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.     

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.     

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。     

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。     

Transgenic inhibition of synaptic transmission reveals role of CA3 output in hippocampal learning

The hippocampus is an area of the brain involved in learning and memory. It contains parallel excitatory pathways referred to as the trisynaptic pathway (which carries information as follows: entorhinal cortex --> dentate gyrus --> CA3 --> CA1 --> entorhinal cortex) and the monosynaptic pathway (entorhinal cortex --> CA1 --> entorhinal cortex). We developed a generally applicable tetanus toxin-based method for transgenic mice that permits inducible and reversible inhibition of synaptic transmission and applied it to the trisynaptic pathway while preserving transmission in the monosynaptic pathway. We found that synaptic output from CA3 in the trisynaptic pathway is dispensable and the short monosynaptic pathway is sufficient for incremental spatial learning. In contrast, the full trisynaptic pathway containing CA3 is required for rapid one-trial contextual learning, for pattern completion-based memory recall, and for spatial tuning of CA1 cells.     

中年CD-1小鼠背海马syntaxin 1水平的改变

应用免疫组化技术检测13月龄(中年)和5月龄CD-1小鼠背海马突触前蛋白syntaxin 1的表达水平.结果显示,13月龄小鼠齿状回、CA1及CA3区各层syntaxin 1的相对含量较5月龄均显著下降.表明中年CD-1小鼠背海马syntaxin 1含量全面下调.     

Unique processing during a period of high excitation/inhibition balance in adult-born neurons

The adult dentate gyrus generates new granule cells (GCs) that develop over several weeks and integrate into the preexisting network. Although adult hippocampal neurogenesis has been implicated in learning and memory, the specific role of new GCs remains unclear. We examined whether immature adult-born neurons contribute to information encoding. By combining calcium imaging and electrophysiology in acute slices, we found that weak afferent activity recruits few mature GCs while activating a substantial proportion of the immature neurons. These different activation thresholds are dictated by an enhanced excitation/inhibition balance transiently expressed in immature GCs. Immature GCs exhibit low input specificity that switches with time toward a highly specific responsiveness. Therefore, activity patterns entering the dentate gyrus can undergo differential decoding by a heterogeneous population of GCs originated at different times.     

Distinct ensemble codes in hippocampal areas CA3 and CA1

The hippocampus has differentiated into an extensively connected recurrent stage (CA3) followed by a feed-forward stage (CA1). We examined the function of this structural differentiation by determining how cell ensembles in rat CA3 and CA1 generate representations of rooms with common spatial elements. In CA3, distinct subsets of pyramidal cells were activated in each room, regardless of the similarity of the testing enclosure. In CA1, the activated populations overlapped, and the overlap increased in similar enclosures. After exposure to a novel room, ensemble activity developed slower in CA3 than CA1, suggesting that the representations emerged independently.     

长期口服阿卡波糖对SAMP8小鼠背海 马synaptotagminⅠ的影响

利用免疫组化法检测长期口服阿卡波糖对SAMP8小鼠背海马突触蛋白synaptotagminⅠ（SytⅠ）表达的影响。结果显示,SytⅠ在背海马CA1、CA3区和齿状回各层均有表达。老年对照组小鼠背海马各区SytⅠ的相对含量显著高于青年对照组（Ps<0.05）。阿卡波糖处理组小鼠背海马各区SytⅠ的相对含量显著低于同龄对照组（Ps<0.05）。上述结果提示长期口服阿卡波糖可减轻SAMP8小鼠背海马年龄相关性SytⅠ增加的水平。     

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.     

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。     

Regional variation of extracellular space in the hippocampus

The factors responsible for the unusual susceptibility of the hippocampus to seizures and ischemic cell damage are not well understood. The CA1 pyramidal subfield of the hippocampus is particularly vulnerable to seizure activity and damage after ischemia. The possibility was examined that regional differences exist in extracellular volume, which might influence neuronal excitability and response to injury in the hippocampus. CA1 stratum pyramidale exhibited an exceptionally low extracellular volume fraction (EVF) of 0.12, whereas the EVFs of CA3 and dentate were considerably higher--0.18 and 0.15, respectively. The EVF of CA1 stratum pyramidale was reversibly reduced by 30 percent when the extracellular potassium concentration was raised from 3.5 to 8.5 mM, a procedure that induced spontaneous electrographic seizures in CA1. Thus there are regional variations in the properties of the extracellular space in the hippocampus that might underlie the propensity of the CA1 region to develop seizures and to suffer damage after ischemia.     

甘麦大枣汤对慢性应激抑郁大鼠HPA轴及海马显微结构的影响

目的 研究甘麦大枣汤对慢性应激抑郁模型大鼠HPA轴及海马显微结构的影响,探讨其可能的抗抑郁机制。方法 将SD大鼠随机分为6组：空白组、模型组、氟西汀组（5.4 mg/kg）、甘麦大枣汤高、中、低剂量组（3.84、1.92、0.96 g/kg）,采用慢性不可预见性温和应激建立抑郁模型,于造模同时给药,连续21 d。采用糖水消耗实验和旷场测试检测大鼠的抑郁样行为,ELISA法检测大鼠血浆促肾上腺皮质激素释放激素（CRH）、促肾上腺皮质激素（ACTH）、皮质酮（CORT）的变化,HE染色观察大鼠海马CA1区、CA3区及齿状回（DG）区的病理结构变化。结果 与空白组比较,抑郁模型组大鼠蔗糖偏食度及自主活动次数显著下降（P<0.01）,血浆CRH、ACTH、CORT含量显著上升（P<0.01）,海马CA1区、CA3区以及DG区神经元均萎缩、缺失,损伤明显;与模型组比较,甘麦大枣汤高剂量组大鼠蔗糖偏食度及活动次数均显著提高（P<0.01）,血浆ACTH、CORT含量下降（P<0.05）,同时海马各区神经元损伤情况得到缓解。结论 甘麦大枣汤能显著改善模型大鼠的抑郁样行为,其作用可能与调节HPA轴高亢,保护海马的损伤有关。     

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.     

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。     

死亡时间对雌性仔猪脑海马组织影响

为研究母猪脑海马死亡后变化情况,试验以同一遗传背景(杜×长×大)、体重及出生日龄相近的健康雌性仔猪作研究对象,采用核磁共振成像检测及光镜技术,检测母猪麻醉状态与死后10 min、1、2、3、6和10 h时段左侧、右侧海马体积,观察两侧海马齿状回区颗粒细胞形态,建立母猪死后海马形态学变化模型,为长期处于应激状态下妊娠母猪心理疾病的核磁共振诊断提供理论依据。核磁检测结果表明,仔猪死亡10 h内,与活体对照组海马体积比较,左侧海马体积无显著变化(P=0.901);右侧及总海马体积在死亡3 h内无显著性变化(右侧P=0.078;总P=0.104),但从死亡6 h开始显著变小(右侧P0.01;总P0.05);光镜观察表明,仔猪死亡3 h内,左侧及右侧海马齿状回区颗粒细胞形态与活体对照组相比,均未发生严重损害。死亡3 h内,仔猪脑海马组织无显著生理变化。     

Spatial representation in the entorhinal cortex

As the interface between hippocampus and neocortex, the entorhinal cortex is likely to play a pivotal role in memory. To determine how information is represented in this area, we measured spatial modulation of neural activity in layers of medial entorhinal cortex projecting to the hippocampus. Close to the postrhinal-entorhinal border, entorhinal neurons had stable and discrete multipeaked place fields, predicting the rat's location as accurately as place cells in the hippocampus. Precise positional modulation was not observed more ventromedially in the entorhinal cortex or upstream in the postrhinal cortex, suggesting that sensory input is transformed into durable allocentric spatial representations internally in the dorsocaudal medial entorhinal cortex.     

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.     

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.     

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。