海马——探索认知功能细胞分子机制的重要模型

哺乳动物脑中的海马结构被发现已经有几个世纪了,而初步确定其功能却是近几十年神经科学领域的重大发现．目前普遍认为海马是与记忆密切相关的,并把海马作为揭示学习记忆等认知过程细胞分子基础的重要模型．就近年在《生物化学与生物物理进展》上发表的相关文章进行了评论．     

Relocation of an Extrasynaptic GABAA Receptor to Inhibitory Synapses Freezes Excitatory Synaptic Strength and Preserves Memory

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Memory retention of appetitive and aversive conditioning in the damselfish Stegastes fuscus

We compared the memory of damselfish Stegastes fuscus in an aversive and appetitive conditioning task. Fish were trained to associate the sides of the tank that corresponded to the presence of a positive (conspecific presence) or negative (electroshock) stimulus. After two conditioning sessions, they were tested for learning. The fish conditioned to the stimulus were then re-tested for memory retention after 5, 10 or 15 days. Both the positive and negative rewards were associated with a specific side of the tank, indicating learning ability. Additionally, in both contexts, S. fuscus stored the information learned and showed similar behavioural patterns after 5, 10 and 15 days, suggesting long-lasting memory. For the ecological context, long lasting memories of social encounters outcomes and negative experiences of threatening situations may confer advantages that ultimately affect fishes’ fitness.     

Astrocytes and Interneurons in Memory Processing in the Chick Hippocampus: Roles for G-Coupled Protein Receptors,GABA(B) and mGluR1

Glutamate and GABA acting at mGluR1 and GABA_B receptors, respectively, have roles in memory processing in the hippocampus up to 35 min after bead discrimination learning in the young chick. Activation of mGluR1 receptors is important at 2.5 and 30 min after training, but modulation of these receptors between these two times has no effect on memory. This timing is similar to the action of glutamate on NMDA receptors. The GABA_B antagonist, phaclofen, and the inhibitor of astrocytic oxidative metabolism, fluoroacetate, inhibited memory when injected between 2.5 and 30 min. Paradoxically, a high dose of the GABA_B agonist, baclofen, also inhibited memory, but a low dose promoted memory consolidation—an effect possibly caused by too much information and loss of the ‘message’. These results are interpreted in terms interactions between interneurons, astrocytes and pyramidal cells and demonstrate the importance of all cell types in memory processing in the hippocampus.     

Rapid and Transient Learning-Associated Increase in NMDA NR1 Subunit in the Rat Hippocampus

Several lines of evidence indicate that glutamate NMDA receptors are critically involved in long-term potentiation (LTP) and in certain forms of learning. It was previously demonstrated that memory formation of an inhibitory avoidance task in chick is specifically associated with an increase in the density of NMDA receptor in selected brain regions. Here we report on the effect of a one trial inhibitory avoidance training in rats, a hippocampal-dependent learning task, on the levels of different subunits of the glutamate NMDA receptor in synaptic plasma membranes (SPM) isolated from the hippocampus. Training rats on a one trial inhibitory avoidance task results in a rapid, transient and selective increase (+33 %, p < 0.05) in NMDA NR1 subunit expression in hippocampal SPM of rats sacrificed 30 min posttraining. No changes were observed at 0 or 120 min after training or in shocked animals in comparison to naive control rats. In addition, no training-associated increase in the levels of NMDA NR2A and NR2B or AMPA GluR 2/3 subunits was observed at any timepoint tested. In conclusion, the present findings support the hypothesis that alterations in expression of synaptic NMDA NR1 subunits in the hippocampus are specifically associated with memory formation of an inhibitory avoidance task and strongly suggest that hippocampal NMDA receptors are crucially involved in the neural mechanisms underlying certain forms of learning.These authors contributed equally to this work     

B-50/GAP-43 Phosphorylation and PKC Activity are Increased in Rat Hippocampal Synaptosomal Membranes After an Inhibitory Avoidance Training

Several lines of evidence indicate that protein kinase C (PKC) is involved in long-term potentiation (LTP) and in certain forms of learning. Recently, we found a learning-specific, time-dependent increase in [³H]phorbol dibutyrate binding to membrane-associated PKC in the hippocampus of rats subjected to an inhibitory avoidance task. Here we confirm and extend this observation, describing that a one trial inhibitory avoidance learning was associated with rapid and specific increases in B-50/GAP-43 phosphorylation in vitro and in PKC activity in hippocampal synaptosomal membranes. The increased phosphorylation of B-50/GAP-43 was seen at 30 min (+35% relative to naive or shocked control groups), but not at 10 or 60 min after training. This learning-associated increase in the phosphorylation of B-50/GAP-43 is mainly due to an increase in the activity of PKC. This is based on three different sets of data: 1) PKC activity increased by 24% in hippocampal synaptosomal membranes of rats sacrificed 30 min after training; 2) B-50/GAP-43 immunoblots revealed no changes in the amount of this protein among the different experimental groups; 3) phosphorylation assays, performed in the presence of bovine purified PKC or in the presence of the selective PKC inhibitor CGP 41231, exhibited no differences in B-50/GAP-43 phosphorylation between naive and trained animals. In conclusion, these results support the contention that hippocampal PKC participates in the early neural events of memory formation of an aversively-motivated learning task.     

The impact of genetic background on neurodegeneration and behavior in seizured mice

We used pilocarpine-induced seizures in mice to determine the impact of genetic background on the vulnerability of hippocampal neurons and associated changes of behavioral performance. The susceptibility of hippocampal neurons to seizure-induced cell death paralleled the severity of the seizures and depended on genetic background. Hippocampal neurons in C57BL/6 mice were most resistant to cell death, whereas they were highly vulnerable in FVB/N mice. The degree of neuronal degeneration in F1 hybrid mice obtained by crossing the two strains was at an intermediate level between the parent strains. Two weeks after the severe seizures, performance in a water-maze place navigation task showed a bimodal distribution. Seventeen of 19 (90%) F1 mice were completely unable to learn while the other two learned reasonably well. Of 28 C57BL/6 mice with similarly severe seizures, six were as strongly impaired as their F1 counterparts (22%). The remaining 22 performed normally, indicating a much lower probability of C57BL/6 mice to be affected. Treated mice showed a deficit of open-field exploration which was strongly correlated with the impairment in the place navigation task and was again more severe in F1 mice. Our results show that the vulnerability of hippocampal neurons to pilocarpine-induced seizures, as well as the associated behavioral changes, depended on genetic background. Furthermore, they confirm and extend our earlier finding that a relatively modest reduction of hippocampal cell death can be associated with dramatic changes of behavioral performance and emphasize the importance of tightly-controlled genetic backgrounds in biological studies.     

The Molecular Biology of Memory Storage: A Dialog Between Genes and Synapses

The biology of learning, and short-term and long-term memory, as revealed by Aplysia and other organisms, is reviewed.     

老年大鼠学习记忆减退的神经基础

对由Ｍｏｒｒｉｓ水迷宫分得的青年、老年记忆正常和记忆减退鼠的脑组织分别进行突触、ＡＣｈＥ纤维、突触素、小白蛋白神经元以及突触体钙离子浓度、膜流动性的定量分析。结果表明老年记忆减退鼠新皮质、海马结构突触素含量、突触、胆碱能纤维、小白蛋白阳性神经元密度及突触体膜流动笥较老年记忆正常和青年鼠明显降低。老年记忆正常鼠与青年鼠各项均无显著差异。本研究提示各研究指标的异常与老年学习记忆减退密切相关。     

Efficient learning in children with rapid GABA boosting during and after training

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间歇性θ节律经颅磁刺激改善大鼠工作记忆的海马与前额叶跨脑区神经网络效应研究

目的 间歇性θ节律刺激（iTBS）作为一种新型的经颅磁刺激模式，已经广泛应用于探索大脑认知功能和神经调控等方面，但其电生理调控机制尚不清晰，探索iTBS对大脑认知功能的影响及其电生理机制，对脑疾病的治疗和磁刺激的临床应用具有重要意义。方法 本文利用iTBS制备磁刺激大鼠模型，采集记录大鼠在执行工作记忆（WM）任务过程中腹侧海马（vHPC）和内侧前额叶皮层（mPFC）的局部场电位（LFPs）信号，应用格兰杰因果网络分析方法，研究了iTBS对大鼠WM过程中vHPC与mPFC跨脑区神经网络协同和信息交互的影响。结果 iTBS增强了大鼠的学习记忆能力，使其完成工作记忆任务所需时长减少（2.67±1.63）d（P<0.05），iTBS显著改善了大鼠的行为学表现；同时iTBS增强了大鼠在WM期间vHPC与mPFC脑区的自因果网络连接，增加了网络连接强度、连接密度和全局效率（P<0.05）；并且iTBS增强了vHPC与mPFC脑区的跨脑区网络连接，增加了vHPC-mPFC跨脑区的节点度和因果流向（P<0.05）。结论 iTBS磁刺激对大鼠工作记忆行为学及相关脑区神经网络均有显著的积极作用，iTBS可以促进大鼠认知能力，提高大脑神经网络的信息交互和传递效率，iTBS的神经调控机制可能是通过增强大脑vHPC与mPFC之间的网络连接和信息交互来提高工作记忆能力。     

The Effect of Severe Zinc Deficiency and Zinc Supplement on Spatial Learning and Memory

Zinc deficiency during pregnancy and during lactation has been shown to impair cognitive function and motor activity in offspring rats. In the present study, the effect of zinc deficiency and zinc supplement on spatial learning and memory in Morris Water Maze (MWM) and motor activity in open field were investigated. Pregnant rats after mating were divided to three groups. Control group fed a standard diet and a zinc deficient (ZnD) group fed a diet deficient in zinc (0.5–1.5 ppm) and a zinc supplement (ZnS) group fed a standard diet and enhanced zinc in the drinking water (10 ppm). All the diets were exposed during the last trisemester of pregnancy and during lactation. Rat’s offspring in these groups were tested for spatial learning and memory in MWM at post natal day (PND) 56 and were tested for motor activity in open field at PND 66.The Escape Latency (EL) and Traveled Distance (TD) in the ZnD group were increased but Percentage of Time Spent in the target quadrant (PTS) was decreased compared to the control group. In addition, these were no significant differences in EL and TD, but PTS had significant increase in ZnS compared to the control group. In the open field, Total Distance Moved (TDM) and Time of Motor Activity (TMA) for the ZnD were decreased compared to the control group, but there were no significant differences in TDM and TMA between control and ZnS groups. These findings suggest that zinc deficiency during the last trimester of pregnancy and during lactation impaired spatial learning and memory in their offsprings and has also negative effect on motor activity. In addition, ZnS has a significant effect on spatial learning and memory but no effect on motor activity in their offsprings.