Enhanced contextual fear memory in central serotonin-deficient mice

Central serotonin (5-HT) dysregulation contributes to the susceptibility for mental disorders, including depression, anxiety, and posttraumatic stress disorder, and learning and memory deficits. We report that the formation of hippocampus-dependent spatia

Morphine withdrawal affects both delayed-escape behaviour in Morris water maze and hippocampal NR2A/2B expression ratio

Repeated low-dose morphine treatment facilitates delayed-escape behaviour of hippocampus-dependent Morris water maze and morphine withdrawal influences hippocampal NMDA receptor-dependent synaptic plasticity. Here, we examined whether and how morphine wit

Glycine uptake regulates hippocampal network activity via glycine receptor-mediated tonic inhibition

Functional glycine receptors (GlyRs) are enriched in the hippocampus, but their role in hippocampal function remains unclear. Since the concentration of ambient glycine is determined by the presence of powerful glycine transporter (GlyT), we blocked the r

GABA Transporter-1 Activity Modulates Hippocampal Theta Oscillation and Theta Burst Stimulation-Induced Long-Term Potentiation

The network oscillation and synaptic plasticity are known to be regulated by GABAergic inhibition, but how they are affected by changes in the GABA transporter activity remains unclear. Here we show that in the CA1 region of mouse hippocampus, pharmacolog

Sexual Behavior Modulates Contextual Fear Memory Through Dopamine D1/D5 Receptors

Traumatic events always lead to aversive emotional memory, i.e., fear memory. In contrast, positive events in daily life such as sex experiences seem to reduce aversive memory after aversive events. Thus, we hypothesized that post-traumatic pleasurable ex

Opioid Withdrawal for 4 Days Prevents Synaptic Depression Induced by Low Dose of Morphine or Naloxone in Rat Hippocampal CA1 Area In Vivo

The formation of memory is believed to depend on experience- or activity-dependent synaptic plasticity, which is exquisitely sensitive to psychological stress since inescapable stress impairs long-term potentiation (LTP) but facilitates long-term depression (LTD). Our recent studies demonstrated that 4 days of opioid withdrawal enables maximal extents of both hippocampal LTP and drug-reinforced behavior; while elevated-platform stress enables these phenomena at 18 h of opioid withdrawal. Here, we examined the effects of low dose of morphine (0.5 mg kg(-1), i.p.) or the opioid receptor antagonist naloxone (1 mg kg(-1), i.p.) on synaptic efficacy in the hippocampal CA1 region of anesthetized rats. A form of synaptic depression was induced by low dose of morphine or naloxone in rats after 18 h but not 4 days of opioid withdrawal. This synaptic depression was dependent on both N-methyl-D-aspartate receptor and synaptic activity, similar to the hippocampal long-term depression induced by low frequency stimulation. Elevated-platform stress given 2 h before experiment prevented the synaptic depression at 18 h of opioid withdrawal; in contrast, the glucocorticoid receptor (GR) antagonist RU38486 treatment (20 mg kg(-1), s.c., twice per day for first 3 days of withdrawal), or a high dose of morphine reexposure (15 mg kg(-1), s.c., 12 h before experiment), enabled the synaptic depression on 4 days of opioid withdrawal. This temporal shift of synaptic depression by stress or GR blockade supplements our previous findings of potentially correlated temporal shifts of LTP induction and drug-reinforced behavior during opioid withdrawal. Our results therefore support the idea that stress experience during opioid withdrawal may modify hippocampal synaptic plasticity and play important roles in drug-associated memory. (C) 2009 Wiley-Liss, Inc.

Disconnection of the hippocampal-prefrontal cortical circuits impairs spatial working memory performance in rats

There is a unidirectional, ipsilateral and monosynaptic projection from the hippocampus to the prefrontal cortex. The cognitive function of hippocampal-prefrontal cortical circuit is not well established. In this paper, we use muscimol treated rats to inv

The effects of centrally administered fluorocitrate via inhibiting glial cells on working memory in rats

Although prefrontal and hippocampal neurons are critical for spatial working memory, the function of glial cells in spatial working memory remains uncertain. In this study we investigated the function of glial cells in rats' working memory. The glial cell

海马在情绪记忆中的作用

海马是中脑边缘系统的一个重要区域，不仅在学习和记忆中起着重要作用， 还在应激调控中起着关键作用。越来越多的报道表明，海马可能参与毒品成瘾。 本文围绕海马与成瘾、海马与应激的相互关系，应用行为学及电生理技术手段探 讨了海马在成瘾中的作用，并对应激的作用机制进行了研究。 第一部分试验首先研究了长期成瘾药物暴露对两种不同类型学习记忆的影 响，从而揭示成瘾对不同脑区的影响；我们还研究了长期毒品戒断对学习和记忆 的影响。用条件化位置偏爱/厌恶模型对海马在成瘾相关记忆中的作用进行了探 讨。实验结果提示，在成瘾过程中不同脑区发生了不同程度的适应性改变，从而 影响了该脑区相关的正常学习和记忆，其中慢性吗啡暴露损伤了海马依赖的空间 记忆提取，但长期戒断（戒断5 个星期）可以缓解成瘾导致的这些影响。另外， 海马在成瘾相关记忆中同样发挥了重要作用。吗啡偏爱形成后的环境线索再暴露 损伤海马突触长时程增强，提示了海马在环境线索诱导的药物渴求和复吸中可能 起着关键性作用。 第二部分试验主要探索了应激效应的作用机制及海马VR1 受体对抗应激效 应。发现含NR2B 的NMDA 受体参与了应激导致的海马突触可塑性改变，其阻 断剂Ro25-6981 阻断了应激易化的海马长时程抑制，避免了应激损伤的长时程增 强。另一方面，应激损伤海马依赖性的空间记忆提取，但是辣椒素(VR1 受体的 激动剂)直接注射入海马能逆转这种应激的损伤效应。相反，VR1 受体拮抗剂 capsazepin 处理产生了类似应激的损伤效应。提示了海马内VR1 受体可能是海马 记忆功能的一种重要受体系统。

1. 大鼠海马-前额叶回路在学习记忆中的作用2. 芬克罗酮改善恒河猴空间工作记忆的谷氨酸机制

一、大鼠海马-前额叶回路在学习记忆中的作用 解剖学研究证实大鼠和猴的海马结构（hippocampal formation, HF；本文‘海马 (hippocampus, Hip)’一词即指海马结构）和前额叶 (prefrontal cortex, PFC) 之间存在一条单向、同侧和单突触的神经回路，即海马-前额叶回路（Hip-PFC回路）。Hip和PFC均参与学习记忆等多种认知功能，PFC是工作记忆的关键脑区，而Hip是空间参考记忆的关键脑区。虽然人们已经对PFC和Hip进行了广泛深入的研究，但对Hip-PFC回路参与哪些认知功能还知之甚少。本研究的目的就是通过暂时阻断Hip-PFC回路，探讨其在学习和记忆中的作用。 在大鼠，Hip-PFC回路中的纤维主要从Hip腹部 (ventral hippocampus, VH)发出，投射到PFC的前边缘皮质(prelimbic cortex, PLC)、下边缘皮质 (infralimbic cortex, ILC) 和外侧前额叶 (lateral prefrontal cortex) 等亚区，其中PLC是Hip-PFC主要投射的区域。我们通过给动物安装慢性导管向脑内注射GABAA受体激动剂muscimol (MU) 阻断Hip-PFC回路。注射位点包括 ①双侧PLC，②双侧VH，③一侧VH和对侧PLC (VH-PLC)。我们首先观察了在PLC或VH局部注射MU对自由活动大鼠PLC和VH脑电功率的影响，并以此确定在行为实验中所用蝇蕈醇的剂量。然后采用T-迷宫空间交互延缓作业 (spatial delayed alternation task) 测试Hip-PFC回路被阻断的动物的空间工作记忆功能；采用被动回避作业 (passive avoidance task) 测试其情绪相关记忆的能力（训练前给药；24 h后重测试）；采用Morris水迷宫作业 (Morris water maze task) 测试其空间参考记忆的能力（每天训练前给药；训练期（3 d）结束24 h后重测试）。结果表明：在大鼠PLC或VH局部注射0.5 μg/0.25μl MU后30 min显著抑制VH 和PLC的脑电功率 (VH, p < 0.01; PLC, p < 0.05 vs. PBS/baseline)。注射MU (0.5 μg/0.25μl) 到 ①双侧PLC、②双侧VH、③VH-PLC均显著降低动物在空间交互延缓作业 (All p < 0.001, vs. PBS) 和空间Morris水迷宫作业中的成绩 (All p < 0.05, vs. PBS)，表明Hip-PFC回路在空间工作记忆（空间短时记忆）和在空间参考记忆（空间长时记忆）中均起重要作用。在空间交互延缓作业中，双侧PLC被抑制的大鼠的成绩显著低于双侧VH或VH-PLC被抑制的动物，说明PFC在空间工作记忆功能中占有主导地位。在被动回避作业中，双侧VH被抑制动物的回避反应的潜伏期显著短于对照动物 (p < 0.05 vs. PBS)，说明双侧VH被抑制动物的情绪记忆受损；而双侧PLC或VH-PLC被抑制的动物其回避反应的潜伏期与对照动物无显著差异 (PLC, p > 0.9; VH-PLC, p > 0.3 vs. PBS)，表明双侧PLC或VH-PLC被抑制的动物情绪记忆正常。被动回避作业的结果说明VH参与情绪记忆的形成，但Hip-PFC回路在情绪记忆形成中不起重要作用。 以上结果表明，大鼠Hip-PFC回路参与空间工作记忆和空间参考记忆而不是情绪记忆功能。情绪记忆的关键脑结构是杏仁复合体 (amygdala complex, AMC)，VH与AMC有密切的纤维联系。VH被抑制的大鼠情绪记忆受损，说明情绪记忆可能与AMC-Hip回路有关。情绪记忆与空间记忆（参考记忆和工作记忆）在解剖上的分离说明，对于不同类型的记忆来说，其在脑内的信息加工过程是并行的。神经回路内部的信息加工过程则是串行的，回路上任何一个结构的破坏均可导致回路功能的损伤。本研究的结果为学习记忆的“多重记忆系统”理论和记忆信息加工的串行并行机制提供了新的实验证据。 二、芬克罗酮改善成年恒河猴空间工作记忆的谷氨酸机制 芬克罗酮是中科院昆明植物所郝小江等合成的取代吡咯烷酮类化合物。中科院昆明动物所蔡景霞等发现芬克罗酮能改善东莨菪碱、育亨宾等导致的多种动物的不同类型的学习记忆障碍，提高老年动物的学习记忆能力，尤其是老年猴的空间工作记忆。已证实芬克罗酮为部分钙激动剂，可使脑缺血沙土鼠脑内升高的谷氨酸降低，而使正常的沙土鼠海马胞外谷氨酸释放增加。那么芬克罗酮能否提高正常动物的学习记忆，其对正常动物学习记忆的提高是否与其增加谷氨酸的释放有关？本研究采用空间延缓反应作业和谷氨酸NMDA受体拮抗剂MK-801在正常成年猴恒河猴上探讨了以上问题。 结果表明，口服芬克罗酮可显著提高成年猴的空间工作记忆，其量效曲线呈倒‘U’形，符合许多促智药的量效特点。0.25 mg/kg和0.5 mg/kg为芬克罗酮的最佳有效剂量 (p < 0.05 vs. 安慰剂)。肌注MK-801 (0.1 mg/kg) 显著降低成年猴的空间工作记忆 (p < 0.01 vs. 安慰剂)，而口服2.0 mg/kg和4.0 mg/kg的芬克罗酮则显著改善MK-801导致的工作记忆障碍 (p < 0.05 vs. MK-801)。芬克罗酮的所有测试剂量不影响猴在作业中的反应时 (p > 0.05 vs. 安慰剂)，表明芬克罗酮在该剂量范围不影响动物的运动能力。 本研究结果提示，芬克罗酮可能通钙激动作用促进谷氨酸的释放，在一定剂量范围内提高胞外谷氨酸水平，提高正常动物的空间工作记忆等认知功能。 关键词：芬克罗酮，恒河猴，空间工作记忆，空间延缓反应作业，谷氨酸，MK-801

Effects of Naotan Pill on repair of neural cells and cognitive disorders in juvenile rats following hypoxia and ischemia

BACKGROUND: Hypoxia and ischemia induce neuronal damage, decreased neuronal numbers and synaptophysin levels, and deficits in learning and memory functions. Previous studies have shown that lycium barbarum polysaccharide, the most effective component of barbary wolfberry fruit, has protective effects on neural cells in hypoxia-ischemia. OBJECTIVE: To investigate the effects of Naotan Pill on glutamate-treated neural cells and on cognitive function in juvenile rats following hypoxia-ischemia. DESIGN, TIME AND SETTING: The randomized, controlled, in vivo study was performed at the Cell Laboratory of Lanzhou University, Lanzhou Institute of Modern Physics of Chinese Academy of Sciences, and Department of Traditional Chinese Medicine of Gansu Provincial Rehabilitation Center Hospital, China from December 2005 to August 2006. The cellular neurobiology, in vitro experiment was conducted at the Institute of Human Anatomy, Histology, Embryology and Neuroscience, School of Basic Medical Sciences, Lanzhou University, and Department of Traditional Chinese Medicine of Gansu Provincial Rehabilitation Center Hospital, China from March 2007 to January 2008. MATERIALS: Naotan Pill, composed of barbary wolfberry fruit, danshen root, grassleaf sweetflag rhizome, and glossy privet fruit, was prepared by Gansu Provincial Rehabilitation Center, China. Rabbit anti-synaptophysin, choline acetyl transferase polyclonal antibody, streptavidin-biotin complex kit and diaminobenzidine kit (Boster, Wuhan, China), as well as glutamate (Hualian, Shanghai, China) were used in this study. METHODS: Cortical neural cells were isolated from neonatal Wistar rats. Neural cell damage models were induced using glutamate, and administered Naotan Pill prior to and following damage. A total of 54 juvenile Wistar rats were equally and randomly assigned into model, Naotan Pill, and sham operation groups. The left common carotid artery was ligated, and then rat models of hypoxic-ischemic injury were assigned to the model and Naotan Pill groups. At 2 days following model induction, rats in the Naotan Pill group were administered Naotan Pill suspension for 21 days. In the model and sham operation groups, rats received an equal volume of saline. MAIN OUTCOME MEASURES: Neural cell morphology was observed using an inverted phase contrast microscope. Survival rate of neural cells was measured by MTT assay. Synaptophysin and choline acetyl transferase expression was observed in the hippocampal CA1 region of juvenile rats using immunohistochemistry. Cognitive function was tested by the Morris water maze. RESULTS: Pathological changes were detected in glutamate-treated neural cells. Neural cell morphology remained normal after Naotan Pill intervention. Absorbance and survival rate of neural cells were significantly greater following Naotan Pill intervention, compared to glutamate-treated neural cells (P < 0.05). Synaptophysin and choline acetyl transferase expression was lowest in the hippocampal CA1 region in the model group and highest in the sham operation group. Significant differences among groups were observed (P < 0.05). Escape latency and swimming distance were significantly longer in the model group compared to the Naotan Pill group (P < 0.05). CONCLUSION: Naotan Pill exhibited protective and repair effects on glutamate-treated neural cells. Naotan Pill upregulated synaptophysin and choline acetyl transferase expression in the hippocampus and improved cognitive function in rats following hypoxia-ischemia.

抑制前额叶和海马的星形胶质细胞功能对大鼠工作记忆的影响，长期服用芬克罗酮改善老年大鼠学习记忆障碍的突触可塑性机制

长期以来，星形胶质细胞（astrocyte，AS）被认为具有细胞隔离、支持、保护和营养神经元的作用。近来，人们逐渐发现，AS还有许多其他重要的功能。例如，谷氨酸是中枢神经系统中重要的兴奋性神经递质，AS摄取和合成谷氨酸的作用可能影响学习、神经发育及发情周期等多种脑功能，并影响突触形成和突触传递效能。有研究发现，成年海马齿状回颗粒下层具有神经干细胞潜能的AS，可以分化成新生神经元。此外，海马成熟的AS还参与调节神经发生，决定神经干细胞的分化方向。大鼠海马新生神经元与海马依赖性记忆（happocampal- dependent memory）密切相关。提示，AS与学习记忆密切相关。但迄今为止，尚未见AS参与工作记忆的报道。本研究以特异性抑制AS细胞的化合物fluorocitrate（FC）作为工具药来探讨AS在大鼠工作记忆中的作用及作用机制。FC可抑制AS三羧酸循环中乌头酸酶（aconitase）的活性，从而抑制AS摄取谷氨酸的功能，其作用是可逆的，目前已经被广泛用于研究AS的功能。我们通过慢性导管在大鼠双侧前额叶（prefrontal cortex，PFC），双侧海马（hippocampus，HIP）和单侧侧脑室（lateral ventricle，LV）分别注射FC，记录注射后15-75min内自由活动大鼠的脑电图（EEG）功率变化，以判断FC对大鼠PFC和HIP神经元兴奋性的影响，并在注射后15-75min内完成T-迷宫空间交互延缓(spatial delayed alternation task)反应测试，分析动物的空间工作记忆功能。结果发现在双侧PFC和双侧HIP分别注射1，2，5nM FC （0.5μl），仅2，5nM显著增加HIP EEG的功率（ p < 0.05 vs. SAL），但对交互延缓反应成绩无明显影响，所有剂量对PFC的EEG功率没有显著影响，且不影响动物操作交互延缓反应作业的成绩（ALL p > 0.1 vs. SAL）。在单侧LV注射0.05，0.5nM FC （10μl）后，PFC的EEG功率没有明显变化，而HIP的EEG功率有增加。该剂量的FC对大鼠操作空间交互延缓作业的成绩无明显影响。在单侧LV注射2nM FC（10μl）同时显著增加PFC和HIP的EEG功率，并显著提高大鼠操作空间交互延缓反应作业中的正确率，改善大鼠的工作记忆（ p < 0.05 vs. SAL）。单侧LV注射5nM FC（10μl）同时显著降低PFC和HIP的EEG功率（ALL p < 0.05 vs. SAL）和大鼠操作作业的正确率，损伤大鼠的工作记忆（ p < 0.05 vs. SAL）。表明只有在PFC和HIP的EEG功率同时受到影响的时候，大鼠操作作业的正确率才会发生显著改变。已有研究指出，前额叶和海马均参与工作记忆调控。在LV给FC将同时作用于双侧PFC和双侧HIP。因此，我们认为，FC对大鼠空间交互延缓作业成绩的影响可能是通过抑制PFC和HIP的AS功能产生的。在单侧LV注射低浓度（0.05，0.5nM）的FC对大鼠空间交互延缓作业成绩和EEG功率水平均无明显影响，可能与脑内AS的功能尚可，谷氨酸水平升高不明显有关，而高浓度（5nM）FC可能较强地抑制AS摄取胞外谷氨酸的功能，胞外谷氨酸水平过度升高，损伤神经元的活性，使EEG功率降低，结果导致工作记忆受损。高浓度FC也可能直接损伤神经元的活性。本研究结果表明，FC短期抑制PFC和HIP的AS功能，将使PFC和HIP胞外谷氨酸水平升高，从而改变PFC和HIP神经元的兴奋性，使大鼠的空间工作记忆功能发生改变。揭示了工作记忆不仅依赖于PFC-HIP回路中神经元的正常功能，也与PFC-HIP回路中AS的功能正常与否密切相关。

Time-dependent DNA condensation induced by amyloid beta-peptide

The major protein component of the amyloid deposition in Alzheimer's disease is a 39-43 residue peptide, amyloid beta (A beta). A beta is toxic to neurons, although the mechanism of neurodegeneration is uncertain. Evidence exists for non-B DNA conformation in the hippocampus of Alzheimer's disease brains, and A beta was reportedly able to transform DNA conformation in vitro. In this study, we found that DNA conformation was altered in the presence of A beta, and A beta induced DNA condensation in a time-dependent manner. Furthermore, A beta sheets, serving as condensation nuclei, were crucial for DNA condensation, and Cu2+ and Zn2+ ions inhibited A beta sheet-induced DNA condensation. Our results suggest DNA condensation as a mechanism of A beta toxicity.

海洛因成瘾脑灰质密度和结构网络研究

Behavioral and functional imaging studies consistently show that heroin abuse leads to various cognitive impairments, while brain structural changes associated with heroin use remain poorly understood. In the current study, we used voxel-based morphology (VBM), a method sensitive to structural changes of the brain, to investigate the gray concentration in MRI structure images of heroin addicts. Results show that the concentration of the temporal cortex and frontal cortex of heroin users significantly decreased as compared to age/education matched normal controls. Further analysis revealed that this brain structure change was detectable only in the users who had used heroin more than 5 year, but not in the remaining users. These results converge to the abnormality of the brain structure in heroin users and this abnormality is clearly associated with duration of drug use. We then analyzed the large-scale brain structure network in the heroin addicts. As compared to the normal controls, there was significant difference in interregional correlation between the temporal cortex, hippocampus, thalamus, and frontal cortex. Importantly, two major indices of the small-world properties, Clustering coefficient(Cp) and shortest path length (Lp), which are thought to reflect the local specialty and global integrity, were marginal-significantly larger than the normal controls, especially for Lp. These results suggest that chronic use of heroin results in the reorganization of the brain system. Taken together, this thesis has provided compelling evidence for brain structure impairments in chronic heroin users and further characterized the large-scale brain structure network in the same population.