硫胺素缺乏下调与学习相关的成体海马神经发生

目的 研究硫胺素缺乏(TD)对成年小鼠认知功能及其海马神经发生的影响.方法 TD小鼠模型按照TD处理时间分为TD 7、9、14、16、25 d组和正常对照组,每组4～6只小鼠.Y型迷宫检测学习记忆能力,5-溴脱氧尿嘧啶核苷(BrdU)体内掺入及Doublecortin(Dcx)等免疫组化染色检测海马齿状回颗粒下层(DGSG)神经发生.结果 在无病理损害及胆碱能神经变性的TD 9 d组,小鼠学会正确反应的总训练次数(22.3±2.2)与对照组(13.5±3.5)相比差异有统计学意义,而海马DGSG BrdU标记的阳性细胞数(个/DGSG)19.8±0.4及Dcx标记免疫活性(像素/mm2)1537.2±50.2也较对照组(分别为23.9±0.3和2688.9±127.9)显著降低.此时补充硫胺素可上调BrdU阳性细胞数(个/DGSG)23.6±1.9及Dcx免疫活性(像素/mm2)2052.3±269.6,并减少其学会正确反应的训练总次数(16.8±0.5).结论 在病理损害前期,TD导致的学习功能障碍可能与海马神经发生功能下调有关.     

GABA能去抑制水平的变化对海马CAl突触长时程增强的影响

目的 研究改变中间神经元GABA能抑制水平对海马CA1区突触长时程增强(LTP)的影响.同时获得不同浓度Bicuculline阻断GABAA受体介导抑制以及影响海马CA1区突触可塑性详细信息. 方法 应用膜片钳全细胞记录技术记录成年小鼠海马脑片上自发的微小的抑制性突触后电位(mIPSC)和诱发的前馈抑制性突触后电流(IPSC),使用细胞外电生理方法 记录刺激Schaffer侧枝诱发的CA1区辐射层场的兴奋性突触后电位(fEPSP],测量不同浓度Bicuculline对mIPSC、IPSC和fEPSP的作用,以及它们对小鼠海马脑片CA1区突触LTP的影响. 结果 10μmol/L、20μmol/L Bicuculline可以减弱mIPSC和IPSC抑制性突触电流,且20 μmol/L Bicuculline作用更明显;20μmol/L Bicuculline可以明显提高fEPSP的斜率,而5 μmol/L和10 μmol/LBicuculline没有明显作用;5 μmol/L、10 μmol/L、20μmol/L和50μmol/L Bicuculline组100赫兹强直刺激诱发后的fEPSP平均斜率均值都大于对照组,但仅10 μmol/L、20 μmol/L两组相比,差异有统计学意义(P<0.05). 结论 Bicuculline可以减弱GABAA受体介导的抑制以及增加场的fEPSP斜率,并且Bicuculline阻断GABA能抑制到一个关键水平才可以增强海马CA1区突触的LTP.     

补阳还五汤对血管性痴呆大鼠海马CA1区LTP及ERK2与CaMKⅡβ mRNA表达的影响

目的 观察补阳还五汤对血管性痴呆(Vascular Dementia,VD)大鼠海马CA1区突触传递LTP效应及对海马组织ERK2与CaMKⅡβ基因表达的影响.方法 采用四血管阻断法建立大鼠VD动物模型.术后25d行水迷宫检测,30d采用在体大鼠海马CA3侧枝-CA1区长时程增强(LTP)记录方法记录海马CA1区LTP.采用RTPCR方法检测大鼠海马CA1区脑组织ERK2与CaMKⅡβmRNA表达.结果 与模型组比较,补阳还五汤和尼莫地平组水迷宫实验平台象限游泳时间/游泳总时间、平台象限游泳距离/游泳总距离的比值显著增加,LTP检测实验中兴奋性突触后电位(excitatory postsynaptic potential,EPSP)斜率显著上升,大鼠海马ERK2与CaMKⅡβ mRNA表达显著增加.补阳还五汤与尼莫地平组相比,上述各指标均无显著差异.结论 补阳还五汤可显著改善血管性痴呆大鼠学习记忆障碍,其作用可能与增强海马CA1区LTP,上调ERK2与CaMKⅡβ mRNA表达有关.     

神经干细胞移植对阿尔茨海默病大鼠海马突触素表达和学习记忆能力的影响*

背景：前期实验已证实,移植入阿尔茨海默病大鼠脑内的神经干细胞能够存活、增殖,但其是否可替代损伤或坏死的神经细胞而重建神经通路,改善学习记忆能力尚不清楚。突触素是突触重建的重要标记之一。 目的：观察神经干细胞移植对阿尔茨海默病大鼠学习记忆能力及突触表达的影响。 方法：SD大鼠随机数字表法分为正常对照组、阿尔茨海默病模型组、2周移植组和4周移植组,除正常对照组外制备阿尔茨海默病模型。另取新生24 h SD大鼠海马齿状回分离、培养神经干细胞,经Hoechst33258标记后植入2周和4周移植组海马CA1区,行Y迷宫实验检测大鼠的学习记忆能力,然后取脑进行尼氏染色和突触素免疫组织化学染色。阿尔茨海默病模型组则以同样的方法、同样的位点注入等量无菌生理盐水。正常对照组不施以任何处理。 结果与结论：①2周和4周移植组海马CA1区细胞比阿尔茨海默病模型组增多,但仍少于正常对照组(P < 0.05),平均吸光度与正常对照组相比差异无显著性意义(P > 0.05)。②2周移植组和4周移植组大鼠海马结构内突触素吸光度值明显高于正常对照组和阿尔茨海默病模型组(P < 0.05)。③与阿尔茨海默病模型组相比,2周和4周移植组大鼠学习能力和记忆能力均显著增强,正确反应率明显提高(P < 0.05),而与正常对照组相比,差异无显著性意义(P > 0.05)。提示移植入脑内的神经干细胞可促进突触形成,改善学习记忆能力。     

慢性应激刺激成年小鼠对其老年期认知功能的影响

目的:观察慢性应激刺激成年小鼠对其老年期认知功能及海马区神经结构的影响。方法:将8周龄成年雄性小鼠予以慢性束缚性刺激6周(Stress,S组),束缚结束后成年S组小鼠即刻进行水迷宫行为学测试并断头以免疫组化学及硫堇染色方法观察海马区突触素及尼氏小体的变化,并利用医学图像分析系统计算突触素免疫组化反应阳性产物数量;而老年S组小鼠于慢性束缚6周后普通环境下继续饲养11周至老年期(25周龄)再进行上述行为学及病理学检测。对照组小鼠正常环境下饲养并分别于14周龄、25周龄进行上述行为学及病理学检测。结果:成年及老年S组小鼠学习记忆能力明显受损(P<0.05);海马区脑组织突触素免疫反应阳性产物和尼氏小体数量较同龄对照组小鼠明显减少(P<0.01)。结论:给予成年期小鼠慢性应激刺激可导致老年期小鼠认知功能损害,其记忆的损害与年龄老化之间可能具有协同作用。     

APP/PS-1/tau三转基因阿尔茨海默病模型小鼠早期认知功能研究

目的观察APP/PS-1/tau三转基因阿尔茨海默病(3×Tg-AD)模型小鼠空间学习和记忆能力、海马CA1区突触可塑性和可溶性β-淀粉样蛋白42(Aβ42)表达变化,探讨3×Tg-AD小鼠早期认知功能障碍发生机制。方法 4月龄雄性3×Tg-AD小鼠和相匹配的129/C57BL/6杂交野生型小鼠各10只,旷场实验和Morris水迷宫实验观察小鼠在新环境中的焦虑程度和自主活动能力,以及空间学习和记忆能力;记录海马CA1区场兴奋性突触后电位和高频强直电刺激诱导的长时程增强;酶联免疫吸附试验检测海马组织可溶性Aβ42表达变化。结果与对照组相比,3×Tg-AD组小鼠旷场实验结果无明显改变(均P0.05),定位航行实验第3~5天逃避潜伏期延长(P=0.001,0.003,0.001),空间探索实验穿越平台区时间百分比降低(P=0.000),海马CA1区高频强直电刺激诱导的长时程增强下降(均P0.01),海马组织可溶性Aβ42表达水平升高(P=0.000)。结论 4月龄3×Tg-AD小鼠海马组织可溶性Aβ42表达上调,导致海马CA1区突触可塑性受损,出现空间学习和记忆能力下降。     

胰岛素抵抗对大鼠海马及Aβ_(42)代谢的影响

目的建立糖皮质激素所致阿尔茨海默病模型,观察胰岛素抵抗大鼠海马β?淀粉样蛋白42(Aβ42)的表达及对大鼠学习记忆的影响,探讨胰岛素抵抗在糖皮质激素所致阿尔茨海默病(AD)发病机制中的作用。方法 30只健康雄性SD大鼠,随机挑选10只作为空白组(CON)。余下的采用地塞米松腹腔注射21d制作胰岛素抵抗模型,以稳态模型的胰岛素抵抗指数将其分为胰岛素抵抗组及对照组,Y迷宫测定大鼠造模后的学习记忆成绩,HE、Nissl染色观察海马组织形态学改变,免疫组化法及免疫印迹法观察Aβ42在海马CA1区神经元中的表达。结果 (1)Y迷宫试验显示,实验组记忆能力较空白组明显减退,差异有统计学意义(P0.01)。实验组记忆能力对照组减退,差异有统计学意义(P0.05),空白组、对照组2组间差异有统计学意义(P0.05)。(2)Nissl染色:空白组海马CA1区细胞形态规则,排列整齐而密,实验组部分细胞形态欠规则,出现核固缩,坏死,细胞排列紊乱,表明有大量的神经元细胞死亡。对照组的病理结果则介于两者之间。(3)海马CA1Aβ42免疫组化结果:空白组、对照组2组Aβ42阳性细胞表达相似且与实验组比较相对少,平均积分光密度值低,2组差异有统计学意义(P0.05),实验组较对照组明显增多,平均积分光密度值增高,差异有统计学意义(P0.05);(4)海马CA1区Aβ42免疫印迹检测示:实验组Aβ42表达水平较空白组上调,差异有统计学意义(P0.01),实验组Aβ42表达水平较对照组上调,差异具有统计学意义(P0.05)。空白组、对照组间差异无统计学意义(P0.05)。结论 (1)糖皮质激素可致大鼠海马出现神经元损伤和病理学改变。出现胰脑岛素抵抗的大鼠表现尤为明显。但无明显的老年斑及神经原纤维缠结。(2)糖皮质激素可增加Aβ42的表达,胰岛素抵抗大鼠的改变更为明显,说明胰岛素抵抗参与了糖皮质激素所致阿尔茨海默病的发病机制。     

尼莫地平对癫痫大鼠学习记忆及海马超微结构的影响

目的探讨尼莫地平(nimodipin,NIM)对戊四氮(pentylenetetrazol,PTZ)点燃癫痫大鼠学习记忆能力及海马CA3区超微结构的影响。方法动物分为正常对照组、PTZ组和NIM PTZ组,采用PTZ慢性点燃癫痫模型,应用Morris水迷宫观察各组大鼠空间学习记忆能力,电镜观察海马CA3区突触界面结构,并对突触活性参数量化分析。结果PTZ点燃癫痫大鼠存在学习记忆能力下降,其海马CA3区突触后致密物显著变薄、突触小泡显著减少、突触间隙显著增宽(P<0.05);尼莫地平能改善癫痫大鼠学习记忆障碍,与PTZ组比较,突触后致密物增厚、突触小泡增多、突触间隙变窄(P<0.05)。结论PTZ点燃癫痫大鼠存在空间学习记忆受损,可能与突触界面参数改变有关;NIM可以改善癫痫大鼠突触超微结构,提高学习记忆能力。     

重组人促红细胞生成素对慢性脑缺血大鼠学习记忆能力及凋亡相关蛋白P53和Bcl-2表达的影响

目的 研究重组人促红细胞生成素(rhEPO)对慢性脑缺血大鼠学习记忆能力及凋亡相关蛋白P53和Bcl-2表达的影响. 方法 16只健康雄性SD大鼠结扎双侧颈总动脉(2VO)建立永久性慢性脑缺血模型,将其按照随机数字表法分为对照组和实验组,每组各8只.模型建立3d后,实验组每7天经鼻腔给予150 U/125 μL rhEPO,至建模后8周末;对照组于同一时间鼻腔给予等量的生理盐水.8周后应用Morris水迷宫观测2组大鼠的运动及空间学习记忆能力.采用HE染色观察大脑皮层及海马CA1区神经元形态学的变化,并采用图像分析软件对大脑皮层厚度与神经元数目进行比较.免疫组化法检测P53及Bcl-2蛋白的表达水平.原位末端标记(TUNEL)法检测凋亡细胞数. 结果 (1)行为学测试结果显示:实验组平均逃避潜伏期及穿越平台次数均较对照组有所改善,差异有统计学意义(P＜0.05).(2)HE染色结果显示:与实验组相比,对照组大鼠皮层及海马CA1区锥体神经元胞体萎缩、核固缩且皮层厚度变薄,数目减少,差异有统计学意义(P＜0.05).(3)免疫组化结果显示:与对照组相比,实验组Bcl-2的表达明显增强,P53平均灰度值明显增加,差异有统计学意义(P＜0.05).(4)TUNEL染色结果显示:对照组凋亡细胞数较实验组明显增加,差异有统计学意义(P＜0.05). 结论 rhEPO能改善慢性脑缺血大鼠运动、记忆及空间定向能力,这种神经功能保护作用的机制可能与减少神经元凋亡相关.     

慢性应激抑郁大鼠海马CA1神经元突触可塑性研究

目的 探讨慢性轻度不可预见应激(chronic unpredictable mild stress,CUMS)抑郁模型大鼠海马CA1区神经元的突触可塑性改变.方法 将20只雄性Sprague-Dawley (SD)大鼠随机等分为CUMS组和对照组,前者连续28天每天随机接受不同的应激,对照组同样条件下饲养但不给应激,至第28天进行行为测评后处死,在日立(H7500)透射电镜下测量海马CA1神经元突触界面结构参数.结果 CUMS抑郁大鼠海马CA1神经元突触活性区长度(216.64±20.19 nm)及突触后致密物厚度(42.4±5.23 nm)显著小于对照组(321.58±12.27nm,69.6±4.77 nm),差异有统计学意义(P＜0.05),突触界面曲率及宽度与对照组差异无统计学意义(P＞0.05).结论 慢性应激性抑郁大鼠存在海马CA1区神经元突触可塑性的改变.这提示抑郁症的发病机制可能与海马神经元突触可塑性相关.     

Impaired hippocampal neurogenesis is involved in cognitive dysfunction induced by thiamine deficiency at early pre-pathological lesion stage

It has not been reported whether thiamine deficiency (TD) affects hippocampal neurogenesis or not. Here, we explored the influence of TD at early pre-pathological lesion stage on hippocampal neurogenesis and the correlation between affected hippocampal neurogenesis and cognitive dysfunction. We prepared TD mouse model by feeding a thiamine-depleted diet. Learning and memory functions of TD mice were tested with Y-maze. Hippocampal neurogenesis was studied with BrdU, PCNA, Dcx, and NeuN immunohistochemical staining. The results showed significant decline in learning ability and hippocampal neurogenesis simultaneously since 9-days of treatment when the model mice did not exhibit regular pathological lesion, the loss of cholinergic neurons, decrease of NeuN-positive hippocampal cell, and abnormal long-term potentiation of hippocampal CA1 and CA3. Re-administering thiamine reversed the weakened learning ability as well as the impaired hippocampal neurogenesis induced by TD at early pre-pathological lesion stage. The present study demonstrated that hippocampal neurogenesis was vulnerable to TD and the impaired hippocampal neurogenesis is greatly involved in cognitive dysfunction induced by TD at early pre-pathological lesion stage.     

Improved learning and memory of contextual fear conditioning and hippocampal CA1 long-term potentiation in histidine decarboxylase knock-out mice

Some studies suggest that the histaminergic system plays an important role in learning and memory. However, the results seem to be controversial in many behavioral tasks. In the present study, we used HDC knockout (HDC-KO) mice to investigate the effects of long-term histamine deficiency on learning and memory in contextual fear conditioning. We found that HDC-KO mice exhibited improved contextual fear from 1 day after training and this lasted for at least 14 days when compared with the wild-type (WT) controls. Cued fear was also improved 2 days after training in HDC-KO mice. Moreover, injection of histamine (intracerebroventricularly, 10 microg/mouse) immediately after training reversed the improvement in contextual fear conditioning when tested 1 day after training. Electrophysiological data showed that hippocampal CA1 long-term potentiation (LTP) in HDC-KO mice was much greater than that in WT mice, and paired-pulse facilitation decreased 2 h after LTP induction in HDC-KO mice. In contrast, HDC-KO mice showed smaller LTP than did WT mice 1 day after training. Hippocampal glutamate levels significantly increased in HDC-KO mice 1 and 4 days after training. The results indicated that histamine deficiency may improve consolidation of contextual fear conditioning. This improvement may be due to the increased hippocampal CA1 LTP, and presynaptic glutamate release. The relationship between behavior and synaptic plasticity provides support for the involvement of activity-dependent LTP in learning and memory.     

Chlorogenic acid protection of neuronal nitric oxide synthase-positive neurons in the hippocampus of mice with impaired learning and memory

BACKGROUND: Clinical practice and modern pharmacology have confirmed that ehlorogenic acid can ameliorate learning and memory impairments. OBJECTIVE: To observe the effects of chlorogenic acid on neuronal nitric oxide synthase (nNOS)-positive neurons in the mouse hippocampus, and to investigate the mechanisms underlying the beneficial effects of chlorogenic acid on learning and memory. DESIGN, TIME AND SETTING: The present randomized, controlled, neural cell morphological observation was performed at the Institute of Neurobiology, Central South University between January and May 2005.MATERIALS: Forty-eight female, healthy, adult, Kunming mice were included in this study. Learning and memory impairment was induced with an injection of 0.5 μL kainic acid (0.4 mg/mL) into the hippocampus.METHODS: The mice were randomized into three groups (n = 16): model, control, and chlorogenic acid-treated. At 2 days following learning and memory impairment induction, intragastric administration of physiological saline or chlorogenic acid was performed in the model and chlorogenic acid-treated groups, respectively. The control mice were administered 0.5 μ L physiological saline into the hippocampus, and 2 days later, they received an intragastric administration of physiological saline. Each mouse received two intragastric administrations (1 mL solution once) per day, for a total of 35 days. MAIN OUTCOME MEASURES: Detection of changes in hippocampal and cerebral cortical nNOS neurons by immunohistochemistry; determination of spatial learning and memory utilizing the Y-maze device.RESULTS: At day 7 and 35 after intervention, there was no significant difference in the number of nNOS-positive neurons in the cerebral cortex between the model, chlorogenic acid, and control groups (P > 0.05). Compared with the control group, the number of nNOS-positive neurons in the hippocampal CA1-4 region was significantly less in the model group (P < 0.05). However, the control group was not different from the ehlorogenic acid-treated group (P > 0.05). At day 7 following intervention, the number of correct responses in the Y-maze test was greater in the ehlorogenic acid-treated group than in the model group. CONCLUSION: Chlorogenic acid protects kainic acid-induced injury to nNOS-positive neurons in the hippocampal CA1-4 regions, thereby ameliorating learning and memory impairment.     

经颅电刺激对阿尔兹海默病大鼠学习记忆能力和海马CA_1区磷酸化tau蛋白表达情况的影响

目的探讨经颅电刺激对阿尔兹海默病(Alzeheimer’s disease,AD)大鼠学习记忆能力和海马CA_1区磷酸化tau蛋白表达的影响。方法健康SD大鼠,随机分为:正常组、假手术组、模型组及经颅电刺激2 w、4 w、6 w组。采用大鼠侧脑室注射Aβ25-35凝聚态β-淀粉样肽,同时腹腔注射D-半乳糖的方法,建立AD动物模型。Morris水迷宫实验检测各组大鼠学习、记忆能力,HE染色,观察海马CA_1区形态学结构,免疫组化测定海马CA_1区磷酸化tau蛋白表达情况。结果 (1)Morris水迷宫实验大鼠测试学习和记忆能力,经颅电刺激2 w组与模型组比较差异无统计学意义(P0.05),经颅电刺激4 w组、6 w组与模型组比较,逃避潜伏期成绩均好于模型组,差异有统计学意义(P0.05);(2)随电刺激时间延长,经颅电刺激各组磷酸化tau蛋白量逐渐降低,与模型组比较差异有统计学意义(P0.05)。结论经颅电刺激能够改善阿尔兹海默病大鼠的学习记忆能力,机制可能与下调海马CA_1区磷酸化tau蛋白表达有关,对细胞的重塑有积极影响,远期效果有待进一步研究。     

康复训练对血管性痴呆大鼠认知功能障碍的影响及其分子机制

目的探讨康复训练对血管性痴呆大鼠空间学习记忆能力的改善作用,并从分子学角度探讨其机制。方法选择Wistar雄性大鼠25只,随机分为正常对照组(5只)、血管性痴呆组(10只)和康复训练组(10只)。采用双侧颈总动脉阻断法制作血管性痴呆大鼠模型,康复训练组大鼠于手术后2d开始进行康复训练;用Westernblotting方法测定大鼠海马组织中N-甲基-D-天冬氨酸受体1含量,用长时程增强及Morris水迷宫试验评价大鼠空间学习记忆能力。结果Morris水迷宫试验显示,血管性痴呆组大鼠水迷宫隐匿平台逃避潜伏期明显延长,经康复训练后学习记忆能力有所改善,但与正常对照组相比差异仍有统计学意义(P<0.05)。发生血管性痴呆后,大鼠海马组织中N-甲基-D-天冬氨酸受体1含量明显降低,康复训练使其含量较训练前明显升高,但仍未能达到正常对照组水平(P<0.05);血管性痴呆大鼠的长时程增强诱导功能亦明显受到抑制,康复训练后虽明显改善但未恢复至正常水平(P<0.05)。结论康复训练可提高大鼠空间学习记忆能力,促进长时程增强的形成,其分子机制可能与海马组织中N-甲基-D-天冬氨酸受体1表达水平的增高有关。     

Mice lacking the adenosine A1 receptor have normal spatial learning and plasticity in the CA1 region of the hippocampus, but they habituate more slowly

Using mice with a targeted disruption of the adenosine A1 receptor (A1R), we examined the role of A1Rs in hippocampal long-term potentiation (LTP), long-term depression (LTD), and memory formation. Recordings from the Shaffer collateral-CA1 pathway of hippocampal slices from adult mice showed no differences between theta burst and tetanic stimulation-induced LTP in adenosine A1 receptor knockout (A1R-/-), heterozygote (A1R+/-), and wildtype (A1R+/+) mice. However, paired pulse facilitation was impaired significantly in A1R-/- slices as compared to A1R+/+ slices. LTD in the CA1 region was unaffected by the genetic manipulation. The three genotypes showed similar memory acquisition patterns when assessed for spatial reference and working memory in the Morris water maze tasks at 9 months of age. However, 10 months later A1R-/- mice showed some deficits in the 6-arm radial tunnel maze test. The latter appeared, however, not due to memory deficits but to decreased habituation to the test environment. Taken together, we observe normal spatial learning and memory and hippocampal CA1 synaptic plasticity in adult adenosine A1R knockout mice, but find modifications in arousal-related processes, including habituation, in this knockout model.     

Phenytoin reverses the chronic stress-induced impairment of memory consolidation for water maze training and depression of LTP in rat hippocampal CA1 region, but does not affect motor activity

Previous studies have shown that phenytoin can protect hippocampal structure from damage by chronic stress, while whether it can reverse the hippocampal malfunction induced by chronic stress is unknown. We investigated the effects of phenytoin on motor activity of stressed rats and on the long-term memory of water maze spatial training, which is known to depend on hippocampal function. We also explored whether phenytoin could protect long-term potentiation (LTP) in hippocampal CA1 region from depression of chronic stressed rats. Isolated hippocampal slices of rats were used to observe the changes of LTP in hippocampal CA1 field with electrophysiological technique. The results showed that the motor activity of chronic forced-swimming rats was markedly higher than that of control rats, and phenytoin could not affect this change. The performance of water maze spatial training indicated that chronic stress damages long-term memory but not short-term memory, and phenytoin could reverse this long-term memory deficit. The increases of LTP after HFS in control and stress-phenytoin groups were significantly greater than those in stress-saline group (P < 0.05). There were no significant differences between control group and stress-phenytoin group (P > 0.05) and between control and control-phenytoin groups (P > 0.05). These findings provided the first evidence with behavioral and electrophysiological technique that phenytoin could reverse the hippocampal-dependent memory deficit and depression of LTP induced by chronic stress, which may be helpful for exploring the pathogenesis and improving the therapy of depression.     

The Immediate Early Gene Arc Is Not Required for Hippocampal Long-Term Potentiation

Memory consolidation is thought to occur through protein synthesis-dependent synaptic plasticity mechanisms such as long-term potentiation (LTP). Dynamic changes in gene expression and epigenetic modifications underlie the maintenance of LTP. Similar mechanisms may mediate the storage of memory. Key plasticity genes, such as the immediate early gene Arc, are induced by learning and by LTP induction. Mice that lack Arc have severe deficits in memory consolidation, and Arc has been implicated in numerous other forms of synaptic plasticity, including long-term depression and cell-to-cell signaling. Here, we take a comprehensive approach to determine if Arc is necessary for hippocampal LTP in male and female mice. Using a variety of Arc knock-out (KO) lines, we found that germline Arc KO mice show no deficits in CA1 LTP induced by high-frequency stimulation and enhanced LTP induced by theta-burst stimulation. Temporally restricting the removal of Arc to adult animals and spatially restricting it to the CA1 using Arc conditional KO mice did not have an effect on any form of LTP. Similarly, acute application of Arc antisense oligodeoxynucleotides had no effect on hippocampal CA1 LTP. Finally, the maintenance of in vivo LTP in the dentate gyrus of Arc KO mice was normal. We conclude that Arc is not necessary for hippocampal LTP and may mediate memory consolidation through alternative mechanisms.SIGNIFICANCE STATEMENT The immediate early gene Arc is critical for maintenance of long-term memory. How Arc mediates this process remains unclear, but it has been proposed to sustain Hebbian synaptic potentiation, which is a key component of memory encoding. This form of plasticity is modeled experimentally by induction of LTP, which increases Arc mRNA and protein expression. However, mechanistic data implicates Arc in the endocytosis of AMPA-type glutamate receptors and the weakening of synapses. Here, we took a comprehensive approach to determine if Arc is necessary for hippocampal LTP. We find that Arc is not required for LTP maintenance and may regulate memory storage through alternative mechanisms.     

Antagonism of group III metabotropic glutamate receptors results in impairment of LTD but not LTP in the hippocampal CA1 region, and prevents long-term spatial memory

Recently it has emerged that hippocampal long-term depression (LTD) may play an important role in the acquisition and storage of spatial memories. This form of synaptic plasticity is tightly regulated by metabotropic glutamate receptors (mGluRs) that negatively couple to adenylyl cyclase. Activation of group III mGluRs is necessary for persistent hippocampal LTD, but is not required for depotentiation or long-term potentiation (LTP) in the dentate gyrus in vivo. In the CA1 region antagonism of group III mGluRs prevents LTD in vivo. Effects on LTP in vivo are as yet unknown. We investigated the effects of group III mGluR antagonism on LTP and LTD at Schaffer collateral-CA1 synapses, and on spatial learning in the eight-arm radial maze. Daily application of the group III mGluR antagonist (R,S)-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG) resulted in impairment of long-term (reference) memory, with effects becoming apparent 4 days after training and drug treatment began. Short-term (working) memory was unaffected throughout the 10-day study. Application of CPPG prevented LTD, but not LTP, in the CA1 region. These data suggest that activation of group III mGluRs is required for the establishment of spatial long-term memory. Their exclusive role in mediating hippocampal LTD provides correlational evidence for a role for LTD in the type of spatial learning studied.     

维生缺B1缺乏对成体室管膜下神经发生的影响

目的：探讨维生缺B1缺乏（TD）对成年小鼠室管膜下区（SVZ）神经发生的影响。方法：TD小鼠模型按TD喂食时间分为TD7、TD14和TD21d组,正常对照组（Con）小鼠则按标准喂食及时间亦分为Con7、Con14和Con21d组（每组n=6）。小鼠处死前5d腹腔给予5-溴脱氧尿嘧啶核苷（BrdU）。用免疫荧光组化染色分别检测SVZ的BrdU和微管相关蛋白（Dcx）阳性细胞的分布和数目。结果：正常组的BrdU阳性细胞和Dcx阳性细胞在SVZ均匀分布在侧脑室背外侧角,侧脑室外侧壁亦有少量分布,TD14和TD21d组两类阳性细胞的减少主要为侧脑室背外侧角。在TD14和TD2Id组,室管膜下区BrdU标记阳性细胞数（像素／mm^2值分别为74．97±7．75和67．27±10．91）明显低于对照组（像素／mm^2值分别为122．30±8．86和122．99±5．33）,Dcx标记阳性细胞数（像素／mm^2值分别为1485．98±163．21和935．73±273．66）也明显低于对照组（像素／mm^2值分别2359±155．68和2355±100．75）。结论：TD可阻碍成年小鼠SVZ的神经发生。