Levine-Rice model of neonatal hypoxia-ischemia (HI), comprising permanent occlusion of the right common carotid artery and a period of hypoxia (90 min, 8%O(2)-92%N(2)). Starting two weeks after the HI event, animals were stimulated by the enriched environment (1h/day for 9 weeks); subsequent to the stimulation, performance of animals in the water maze was assessed. HI resulted in spatial reference and working memory impairments that were completely reversed by EE. Following the behavioral study, animals were killed and the hippocampal volume and cortical area were estimated. There was a significant reduction of both hippocampal volume and cortical area, ipsilateral to arterial occlusion, in HI animals; environmental stimulation had no effect on these morphological measurements. Presented data indicate that stimulation by the daily environmental enrichment recovers spatial memory deficits caused by neonatal hypoxia-ischemia without affecting tissue atrophy in either hippocampus or cortex.     

有氧运动对记忆的影响及其神经生物学机制

有氧运动是氧气充足时运用大型肌肉群进行有节奏的持续运动。有氧运动可以加快工作记忆任务中的反应速度; 在记忆编码前和记忆巩固阶段进行高强度有氧运动有助于提升情景记忆; 高强度有氧运动可以促进内隐记忆。有氧运动可以促进神经营养因子的产生, 引起长时程增强, 激活海马等与记忆相关的脑区并促进神经元再生。未来可探究有氧运动开始和持续时间的影响、有氧运动强度和认知参与的影响、有氧运动对不同年龄性别群体的影响以及脑源性神经营养因子的中介作用, 从而深入揭示有氧运动对记忆的影响及其神经生物学机制。     

An ecological approach to cognitive enhancement: Complex motor training

Cognitive training has received a lot of attention recently, yielding findings that can be conflicting and controversial. In this paper, we present a novel approach to cognitive training based on complex motor activities. In a randomized controlled design, participants were assigned to one of three conditions: aerobic exercise, working memory training or designed sport — an intervention specifically tailored to include both physical and cognitive demands. After training for eight weeks, the designed sport group showed the largest gains in all cognitive measures, illustrating the efficacy of complex motor activities to enhance cognition. Designed sport training also revealed impressive health benefits, namely decreased heart rate and blood pressure. In this period of skepticism over the efficacy of computerized cognitive training, we discuss the potential of ecological interventions targeting both cognition and physical fitness, and propose some possible applications.     

Auditory specific fear conditioning results in increased levels of synaptophysin in the basolateral amygdala

Auditory fear conditioning is one of the most well characterized models used in studies of learning and memory. In order to ensure the animals have been conditioned to fear the auditory stimulus, animals are generally tested for their response to this stimulus in a different context to that used for training. For this reason it is often unclear how much contextual fear conditioning the animals also acquire when they are trained. In this study, we have established a protocol for fear conditioning in mice which is explicit for auditory cues; mice trained using this protocol, show a very low fear response to contextual cues encountered during training. We have undertaken analysis to look for potential brain changes associated with this model by measuring levels of the synaptic vesicle protein, synaptophysin, in the basolateral nuclei of the amygdala following auditory fear conditioning. Our results show levels of synaptophysin were significantly higher in mice which learnt to associate the auditory stimulus with fear, in comparison to all non-learning control animals. These findings support the idea that synaptic plasticity associated with formation of fear conditioning to a single specific conditioned stimulus occurs within the basolateral nuclei of the amygdala. Furthermore, our results demonstrate the usefulness of this model in looking for changes in the brain specific for a defined learning event.     

Long-term exposure to environmental enrichment since youth prevents recognition memory decline and increases synaptic plasticity markers in aging

Aging-associated brain changes include functional alterations that are usually related with memory decline. Epidemiological reports show that a physically and intellectually active life provides a protective effect on this decline and delays the onset of several neurodegenerative diseases. The cellular mechanisms behind the behavioral-based therapies, such as environmental enrichment (EE) exposure, as a method for alleviating age-related memory impairments, are still unknown. Although some reports have shown the benefits of EE exposure in cognitive outcomes in old mice and in animals with experimental neurodegenerative conditions, the effects of lifelong animal exposure to EE have not been explored in detail. In the present work we tested in a rat model the effects of intermittent lifelong exposure since youth to EE on behavioral performance, object recognition memory and anxiety level, as well as on some morphological and biochemical markers of brain plasticity such as hippocampal neurogenesis, synaptophysin content and synaptic morphology. We found that environmental factors have a positive impact on short-memory preservation, as well as on the maintenance of synapses and in the increase in number of new generated neurons within the hippocampus during aging.     

Effects of environmental enrichment on spatial memory and neurochemistry in middle-aged mice

The present study compared the effects of environmental enrichment on spatial memory, glutamic acid decarboxylase (GAD) activity, and synaptophysin levels in middle-aged male and female mice. Prior to testing, a subset of 18-month-old male and female C57BL/6 mice was housed with two to three toys and a running wheel in the home cage for up to 29 d. Adult mice (7 mo) of both sexes and the remaining middle-aged mice were group (social) housed, but not exposed to enriching objects. After the enrichment period, all mice were tested in a 1-day version of the Morris water maze, in which both spatial and nonspatial memory were assessed. Immediately after testing, the hippocampus and frontoparietal cortex were dissected, and GAD activity and synaptophysin levels were measured. Environmental enrichment reduced the age-related impairment in spatial acquisition and retention; relative to adult social controls, middle-aged enriched mice were unimpaired, whereas middle-aged social controls were impaired. This reduction was similar in middle-aged males and females. Enrichment did not affect cued memory in either sex. Although hippocampal GAD activity was increased by enrichment in males, all other neurochemical measurements were unaffected by enrichment or aging in either sex. These data suggest that environmental enrichment initiated at middle age can reduce age-related impairments in spatial memory in males and females, although the underlying neurobiological mechanisms of this effect remain unknown.     

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。     

经颅直流电刺激提高记忆功能

经颅直流电刺激是最近复兴的非侵入性无创脑刺激方法, 具有轻便、廉价、较为安全的特点。经颅直流电刺激能产生一系列生理变化, 相比传统脑成像方法具有优势, 在工作记忆、陈述性记忆、程序性记忆上已有应用, 可与传统认知训练相结合。经颅直流电刺激虽然不能进行精确定位, 但是能够基于脑区影响个体认知加工过程。经颅直流电刺激在临床上可以作为治疗手段, 对健康人可以作为神经训练的方法, 在心理学领域具有良好的研究前景。     

工作记忆刷新及其训练效应——经颅直流电刺激的作用

工作记忆刷新是执行功能的重要成分之一。以往研究结合n-back任务和经颅直流电刺激（transcranial direct current stimulation ,tDCS）技术探究刷新能力,发现tDCS技术能够一定程度上增强刷新训练效果并引起大脑神经元相关活动的变化,其增强效果能够维持一定的时间,且能够迁移到其他认知任务之中。但tDCS的干预效果在各项研究中存在一定的差异性。其作用效果会受到训练任务与训练方式、电流强度、电极布局和训练时间间隔等因素的影响。未来研究可以探索tDCS结合刷新训练的最佳刺激参数,以获得最优化的干预效果。     

The extracellular protease matrix metalloproteinase-9 is activated by inhibitory avoidance learning and required for long-term memory

Matrix metalloproteinases (MMPs) are a family of extracellularly acting proteolytic enzymes with well-recognized roles in plasticity and remodeling of synaptic circuits during brain development and following brain injury. However, it is now becoming increasingly apparent that MMPs also function in normal, nonpathological synaptic plasticity of the kind that may underlie learning and memory. Here, we extend this idea by investigating the role and regulation of MMP-9 in an inhibitory avoidance (IA) learning and memory task. We demonstrate that following IA training, protein levels and proteolytic activity of MMP-9 become elevated in hippocampus by 6 h, peak at 12-24 h, then decline to baseline values by approximately 72 h. When MMP function is abrogated by intrahippocampal infusion of a potent gelatinase (MMP-2 and MMP-9) inhibitor 3.5 h following IA training, a time prior to the onset of training-induced elevation in levels, IA memory retention is significantly diminished when tested 1-3 d later. Animals impaired at 3 d exhibit robust IA memory when retrained, suggesting that such impairment is not likely attributed to toxic or other deleterious effects that permanently disrupt hippocampal function. In anesthetized adult rats, the effective distance over which synaptic plasticity is impaired by a single intrahippocampal infusion of the MMP inhibitor of the kind that blocks IA memory is approximately 1200 microm. Taken together, these data suggest that IA training induces a slowly emerging, but subsequently protracted period of MMP-mediated proteolysis critical for enabling long-lasting synaptic modification that underlies long-term memory consolidation.     

脑内乙酰胆碱与认知活动的关系

脑内细胞外乙酰胆碱（ACh）的变化主要反映胆碱能神经元的活动,皮层和海马等脑区的ACh主要来源于基底前脑胆碱能神经元的纤维投射。应用微透析等技术在体检测清醒、自由活动动物认知过程中脑内乙酰胆碱的含量,可以研究ACh与特定行为反应和认知活动之间的关系。研究发现当机体需要对新刺激进行分析时,在学习与记忆、空间工作记忆、注意、自发运动和探究行为等认知活动中,基底前脑胆碱能神经元被激活,脑内ACh的释放也随之改变。结果提示脑内胆碱能递质系统活动与认知过程密切相关