Pattern separation in the dentate gyrus and CA3 of the hippocampus

Theoretical models have long pointed to the dentate gyrus as a possible source of neuronal pattern separation. In agreement with predictions from these models, we show that minimal changes in the shape of the environment in which rats are exploring can substantially alter correlated activity patterns among place-modulated granule cells in the dentate gyrus. When the environments are made more different, new cell populations are recruited in CA3 but not in the dentate gyrus. These results imply a dual mechanism for pattern separation in which signals from the entorhinal cortex can be decorrelated both by changes in coincidence patterns in the dentate gyrus and by recruitment of nonoverlapping cell assemblies in CA3.     

Plasticity of hippocampal circuitry in Alzheimer's disease

Two markers of neuronal plasticity were used to compare the response of the human central nervous system to neuronal loss resulting from Alzheimer's disease with the response of rats to a similar neuronal loss induced by lesions. In rats that had received lesions of the entorhinal cortex, axon sprouting of commissural and associational fibers into the denervated molecular layer of the dentate gyrus was paralleled by a spread in the distribution of tritiated kainic acid-binding sites. A similar expansion of kainic acid receptor distribution was observed in hippocampal samples obtained postmortem from patients with Alzheimer's disease. An enhancement of acetylcholinesterase activity in the dentate gyrus molecular layer, indicative of septal afferent sprouting, was also observed in those patients with a minimal loss of cholinergic neurons. These results are evidence that the central nervous system is capable of a plastic response in Alzheimer's disease. Adaptive growth responses occur along with the degenerative events.     

Expression of the beta-nerve growth factor gene in hippocampal neurons

In situ hybridization with complementary DNA probes for nerve growth factor (NGF) was used to identify cells containing NGF messenger RNA in rat and mouse brain. The most intense labeling occurred in hippocampus, where hybridizing neurons were found in the dentate gyrus and the pyramidal cell layer. The neuronal identity of NGF mRNA-containing cells was further assessed by a loss of NGF-hybridizing mRNA in hippocampal areas where neurons had been destroyed by kainic acid or colchicine. RNA blot analysis also revealed a considerable decrease in the level of NGF mRNA in rat dentate gyrus after a lesion was produced by colchicine. This lesion also caused a decrease in the level of Thy-1 mRNA and an increase in the level of glial fibrillary acidic protein mRNA. Neuronal death was thus associated with the disappearance of NGF mRNA. These results suggest a synthesis of NGF by neurons in the brain and imply that, in hippocampus, NGF influences NGF-sensitive neurons through neuron-to-neuron interactions.     

Mapping patterns of c-fos expression in the central nervous system after seizure

A dramatic and specific induction of c-fos was observed in identifiable neuronal populations in vivo after administration of the convulsant Metrazole. This effect was time- and dose-dependent and was abolished by prior treatment with the anticonvulsant drugs diazepam or pentobarbital. About 60 minutes after administration of Metrazole, c-fos messenger RNA reached a maximum and declined to basal levels after 180 minutes. A further decrease below that in normal brain was observed before a return to basal levels after 16 hours. While Metrazole still elicited seizures during this period, reinduction of c-fos was largely refractory. At 90 minutes, c-fos protein was observed in the nuclei of neurons in the dentate gyrus, and in the pyriform and cingulate cortices. Subsequently, c-fos protein appeared throughout the cortex, hippocampus, and limbic system. Thus, seizure activity results in increased c-fos gene expression in particular subsets of neurons.     

仔猪神经干细胞体外培养及鉴定

由仔猪脑部海马体齿状回分离得到神经干细胞,利用无血清培养基添加特定生长因子方式培养;采用RT-PCR鉴定神经干细胞和诱导分化后细胞生物特性;利用免疫荧光化学技术检测克隆的细胞抗原和分化后特异性成熟神经细胞抗原表达。由海马体齿状回分离的细胞群具有连续克隆能力;根据免疫荧光检测,脑神经干细胞表达巢蛋白、配对盒因子6和解整合素样金属蛋白酶10;体外培养下NSCs可被诱导分化为神经源性细胞,且表达微管相关蛋白2、胶质纤维酸性蛋白和髓鞘碱性蛋白。分离和培育NSCs细胞结果显示,其具有更新能力和分化为神经元和胶质细胞的潜能,可为干细胞移植提供基础数据。     

Selective loss of hippocampal granule cells in the mature rat brain after adrenalectomy

Adrenalectomy of adult male rats resulted in a nearly complete loss of hippocampal granule cells 3 to 4 months after surgery. Nissl and immunocytochemical staining of hippocampal neurons revealed that the granule cell loss was selective; there was no apparent loss of hippocampal pyramidal cells or of gamma-amino butyric acid (GABA)-, somatostatin-, neuropeptide Y-, calcium binding protein-, or parvalbumin-containing hippocampal interneurons. The hippocampal CA1 pyramidal cells of adrenalectomized animals exhibited normal electrophysiological responses to afferent stimulation, whereas responses evoked in the dentate gyrus were severely attenuated. Corticosterone replacement prevented both the adrenalectomy-induced granule cell loss and the attenuated physiological response. Thus, the adrenal glands play a role in maintaining the structural integrity of the normal adult brain.     

Pattern separation in the human hippocampal CA3 and dentate gyrus

Pattern separation, the process of transforming similar representations or memories into highly dissimilar, nonoverlapping representations, is a key component of many functions ascribed to the hippocampus. Computational models have stressed the role of the hippocampus and, in particular, the dentate gyrus and its projections into the CA3 subregion in pattern separation. We used high-resolution (1.5-millimeter isotropic voxels) functional magnetic resonance imaging to measure brain activity during incidental memory encoding. Although activity consistent with a bias toward pattern completion was observed in CA1, the subiculum, and the entorhinal and parahippocampal cortices, activity consistent with a strong bias toward pattern separation was observed in, and limited to, the CA3/dentate gyrus. These results provide compelling evidence of a key role of the human CA3/dentate gyrus in pattern separation.     

仔猪海马结构及其周围皮质内生长抑素mRNA的分布

用原位杂交组织化学法研究了５头仔猪海马结构及其周围皮质内生长抑素ｍＲＮＡ的分布。结果表明生长抑素ｍＲＮＡ主要分布于海马的始层和齿状回的多形层，偶见于海马的辐射层和锥体细胞层，此外，在内溴区和海马旁回内也见到标记细胞，主要位于深层。     

Dynamics of the hippocampus during encoding and retrieval of face-name pairs

The medial temporal lobe (MTL) is critical in forming new memories, but how subregions within the MTL carry out encoding and retrieval processes in humans is unknown. Using new high-resolution functional magnetic resonance imaging (fMRI) acquisition and analysis methods, we identified mnemonic properties of different subregions within the hippocampal circuitry as human subjects learned to associate names with faces. The cornu ammonis (CA) fields 2 and 3 and the dentate gyrus were active relative to baseline only during encoding, and this activity decreased as associations were learned. Activity in the subiculum showed the same temporal decline, but primarily during retrieval. Our results demonstrate that subdivisions within the hippocampus make distinct contributions to new memory formation.     

Dentate gyrus NMDA receptors mediate rapid pattern separation in the hippocampal network

Forming distinct representations of multiple contexts, places, and episodes is a crucial function of the hippocampus. The dentate gyrus subregion has been suggested to fulfill this role. We have tested this hypothesis by generating and analyzing a mouse strain that lacks the gene encoding the essential subunit of the N-methyl-d-aspartate (NMDA) receptor NR1, specifically in dentate gyrus granule cells. The mutant mice performed normally in contextual fear conditioning, but were impaired in the ability to distinguish two similar contexts. A significant reduction in the context-specific modulation of firing rate was observed in the CA3 pyramidal cells when the mutant mice were transferred from one context to another. These results provide evidence that NMDA receptors in the granule cells of the dentate gyrus play a crucial role in the process of pattern separation.     

p38MAPK信号通路选择性调节FSH对甾体生成 的诱导作用研究

利用乙烯雌酚(DES)处理23日龄SD大鼠,分离卵巢颗粒细胞(GC)进行无血清培养。结果表明,FSH(50ng/m1)处理GC,可迅速激活有丝分裂原蛋白激酶(p38MAPK),FSH处理5min便可观察到磷酸化的p38MAPK;FSH处理30min,磷酸化的p38MAPK水平达到最高;向培养液中加入H89(蛋白激酶A抑制剂,10μM),则显著抑制了FSH对p38MAPK的激活作用,提示这种激活作用依赖于蛋白激酶A(PKA)。用SB203580(p38MAPK抑制剂,20μM)抑制p38MAPK激活,则进一步提高了FSH对孕酮和甾体生成快速调节蛋白(StAR)的诱导作用,同时降低了FSH对雌激素生成的促进作用(p<0.01)。RT-PCR结果显示:抑制p38MAPK活性后,FSH对StARmRNA刺激作用明显增强,但对细胞色素P450芳香化酶(P450arom)mRNA的诱导作用却减弱了(p<0.05)。激光共聚焦和蛋白印迹结果显示:在GC中,StAR蛋白主要分布在线粒体中;与对照组相比,FSH显著提高了StAR的荧光强度和蛋白水平;抑制p38MAPK活性则增强了FSH对StAR蛋白表达的诱导作用。     

Lesion-induced sprouting in the rat dentate gyrus is inhibited by repeated ethanol administration

The effect of ethanol on hippocampal axonal sprouiting was studied with a histochemical technique for identifying acetylcholinesterase. Unilateral lesion of the entorhinal cortex in adult rats produced an increase in the density of acetylcho-linesterase staining in the outer molecular layer and a concomitant increase in the width of the pale-staining commissural-associational zone of the dentate gyrus. Other rats were given ethanol (11.3 +/- 0.45 grams per kilogram) for 2 weeks before and 9 days after receiving the lesion. Ethanol abolished the expansion of the commissural-associational zone. The effect of ethanol on sprouting axons suggests that it may inhibit recovery of function after brain injury.     

Reversal of neurological defects in a mouse model of Rett syndrome

Rett syndrome is an autism spectrum disorder caused by mosaic expression of mutant copies of the X-linked MECP2 gene in neurons. However, neurons do not die, which suggests that this is not a neurodegenerative disorder. An important question for future therapeutic approaches to this and related disorders concerns phenotypic reversibility. Can viable but defective neurons be repaired, or is the damage done during development without normal MeCP2 irrevocable? Using a mouse model, we demonstrate robust phenotypic reversal, as activation of MeCP2 expression leads to striking loss of advanced neurological symptoms in both immature and mature adult animals.     

胚胎晚期母体暴露细菌脂多糖对中年CD-1子鼠背海马synaptotagmi Ⅳ的影响

对胚胎晚期母体腹腔注射细菌脂多糖或生理盐水,利用免疫组化法对CD-1中年子鼠背海马CA1、CA3区和齿状回各层突触蛋白synaptotagmin IV的表达进行研究。结果显示synaptotagmin Ⅳ在背海马各层均有表达。与盐水对照组相比,细菌脂多糖处理组子鼠背海马CA1、CA3区各层和齿状回分子层的synaptotagmin Ⅳ含量显著增高(Ps<0.05)。结果表明胚胎晚期母体暴露细菌脂多糖可显著增加中年子鼠背海马Syt IV表达。     

Protection of dentate hilar cells from prolonged stimulation by intracellular calcium chelation

Prolonged afferent stimulation of the rat dentate gyrus in vivo leads to degeneration only of those cells that lack immunoreactivity for the calcium binding proteins parvalbumin and calbindin. In order to test the hypothesis that calcium binding proteins protect against the effects of prolonged stimulation, intracellular recordings were made in hippocampal slices from cells that lack immunoreactivity for calcium binding proteins. Calcium binding protein-negative cells showed electrophysiological signs of deterioration during prolonged stimulation; cells containing calcium binding protein did not. When neurons without calcium binding proteins were impaled with microelectrodes containing the calcium chelator BAPTA, and BAPTA was allowed to diffuse into the cells, these cells showed no deterioration. These results indicate that, in a complex tissue of the central nervous system, an activity-induced increase in intracellular calcium can trigger processes leading to cell deterioration, and that increasing the calcium binding capacity of a cell decreases its vulnerability to damage.     

SAMP8小鼠衰老海马complexin含量呈环路特异性下降

利用免疫组化技术检测年龄对SAMP8小鼠海马突触前蛋白complexin1/2表达的影响。结果显示,与4.5月龄相比,13月龄组齿状回多形细胞层和外分子层及CA1区放射层的complexin1/2相对含量均显著下降,8月龄组后两者也下降。此外13月龄组CA3透明层complexin1/2低于表达较8月龄组。这些结果提示在SAMP8鼠海马complexin1/2含量随年龄增加而呈现环路特异性下降。     

镰刀菌毒素在小麦组织离体培养中的类激素活性

通过使用含镰刀菌粗毒素的诱导培养基,研究了镰刀菌毒素在小麦离体组织脱分化中的作用.发现禾谷镰刀菌粗毒素在小麦组织离体培养中具有关激素活性和毒害双重作用.毒素的类激素活性因所用外植体而异,在幼穗组织中表现较为显着,最适浓度下,3个供试品种的愈伤组织产量比对照均高出1倍.同时,镰刀菌毒素还能影响被诱导愈伤组织的继代和分化性能,降低其存活率、生长势和绿苗分化频率.镰刀菌毒素的类激素活性和毒害作用在不同抗性品种的实验中显示出毒素浓度上的差异,感抗品种之间具有明显的界限.     

青春期双酚A暴露对老年CD-1小鼠海马 齿状回Synaptotagmin 1含量的影响

探讨青春期双酚A暴露对老年期齿状回Synaptotagmin 1（Syt 1）含量的影响。结果显示,18月龄CD-1小鼠齿状回Syt 1相对含量显著高于6月龄小鼠（Ps<0.05）;青春期双酚A暴露高剂量小鼠齿状回Syt 1表达量显著高于同年龄对照小鼠（Ps<0.05）,雌鼠更明显。这些结果进一步支持小鼠海马Syt 1呈年龄相关性增加的结论,青春期双酚A暴露可加剧这种增加。     

High-speed imaging reveals neurophysiological links to behavior in an animal model of depression

The hippocampus is one of several brain areas thought to play a central role in affective behaviors, but the underlying local network dynamics are not understood. We used quantitative voltage-sensitive dye imaging to probe hippocampal dynamics with millisecond resolution in brain slices after bidirectional modulation of affective state in rat models of depression. We found that a simple measure of real-time activity-stimulus-evoked percolation of activity through the dentate gyrus relative to the hippocampal output subfield-accounted for induced changes in animal behavior independent of the underlying mechanism of action of the treatments. Our results define a circuit-level neurophysiological endophenotype for affective behavior and suggest an approach to understanding circuit-level substrates underlying psychiatric disease symptoms.