不同发展阶段的习得性长时程突触增强对新学习的影响

在慢性实验条件下观察到大鼠由学习训练所产生的海马CA_3区习得性长时程突触增强,它的不同发展阶段对新学习任务的习得有不同的作用:(1)在它的形成阶段及巩固阶段对新学习均有易化作用,虽然两个阶段突触效应增强的程度都处于相同的高水平,但后者的易化作用相对要大些,提示这两个发展阶段突触的可塑性变化是有差异的;还有,新学习任务的训练并没有引起突触效应的进一步增强,表明突触效应的长时程增强有“饱和”现象。(2)在它消退后,对新学习任务的习得没有影响。上述结果提示学习的组织形式不同,可从突触机制上影响学习的效果,并进一步证明习得性长时程突触增强是学习和记忆的神经基础。     

去甲肾上腺素对习得性长时程突触增强的影响

在大鼠条件性饮水反应的建立和巩固过程中,在每天训练之前,通过预先与记录电极一起埋植在海马齿状回的注药管,微量注射去甲肾上腺素(NE),观察其对海马齿状回的习得性长时程突触增强的影响。结果表明:NE能增强突触效应;训练作业前注NE易化了习得性长时程突触增强的形成,但对其巩固无影响;同时相应地易化了动物条件反应的建立。提示NE参与海马齿状回的习得性长时程增强的形成。本文对其可能的作用机制进行了讨论。     

神经颗粒素与学习记忆关系研究进展

神经颗粒素（Neurogranin,NG）是一种新发现的脑特异性蛋白质。它分布在多个脑区,特别在对学习记忆至关重要的脑区海马。该物质自发现以来,许多学者对其生物学作用,特别是与学习记忆的关系进行了大量的研究,并取得了相当的进展。研究表明NG参与了在学习记忆功能中起核心作用的脑内几种蛋白信号传导途径、长时程增强（Long-term potentiation, LTP）和长时程抑制（Long-term depression, LTD）等突触可塑性机制。NG基因敲除后,动物出现学习记忆能力缺陷。因而它可能涉及学习记忆的形成和巩固     

NMDA受体在海马习得性长时程突触增强形成中的作用

本文应用慢性埋植技术以电生理学结合行为学的方法,在大鼠条件性饮水反应的建立中,于每实验日训练开始前给海马CA_3区微量注射NMDA受体拮颃剂2-amino-5-phosphonovalerate(APV),观察它对海马CA_s区突触效应及与之相关的条件性行为反应的影响。发现注射APV后对CA_3区突触效应的习得性长时程增强的产生有显著的抑制性影响,相应地条件性饮水反应的建立也受到显著的抑制,提示NMDA受体参与习得性LTP的产主。     

海马齿状回突触效应的习得性长时程增强

本实验应用慢性埋植电极技术以电生理学给合行为学的方法,观察大白鼠海马齿状回在以视觉和味觉信号为条件信号的条件反应的建立、巩固和消退过程中突触效应的变化。结果表明在明暗辨别学习中出现突触效应长时程增强(LTD),其保持时间的长短与巩固性训练的多少呈正相关,LTP消退,习得行为也消退。对照实验证明它并非测试本身所引起,提示此习得性LTP与学习和记忆活动是密切相关的。但在建立条件性味觉厌恶中,却无LTP出现。这就从突触水平上进一步证明我们提出的海马在不同感觉信息的记忆活动中其作用是不同的及海马不仅在记忆的形成,而且在其保持和再现中也有重要作用的观点。     

催产素调控心理韧性:基于对海马的作用机制

心理韧性指个体面对逆境、挫折或重大威胁等应激情境下的有效且灵活适应的能力, 促进机体恢复正常的生理和心理功能。研究表明海马是调控心理韧性的重要脑区, 且催产素可能通过作用于海马增强心理韧性。海马内部环路内嗅皮层-齿状回-CA3可能调节恐惧记忆的泛化和消退以增强心理韧性; 海马外部环路齿状回-杏仁核-伏隔核及海马-伏隔核环路调节情绪, 可能分别通过促进奖赏和带来厌恶进而增强或降低心理韧性。催产素作用于海马增强心理韧性的可能途径有:催产素促进海马神经发生, 降低海马腹侧成熟神经元对应激的敏感性, 提高海马“模式分离”功能, 降低应激记忆泛化; 催产素恢复海马谢弗侧枝-CA1突触长时程增强, 促进机体适应应激; 催产素降低海马糖皮质激素受体水平, 重新建立机体稳态。     

同一学习中海马不同区的习得性长时程突触增强的形成

本研究探查大鼠分辨学习中海马齿状回(DG)和CA_3区突触效应的变化及其相互关系,以探讨同一学习中海马不同区突触可塑性变化的特点及其相互关系,进一步论证习得性长时程增强(LTP)是学习和记忆的神经基础。发现:(1)穿通纤维的单个刺激可在DG和CA_3同时记录到潜伏期、峰值和波形各异的群体峰电位(PS);在一定范围内PS随刺激强度的增加而增大,但DG的PS增大程度比CA_3的小;据此,检测刺激的强度应选在该范围内。(2)随着行为训练,DG和CA_3区的突触传递同时产生LTP,两者LTP的发展是显著正相关关系(P<0.01),PS峰值同时达到最高水平,且先于分辨反应达学会标准,首次表明在同一学习中大鼠海马的DG和CA_3的习得性LTP是同时产生的。本研究还表明,在慢性实验下同时记录和分析行为学习中海马两个区突触效应的变化及其相互关系是可能的,这给从神经环路角度研究学习和记忆的突触机制提供了有用的模型。     

神经颗粒素与脑老化、疾病及应激关系

神经颗粒素是一种神经元特异性、Ca2＋敏感性的鈣调蛋白（CaM）结合蛋白,是蛋白激酶C的突触后底物,与信号传导和长时程增强（LTP）有关。这是一种新发现的脑特异性蛋白质。主要分布在前脑和海马,在皮质、海马CA1-CA3区、齿状回、纹状体和杏仁核中高表达。在大脑发育的不同阶段,神经颗粒素在脑内的含量和分布区域会发生变化,其生物学作用受到国内外学者的关注。近年来国外学者开始对神经颗粒素与脑老化、疾病及应激关系进行考查。该文将着重介绍对神经颗粒素在脑老化、疾病和应激过程中所扮演的角色的研究工作及其新发现,目的是对脑与行为关系的理解及有关的脑机制的研究提供一个新的视点。     

应激对兴奋性突触传递的影响及其分子机制

应激与抑郁症、心血管疾病及肿瘤等重大疾病的发生有着密切关系。前额叶皮层和海马是调控应激反应的重要组织,也是应激作用的靶器官。兴奋性突触传递是大脑功能活动的重要基础,应激通过改变递质的释放和代谢及受体的转运和表达,影响突触传递功能。包括表观遗传在内的多种细胞内信号通路参与了应激的作用机制。揭示这些信号通路可为研发治疗应激相关疾病的药物提供潜在的靶点。     

不同学习方式下习得性长时程突触增强形成的特点

一般认为,突触传递的长时程增强(Long-term potentiation,LTP)可能是学习和记忆的神经基础。我室的系列工作表明,大鼠在条件性行为的建立中,海马齿状回、CA_3、CA_1区均出现LTP样变化,并将之称为习得性LTP(Learning-de-pendent LTP),而且发现每次训练作业后突触效应的增强,经一段时间(4小时)后就     

Transgenic mice expressing a truncated form of CREB-binding protein (CBP) exhibit deficits in hippocampal synaptic plasticity and memory storage

Deletions, translocations, or point mutations in the CREB-binding protein (CBP) gene have been associated with Rubinstein-Taybi Syndrome; a human developmental disorder characterized by retarded growth and reduced mental function. To examine the role of CBP in memory, transgenic mice were generated in which the CaMKII alpha promoter drives expression of an inhibitory truncated CBP protein in forebrain neurons. Examination of hippocampal long-term potentiation (LTP), a form of synaptic plasticity thought to underlie memory storage, revealed significantly reduced late-phase LTP induced by dopamine-regulated potentiation in hippocampal slices from CBP transgenic mice. However, four-train induced late-phase LTP is normal. Behaviorally, CBP transgenic mice exhibited memory deficits in spatial learning in the Morris water maze and deficits in long-term memory for contextual fear conditioning, two hippocampus-dependent tasks. Together, these results demonstrate that CBP is involved in specific forms of hippocampal synaptic plasticity and hippocampus-dependent long-term memory formation.     

Synaptic plasticity in hippocampal CA1 neurons of mice lacking type 1 inositol-1,4,5-trisphosphate receptors

In hippocampal CA1 neurons of wild-type mice, delivery of a standard tetanus (100 pulses at 100 Hz) or a train of low-frequency stimuli (LFS; 1000 pulses at 1 Hz) to a naive input pathway induces, respectively, long-term potentiation (LTP) or long-term depression (LTD) of responses, and delivery of LFS 60 min after tetanus results in reversal of LTP (depotentiation, DP), while LFS applied 60 min before tetanus suppresses LTP induction (LTP suppression). To evaluate the role of the type 1 inositol-1,4,5-trisphosphate receptor (IP3R1) in hippocampal synaptic plasticity, we studied LTP, LTD, DP, and LTP suppression of the field excitatory postsynaptic potentials (EPSPs) in the CA1 neurons of mice lacking the IP3R1. No differences were seen between mutant and wild-type mice in terms of the mean magnitude of the LTP or LTD induced by a standard tetanus or LFS. However, the mean magnitude of the LTP induced by a short tetanus (10 pulses at 100 Hz) was significantly greater in mutant mice than in wild-type mice. In addition, DP or LTP suppression was attenuated in the mutant mice, the mean magnitude of the responses after delivery of LFS or tetanus being significantly greater than in wild-type mice. These results suggest that, in hippocampal CA1 neurons, the IP3R1 is involved in LTP, DP, and LTP suppression but is not essential for LTD. The facilitation of LTP induction and attenuation of DP and LTP suppression seen in mice lacking the IP3R1 indicates that this receptor plays an important role in blocking synaptic potentiation in hippocampal CA1 neurons.     

Mice lacking the ERK1 isoform of MAP kinase are unimpaired in emotional learning

The extracellular signal-regulated kinases (ERKs) are members of the mitogen-activated protein kinase (MAPK) superfamily of enzymes and have recently garnered considerable attention in the field of learning and memory. ERK activation has been shown to be required for the induction of long-term potentiation (LTP) in the rat hippocampus and for the formation of associative and spatial memories in both the rat and the mouse. However, the individual roles for the two isoforms of ERK have yet to be deciphered. To investigate the specific contribution of the ERK1 (p44) isoform of MAPK to mammalian learning, we performed a general behavioral and physiological characterization of mice lacking the ERK1 gene. The ERK1-null animals demonstrated significantly higher levels of activity in the open field test. However, we observed no other discernible deficits in the ERK1 knockout mice in our behavioral testing. Specifically, no differences were observed in the acquisition or retention (24 h and 2 wk after training) of either contextual or cue fear conditioning between the ERK1^−/− and their wild-type littermate controls. In addition, no learning phenotype was observed in the passive avoidance test. When hippocampal slices were analyzed, we found no deficits in baseline synaptic transmission or in tetanus-induced LTP in hippocampal area CA1. We found no apparent compensatory changes in the expression of ERK2 (p42 MAPK). We conclude that hippocampus- and amygdala-dependent emotional learning does not depend critically on the activity of ERK1.     

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.     

Cholinergic modulation of hippocampal CA1 basal-dendritic long-term potentiation

Extensive research suggests that long-term potentiation (LTP) may serve as a cellular mechanism for memory and that alterations in synaptic plasticity may underlie the gross memory impairments observed in patients with Alzheimer's disease. Cholinergic facilitation of hippocampal LTP in the behaving rat is a useful model for the study of the effects of anticholinesterase or other drugs on synaptic plasticity. Field excitatory postsynaptic potentials were recorded from the hippocampal CA1 region following excitation of the basal dendrites in behaving male Long-Evans rats. LTP was induced by a high-frequency train (200 Hz for 0.5s duration) following injection of the acetylcholinesterase inhibitor eserine sulfate (0.5 mg/kg, i.p.), specific muscarinic M1 receptor antagonist pirenzepine (21.2 microg/microl, i.c.v.), or saline (i.p. or i.c.v.). Pirenzepine was found to block basal-dendritic LTP when LTP was induced during walking, but not when LTP was induced during immobility. Eserine facilitated LTP when induction occurred during either immobility or walking. The present study demonstrates that an anticholinesterase enhances LTP in CA1 of the behaving rat, and that facilitation of basal-dendritic LTP during walking is mediated by muscarinic M1 receptors.     

On the Respective Roles of Nitric Oxide and Carbon Monoxide in Long-Term Potentiation in the Hippocampus

Perfusion of hippocampal slices with an inhibitor of nitric oxide (NO) synthase-blocked induction of long-term potentiation (LTP) produced by a one-train tetanus and significantly reduced LTP by a two-train tetanus, but only slightly reduced LTP by a four-train tetanus. Inhibitors of heme oxygenase, the synthetic enzyme for carbon monoxide (CO), significantly reduced LTP by either a two-train or four-train tetanus. These results suggest that NO and CO are both involved in LTP but may play somewhat different roles. One possibility is that NO serves a phasic, signaling role, whereas CO provides tonic, background stimulation. Another possibility is that NO and CO are phasically activated under somewhat different circumstances, perhaps involving different receptors and second messengers. Because NO is known to be activated by stimulation of NMDA receptors during tetanus, we investigated the possibility that CO might be activated by stimulation of metabotropic glutamate receptors (mGluRs). Consistent with this idea, long-lasting potentiation by the mGluR agonist tACPD was blocked by inhibitors of heme oxygenase but not NO synthase. Potentiation by tACPD was also blocked by inhibitors of soluble guanylyl cyclase (a target of both NO and CO) or cGMP-dependent protein kinase, and guanylyl cyclase was activated by tACPD in hippocampal slices. However, biochemical assays indicate that whereas heme oxygenase is constitutively active in hippocampus, it does not appear to be stimulated by either tetanus or tACPD. These results are most consistent with the possibility that constitutive (tonic) rather than stimulated (phasic) heme oxygenase activity is necessary for potentiation by tetanus or tACPD, and suggest that mGluR activation stimulates guanylyl cyclase phasically through some other pathway.     

On the Respective Roles of Nitric Oxide and Carbon Monoxide in Long-Term Potentiation in the Hippocampus

Perfusion of hippocampal slices with an inhibitor nitric oxide (NO) synthase blocked induction of long-term potentiation (LTP) produced by a one-train tetanus and significantly reduced LTP by a two-train tetanus, but only slightly reduced LTP by a four-train tetanus. Inhibitors of heme oxygenase, the synthetic enzyme for carbon monoxide (CO), significantly reduced LTP by either a two-train or four-train tetanus. These results suggest that NO and CO are both involved in LTP but may play somewhat different roles. One possibility is that NO serves a phasic, signaling role, whereas CO provides tonic, background stimulation. Another possibility is that NO and CO are phasically activated under somewhat different circumstances, perhaps involving different receptors and second messengers. Because NO is known to be activated by stimulation of NMDA receptors during tetanus, we investigated the possibility that CO might be activated by stimulation of metabotropic glutamate receptors (mGluRs). Consistent with this idea, long-lasting potentiation by the mGluR agonist tACPD was blocked by inhibitors of heme oxygenase but not NO synthase. Potentiation by tACPD was also blocked by inhibitors of soluble guanylyl cyclase (a target of both NO and CO) or cGMP-dependent protein kinase, and guanylyl cyclase was activated by tACPD in hippocampal slices. However, biochemical assays indicate that whereas heme oxygenase is constitutively active in hippocampus, it does not appear to be stimulated by either tetanus or tACPD. These results are most consistent with the possibility that constitutive (tonic) rather than stimulated (phasic) heme oxygenase activity is necessary for potentiation by tetanus or tACPD, and suggest that mGluR activation stimulates guanylyl cyclase phasically through some other pathway.     

Effects of reversible inactivation of locus coeruleus on long-term potentiation in perforant path-DG synapses in rats

The locus coeruleus (LC) is the main source of noradrenergic innervations to the forebrain and the hippocampal formation but does not receive noradrenergic projections itself. Previous studies have suggested that hippocampal neural response is modulated by the noradrenergic pathway and that the experimental activation of the LC can potentiate hippocampal responses. Most studies have suggested that the noradrenergic system has controversial effects on long-term potentiation (LTP) in hippocampal neurons, because its influence on synaptic plasticity in perforant path-DG synapses is ambiguous. The aim of this article was to study the LC's role in baseline activity and LTP in perforant path-DG cells of hippocampus by in vivo LC inactivation. Rats were anesthetized with urethane, and LC was temporarily suppressed by intra-LC injection of lidocaine. Population spike (PS) amplitude and excitatory postsynaptic potential (EPSP) slope in DG were recorded 10 min before and 5, 10, 20, 40, 60, and 120 min after tetanization (400 Hz). Saline or lidocaine was injected during the baseline recording (experiment 1), 5 min before tetanus (experiment 2), and 5 min after tetanus (experiment 3). The results from this study indicated that the LC inactivation has no effect on baseline activity of granular cells or maintenance of LTP after tetanization. Moreover, LC inactivation before tetanus had no effect on LTP induction but decreased PS-LTP amplitude 60 and 120 min after tetanization. Taken together, the LC noradrenergic system likely influences LTP induction in later time periods while it has no effect on LTP in earlier time periods.     

Selective modulation of some forms of schaffer collateral-CA1 synaptic plasticity in mice with a disruption of the CPEB-1 gene

CPEB-1 is a sequence-specific RNA binding protein that stimulates the polyadenylation-induced translation of mRNAs containing the cytoplasmic polyadenylation element (CPE). Although CPEB-1 was identified originally in Xenopus oocytes, it has also been found at postsynaptic sites of hippocampal neurons where, in response to N-methyl-D-aspartate receptor activation, it is thought to induce the polyadenylation and translation of alphaCaMKII and perhaps other CPE-containing mRNAs. Because some forms of synaptic modification appear to be influenced by local (synaptic) protein synthesis, we examined long-term potentiation (LTP) in CPEB-1 knockout mice. Although the basal synaptic transmission of Schaffer collateral-CA1 neurons was not affected in the knockout mice, we found that there was a modest deficit in LTP evoked by a single train of 100 Hz stimulation, but a greater deficit in LTP evoked by one train of theta-burst stimulation. In contrast, LTP evoked by either four trains of 100 Hz stimulation or five trains of theta-burst stimulation were not or were only modestly affected, respectively. The deficit in LTP evoked by single stimulation in knockout mice appeared several minutes after tetanic stimulation. Long-term depression (LTD) evoked by 1 Hz stimulation was moderately facilitated; however, a stronger and more enduring form of LTD induced by paired-pulse 1 Hz stimulation was unaffected. These data suggest that CPEB-1 contributes in the translational control of mRNAs that is critical only for some selected forms of LTP and LTD.