大鼠纹状体边缘区和海马空间学习功能比较的研究

目的　 研究纹状体边缘区和海马在空间学习功能方面有无区别。方法　 将大鼠穹隆海马伞切断及向边缘区注射海人藻酸 ,用Morris水迷宫测试两实验组和相应对照组的空间学习能力的变化。结果　 穹隆海马伞组和边缘区注射海人藻酸组的平均逃避潜伏期与对照组相比均有延长 ,而且延长幅度大致相同。穿环数均有所下降 ,幅度也大致相同。 结论　 纹状体边缘区同海马一样 ,与大鼠的空间学习功能有着密切关系。     

腺病毒介导BDNF基因转移对大鼠创伤性脑损伤后iNOS表达及细胞凋亡的影响

研究重组腺病毒介导的脑源性神经营养因子（brain derived neurotrophic factor,BDNF)基因转移对创伤性脑损伤（TBI）后诱导型一氧化氮合酶（inducible nitric oxide synthase,iNOS)表达及细胞凋亡的影响。将重组腺病毒载体4μl注入承受单侧大脑皮质重锤打击的大鼠海马,对照组注射病毒缓冲液。伤后3h及1,3,7,14d利用免疫组化单标／双标染色。原位杂交／组化染色及DNA末端原位标记等方法,检测伤侧大脑皮质和海马各多区iNOS、BDNF及凋亡相关信号表达的改变。与对照组相比,同伤组大脑皮质及海马各区iNOS阳性细胞于伤后3h开始显著增多,7d达高峰。多数iNOS阳性细胞同时呈现凋亡相关蛋白阳性反应或TUNEL阳性反应,但很少同时表达BDNF mRNA。注射病毒载体组后3,7d,海马CA1区和DH区表达iNOS、凋亡相关蛋白的细胞及凋亡细胞显著减少（P均＜0．01）,而表达BDNF mRNA的神经元显著增多。提示,TBI诱导海马细胞表达iNOS及诱导海马细胞凋亡;腺病毒介导的BDNF基因转移通过抑制iNOS表达、增加BDNF表达及减少细胞凋亡的机制保护海马神经元。     

脑缺血再灌注拟血管性痴呆小鼠皮层及海细胞病理形态学动态观察

目的观察脑缺血再灌注拟血管性痴呆小鼠大脑皮层及海马细胞病理形态学的较长期演变.方法复制脑缺血再灌注拟血管性痴呆小鼠模型,分别于术后7d、15d、30d脑部取材,石蜡切片,HE与Nissl染色,对皮层及海马细胞病理形态学进行较长期动态观察.结果 7d模型小鼠大脑皮质变薄,部分神经细胞核固缩,局限性神经元数目减少,出现筛网状结构,胶质细胞增生,15d、30d镜下与7d基本相同.海马CA1区细胞脱失,随时间推移逐渐加重,至术后30d,海马CA1区细胞几乎完全脱失,胶质细胞大量增生,形成结节,CA2、CA3区细胞也严重脱失,呈现海马硬化.结论海马锥体细胞的迟发性坏死是缺血性脑血管病致痴呆的病理学基础.     

健康人脑空间工作记忆的脑功能磁共振研究

目的 通过功能磁共振成像(unctional magnetic resonance imaging, fMRI)技术研究健康人脑空间工作记忆的功能脑区.方法 10名右利手健康志愿者进行空间工作记忆任务的同时进行fMRI扫描,实验采用组块设计和SPM99软件进行数据分析和脑功能区定位.结果 大脑皮质所激活的主要脑区有双侧顶叶(BA7/40,BA:Brodmann area,布鲁德曼分区),双侧额叶(BA6/9/47),双侧枕颞交界处(BA19/37);被激活的大脑皮质下结构有右侧尾状核、左侧丘脑和左侧中脑黑质;双侧小脑也均被显著激活(P<0.001).结论 人脑处理空间工作记忆信息是由大脑皮质下结构及小脑与大脑皮质共同完成的.     

大鼠慢性脑缺血后海马CA_1区HCN1及p38MAPK的表达

目的探讨慢性脑缺血后大鼠海马HCN1及p38MAPK表达变化及意义。方法双侧颈总动脉永久性结扎(two vessels occlusion,2VO)制备慢性脑缺血模型,40只雄性Wistar大鼠随机分为缺血1 m组和缺血2 m组,每组均设对照组,共4组。应用Morris水迷宫、HE染色、Western blot及免疫荧光双重染色观察各组大鼠认知功能改变、海马CA1区形态学变化、HCN1和p38MAPK定位及表达情况。结果与对照组相比,大鼠缺血1 m时即出现空间学习记忆能力障碍,且缺血2 m组较1 m组更加显著,具有统计学意义(P<0.05);缺血1 m组海马CA1区可见锥体细胞变性,排列松散,个别细胞脱失,伴炎细胞浸润及胶质细胞增生;缺血2 m组海马CA1区可见锥体细胞排列紊乱,细胞脱失明显;HCN1和p38MAPK共同表达于海马CA1区锥体细胞,并且随着缺血时间的延长,海马区p38MAPK表达上调、HCN1表达下调,具有显著性差异(P<0.05)。结论慢性脑缺血导致海马CA1区神经元损伤进而影响认知功能;HCN1和p38MAPK在海马CA1区锥体细胞共同表达;随着缺血时间延长p38MAPK表达上调,HCN1表达下调,推测是慢性脑缺血大鼠认知功能损伤机制之一。     

血管性轻度认知功能损害对大鼠前脑神经元和胶质细胞的影响

目的：观察血管性轻度认知功能损害（VMCI）大鼠模型的前脑神经元、星形胶质细胞和小胶质细胞数的变化。方法：用分次结扎大鼠双侧颈总动脉（BCCAO）40d建立VMCI模型（BCCAO组）,以假手术组（SHAM组）为对照,每组n=6。在模型建立前和建立后40d对大鼠进行感觉、运动神经功能和步态的评估,采用T型迷宫评估额叶皮质下环路相关的空间工作记忆和海马相关的空间及非空间相关记忆,免疫组化染色分别检测不同脑区的神经元和胶质细胞数的变化。结果：两组大鼠均无明确感觉和运动神经功能缺失,但BCCAO组的大鼠出现步态障碍。T型迷宫评估,BCCAO组的大鼠额叶皮质下环路相关的空间工作记忆和海马相关的空间及非空间相关记忆受损。两组大鼠海马CA1区β-tubulin阳性细胞面积百分比的定量分析差异无统计学意义（P〉0．05）。BCCAO组在CC区、ic区和opt区GFAP的阳性细胞面积百分比明显高于SHAM组（P〈0．05）;BCCAO组CC区、ic区和opt区和海马CA1区的CD11b阳性细胞面积百分比亦明显高于SHAM组（P〈0．05）。结论：VMCI模型大鼠表现为无运动障碍的步态损害和轻度的空间工作记忆障碍;VMCI早期可不表现为神经元数量的缺失,但其功能可能已经受损,病理特点还包括发挥神经毒性作用的小胶质细胞的活化和白质病变。     

轻度认知损害患者空间导航能力相关皮质下核团体积研究

目的探讨轻度认知损害患者皮质下核团体积与空间导航能力之间的关系。方法采用计算机空间导航障碍测试系统测试30例轻度认知损害患者和性别、年龄、受教育程度相匹配的28例正常对照者空间导航能力,FreeSurfer 5.3.0软件对三维T1WI图像进行结构分割,计算皮质下核团(双侧丘脑、尾状核、壳核、苍白球、海马、杏仁体和伏隔核)体积以及全脑体积。Pearson相关分析分析空间导航能力与皮质下核团体积的相关性。结果轻度认知损害患者混合(环境参照和自我参照)导航(P=0.034)、自我参照导航(P=0.004)、环境参照导航(P=0.011)误差距离均大于正常对照者,而双侧丘脑(P=0.953,0.250)、尾状核(P=0.938,0.672)、壳核(P=0.421,0.912)、苍白球(P=0.446,0.360)、海马(P=0.545,0.647)、杏仁体(P=0.565,0.993)、伏隔核(P=0.271,0.796)和全脑(P=0.567)体积组间差异无统计学意义。Pearson相关分析显示,轻度认知损害患者混合(环境参照和自我参照)导航误差距离与左侧苍白球(r=-0.284,P=0.034)和左侧海马(r=-0.265,P=0.048)体积呈负相关,环境参照导航误差距离与左侧壳核体积呈负相关(r=-0.305,P=0.022)。结论轻度认知损害患者空间导航能力与皮质下核团体积相关,对进一步研究空间导航障碍的发生机制具有重要意义。     

β-淀粉样蛋白对海马长时程增强的影响及作用机制

阿尔茨海默病(AD)是老年人群中最普遍的神经退行性疾病,其主要特征是海马区淀粉样蛋白寡聚体的沉积.β-淀粉样蛋白(Aβ)聚合成寡聚状态被认为是AD发病过程中最重要的环节,而海马区是AD发病中的最敏感的区域.AD的早期临床症状即包括与海马相关的认知功能的下降,如空间学习和记忆能力的下降等.长时程增强(LTP)是反映突触可塑性的重要指标之一,被认为与学习和记忆的形成有关.本文结合近年来相关研究,就Aβ对海马LTP的影响及其主要机制作一阐述.     

石杉碱甲、尼莫地平对脑缺血鼠学习记忆障碍与血管内皮生长因子、Caspase-3表达的影响

目的:对脑缺血大鼠采用尼莫地平与石杉碱甲进行药物干预治疗,观察治疗后不同药物组血管内皮生长因子(VEGF)、caspase-3表达水平与学习记忆改善程度。方法:采用免疫组化和Y迷宫检测脑缺血鼠学习记忆功能的变化及VEGF、caspase-3在缺血区的表达。结果:各治疗组VEGF、caspase-3在海马区、大脑皮质、基底节区表达均显著低于脑缺血对照组(A组)P<0.01,尤以海马、大脑皮质区较显著。其中石杉碱甲加尼莫地平干预组(B组)VEGF、caspase-3细胞阳性表达的降低和学习记忆功能的改善,明显好于A、C、D组,P<0.01。结论:石杉碱甲加尼莫地平治疗组与其他药物治疗组比,能有效改善VEGF、caspase-3表达水平和提高学习记忆的能力,为认知障碍早期的治疗提供依据。     

Tau蛋白过度磷酸化对脑淀粉样蛋白生成的影响

目的研究tau蛋白过度磷酸化对脑淀粉样蛋白生成的影响。方法用蛋白磷酸酯酶抑制剂冈田酸（OA）在大鼠侧脑室内注射,每天1次连续8周。用Morris水迷宫和免疫组化方法观察OA组大鼠行为学改变、神经原纤维缠结及淀粉样蛋白的表达;并与对照组比较。结果与对照组相比,OA组大鼠Morris水迷宫平均潜伏期显著延长,学习获取能力较差,空间记忆能力衰退。OA组大鼠的海马CA1区、CA3区、CA4区、齿状回、大脑皮质出现tau蛋白磷酸化,神经原纤维缠结;大脑皮质及海马CA1区、CA3区、齿状回等部位出现β淀粉样蛋白沉积。结论Tau蛋白过度磷酸化可以增加脑部淀粉样蛋白的沉积。     

Sex differences in spatial learning and prefrontal and parietal cortical dendritic morphology in the meadow vole, Microtus pennsylvanicus

The prefrontal and parietal cortex has been implicated in the mediation of spatially related behaviors in male and female laboratory rats. Meadow voles, Microtus pennsylvanicus, are diurnally–crepuscularly active microtine rodents that exhibit a variety of sexually dimorphic spatially associated behaviors in both the laboratory and wild. In the present study we examined both the spatial Morris water maze performance and dendritic architecture and branching of neuronal cells in the prefrontal and parietal cortex of reproductive male and female meadow voles. Males learned the location of the hidden platform in the water task faster than estrous females and on probe trials they spent more time in the previously correct quadrant than females. Dendritic analysis with Golgi–Cox stained sections showed that male voles had significantly more dendritic arborization in the medial prefrontal and parietal cortex than females. These sex differences in both spatial navigation ability and in neural structures related to spatial navigation in meadow voles suggest that the size of neural areas might be shaped by ecological pressures associated with sexually dimorphic spatial behaviors.     

人尿激肽原酶对大鼠脑缺血再灌注后空间学习记忆功能及皮质巢蛋白表达的影响

目的 探讨人尿激肽原酶(HUK)对大鼠局部脑缺血再灌注后缺血侧皮质巢蛋白的表达及空间学习记忆能力障碍的作用. 方法 60只大鼠按随机数字表法分为5组:假手术组、脑缺血组、HUK低剂量组(3.5×10-3PNAU/kg)、HUK中剂量组(8.75×10-3PNAU/kg)和HUK高剂量组(17.5×10-3PNAU/kg),线栓法制作大鼠大脑中动脉阻塞再灌注模型,HUK治疗组于术后2周内腹腔注射HUK.第15天开始各组大鼠采用Morris水迷宫装置评价大鼠的空间学习记忆能力,免疫组化染色检测缺血侧皮质巢蛋白的表达. 结果 脑缺血组大鼠在定向航行试验和空间探索试验中均表现出明显的空间认知功能障碍.在定向航行试验中,HUK中、高剂量治疗组大鼠平均逃避潜伏期与缺血组比较明显缩短,差异有统计学意义(P＜0.05).在空间探索试验中,HUK中、高剂量治疗组大鼠原平台象限停留时间百分比以及穿过原平台位置次数均大于脑缺血组,比较差异有统计学意义(P＜0.05).缺血侧皮质巢蛋白免疫组化染色结果 显示,HUK中、高剂量治疗组大鼠缺血侧皮质巢蛋白的吸光度值明显高于脑缺血组,比较差异有统计学意义(P＜0.05). 结论 HUK可以明显改善大鼠局部脑缺血再灌注后的空间学习记忆能力,其机制可能与HUK增加缺血侧皮质巢蛋白的表达,促进神经再生有关.     

Where is the “where” in the brain? A meta‐analysis of neuroimaging studies on spatial cognition

Spatial representations are processed in the service of several different cognitive functions. The present study capitalizes on the Activation Likelihood Estimation (ALE) method of meta‐analysis to identify: (a) the shared neural activations among spatial functions to reveal the “core” network of spatial processing; (b) the specific neural activations associated with each of these functions. Following PRISMA guidelines, a total of 133 fMRI and PET studies were included in the meta‐analysis. The overall analysis showed that the core network of spatial processing comprises regions that are symmetrically distributed on both hemispheres and that include dorsal frontoparietal regions, presupplementary motor area, anterior insula, and frontal operculum. The specific analyses revealed the brain regions that are selectively recruited for each spatial function, such as the right temporoparietal junction for shift of spatial attention, the right parahippocampal gyrus, and the retrosplenial cortex for navigation and spatial long‐term memory. The findings are integrated within a systematic review of the neuroimaging literature and a new neurocognitive model of spatial cognition is proposed.     

Spatial navigation and hippocampal place cell firing: the problem of goal encoding

Place cells are hippocampal neurons whose discharge is strongly related to a rat's location in the environment. The existence of such cells, combined with the reliable impairments seen in spatial tasks after hippocampal damage, has led to the proposal that place cells form part of an integrated neural system dedicated to spatial navigation. This hypothesis is supported by the strong relationships between place cell activity and spatial problem solving, which indicate that the place cell representation must be both functional and in register with the surroundings for the animal to perform correctly in spatial tasks. The place cell system nevertheless requires other essential elements to be competent, such as a component that specifies the overall goal of the animal and computes the path required to take the rat from its current location to the goal. Here, we propose a model of the neural network responsible for spatial navigation that includes goal coding and path selection. In this model, the hippocampal formation allows for place recognition, and stores the set of places that can be accessed from each position in the environment. The prefrontal cortex is responsible for encoding goal location and for route planning. The nucleus accumbens translates paths in neural space into appropriate locomotor activity that moves the animal towards the goal in real space. The complete model assumes that the hippocampal output to nucleus accumbens and prefrontal cortex provides information for generating solutions to spatial problems. In support of this model, we finally present preliminary evidence that the goal representation necessary for path planning might be encoded in the prelimbic/infralimbic region of the medial prefrontal cortex.     

Changes in adult brain and behavior caused by neonatal limbic damage: implications for the etiology of schizophrenia

We tested the hypothesis that limbic damage in early development can cause aberrant maturation of brain structures known to be abnormal in adult schizophrenics: the hippocampus, prefrontal cortex, ventricles, and forebrain dopamine systems. We measured brain morphology, locomotor response to apomorphine, and cognitive processes in adult rats which received electrolytic damage to amygdala or hippocampus 48 h after birth. The behavioral measurements involved tasks which depend upon the integrity of the hippocampus or prefrontal cortex, and a task sensitive to forebrain dopamine system activation. The tasks included place navigation, egocentric spatial ability, and apomorphine-induced locomotion. The rats with lesions showed poor performance on the place navigation and egocentric spatial tasks and more apomorphine-induced locomotion after puberty than the sham lesion group. Regardless of lesion location, the adult rats showed smaller amygdalae and hippocampi, and larger lateral ventricles. Analyzing the lesion and sham rats together, adult amygdala volume was found to be positively correlated with cerebral cortex, prefrontal cortex, and hippocampal volumes and place navigation performance, and was negatively correlated with lateral ventricle volume. This study contributes to our understanding of the pathogenesis of schizophrenia by showing that early damage to limbic structures produced behavioral, morphological, and neuropharmacological abnormalities related to pathology in adult schizophrenics.     

Applications of the Morris water maze in the study of learning and memory

The Morris water maze (MWM) was described 20 years ago as a device to investigate spatial learning and memory in laboratory rats. In the meanwhile, it has become one of the most frequently used laboratory tools in behavioral neuroscience. Many methodological variations of the MWM task have been and are being used by research groups in many different applications. However, researchers have become increasingly aware that MWM performance is influenced by factors such as apparatus or training procedure as well as by the characteristics of the experimental animals (sex, species/strain, age, nutritional state, exposure to stress or infection). Lesions in distinct brain regions like hippocampus, striatum, basal forebrain, cerebellum and cerebral cortex were shown to impair MWM performance, but disconnecting rather than destroying brain regions relevant for spatial learning may impair MWM performance as well. Spatial learning in general and MWM performance in particular appear to depend upon the coordinated action of different brain regions and neurotransmitter systems constituting a functionally integrated neural network. Finally, the MWM task has often been used in the validation of rodent models for neurocognitive disorders and the evaluation of possible neurocognitive treatments. Through its many applications, MWM testing gained a position at the very core of contemporary neuroscience research.     

Real world navigation independence in the early blind correlates with differential brain activity associated with virtual navigation

Navigating is a complex cognitive task that places high demands on spatial abilities, particularly in the absence of sight. Significant advances have been made in identifying the neural correlates associated with various aspects of this skill; however, how the brain is able to navigate in the absence of visual experience remains poorly understood. Furthermore, how neural network activity relates to the wide variability in navigational independence and skill in the blind population is also unknown. Using functional magnetic resonance imaging, we investigated the neural correlates of audio‐based navigation within a large scale, indoor virtual environment in early profoundly blind participants with differing levels of spatial navigation independence (assessed by the Santa Barbara Sense of Direction scale). Performing path integration tasks in the virtual environment was associated with activation within areas of a core network implicated in navigation. Furthermore, we found a positive relationship between Santa Barbara Sense of Direction scores and activation within right temporal parietal junction during the planning and execution phases of the task. These findings suggest that differential navigational ability in the blind may be related to the utilization of different brain network structures. Further characterization of the factors that influence network activity may have important implications regarding how this skill is taught in the blind community. Hum Brain Mapp 35:2768–2778, 2014. © 2013 Wiley Periodicals, Inc .     

Rhesus monkey neural stem cell transplantation promotes neural regeneration in rats with hippocampal lesions

Rhesus monkey neural stem cells are capable of differentiating into neurons and glial cells.Therefore,neural stem cell transplantation can be used to promote functional recovery of the nervous system.Rhesus monkey neural stem cells(1×105 cells/μL) were injected into bilateral hippocampi of rats with hippocampal lesions.Confocal laser scanning microscopy demonstrated that green fluorescent protein-labeled transplanted cells survived and grew well.Transplanted cells were detected at the lesion site,but also in the nerve fiber-rich region of the cerebral cortex and corpus callosum.Some transplanted cells differentiated into neurons and glial cells clustering along the ventricular wall,and integrated into the recipient brain.Behavioral tests revealed that spatial learning and memory ability improved,indicating that rhesus monkey neural stem cells noticeably improve spatial learning and memory abilities in rats with hippocampal lesions.     

创伤性颅脑损伤后的成年神经细胞再生

创伤性颅脑损伤能够导致严重的神经功能障碍。研究表明,成年哺乳动物脑内存在持续的内源性神经细胞再生,这可能有助于脑创伤的修复。适度的创伤能够刺激海马和脑室下区的神经细胞再生,神经细胞再生有助于海马神经功能的修复,一些促进神经细胞再生的外界因素同样能够改善海马功能,由于缺乏脑室下区及其相关脑区功能评价的理想指标,神经细胞再生对于这些部位的功能修复情况尚处于探索阶段。亦有证据表明,大脑皮层中可能存在处于静息状态的神经前体细胞,在一定条件下,它们可能会再次进入细胞周期从而诱发神经细胞再生。对于人类大脑皮层神经细胞再生的研究目前主要限制在组织的体外培养阶段,研究显示人类大脑皮层存在向神经细胞分化的前体细胞,这些细胞可能对于脑创伤修复有潜在意义。     

Increased Hippocampal Excitability and Altered Learning Dynamics Mediate Cognitive Mapping Deficits in Human Aging

Learning the spatial layout of a novel environment is associated with dynamic activity changes in the hippocampus and in medial parietal areas. With advancing age, the ability to learn spatial environments deteriorates substantially but the underlying neural mechanisms are not well understood. Here, we report findings from a behavioral and a fMRI experiment where healthy human older and younger adults of either sex performed a spatial learning task in a photorealistic virtual environment (VE). We modeled individual learning states using a Bayesian state-space model and found that activity in retrosplenial cortex (RSC)/parieto-occipital sulcus (POS) and anterior hippocampus did not change systematically as a function learning in older compared with younger adults across repeated episodes in the environment. Moreover, effective connectivity analyses revealed that the age-related learning deficits were linked to an increase in hippocampal excitability. Together, these results provide novel insights into how human aging affects computations in the brain''s navigation system, highlighting the critical role of the hippocampus.SIGNIFICANCE STATEMENT Key structures of the brain''s navigation circuit are particularly vulnerable to the deleterious consequences of aging, and declines in spatial navigation are among the earliest indicators for a progression from healthy aging to neurodegenerative diseases. Our study is among the first to provide a mechanistic account about how physiological changes in the aging brain affect the formation of spatial knowledge. We show that neural activity in the aging hippocampus and medial parietal areas is decoupled from individual learning states across repeated episodes in a novel spatial environment. Importantly, we find that increased excitability of the anterior hippocampus might constitute a potential neural mechanism for cognitive mapping deficits in old age.