BACKGROUND & AIMS: Although reductions in neurotransmission have been reported in response to agonist-mediated adenosine A1 receptor activation, the implications of A2 receptor activation on synaptic transmission have not been well explored. We examined the role adenosine A2 receptors play in the efficacy of neurotransmission between the Schaffer collateral-CA1 pathway in the rat transverse hippocampal slice. A2 receptor blockade in the presence of complete A1 receptor inhibition led to a reversible reduction of the field excitatory post-synaptic potential (EPSP) slope in response to low-frequency test pulses (0.033 Hz) indicating that A2 receptors can enhance synaptic transmission. A2 receptor blockade by the A2 antagonist, DMPX (3,7-dimethyl-1-propargylxanthine) prevented the induction of tetanus-induced long-term potentiation (LTP) of the EPSP. In contrast, no such effect on LTP induction was observed during A1 receptor blockade. We also examined the effects of DMPX on the induction of LTP during continued A1 receptor blockade with CPT. Under this condition, LTP was significantly reduced when compared to LTP induced in the presence of CPT alone. A similar result was found using the highly polar A2 antagonist 8-SPT (8-(p-sulfophenyl)theophylline) suggesting that the effects of DMPX on LTP were not due to a direct action on an intracellular intermediate. DMPX had no effect on LTP expression if applied 45 min following the tetanus indicating that A2 receptors play no significant role in the maintenance phase of LTP. Selective A2a receptor activation did not alter the field EPSP. Similarly, selective blockade of the A2a receptor did not interfere with tetanus-induced LTP. Increases in neuronal firing rates can result in elevations in the concentration of extracellular adenosine. Together, these results suggest that the A2 receptors may play an important role in the induction although not the maintenance of hippocampal LTP and that the effect is likely to be mediated by the A2b receptor.

背景与目标： 尽管已经报道了对激动剂介导的腺苷A1受体激活的反应，神经传递的减少，但尚未很好地探讨A2受体激活对突触传递的影响。我们检查了腺苷A2受体在大鼠横贯海马切片中Schaffer侧支CA1途径之间的神经传递功效中所起的作用。在完全抑制A1受体的情况下，对A2受体的阻滞导致响应低频测试脉冲（0.033 Hz）的场兴奋性突触后突触电位（EPSP）斜率可逆降低，表明A2受体可以增强突触传递。 A2拮抗剂DMPX（3,7-二甲基-1-炔丙基黄嘌呤）对A2受体的阻滞阻止了破伤风引起的EPSP的长期增强（LTP）的诱导。相反，在A1受体阻断期间未观察到对LTP诱导的这种作用。我们还检查了CMP持续阻断A1受体期间DMPX对LTP诱导的影响。在这种情况下，与仅在CPT存在下诱导的LTP相比，LTP显着降低。使用高极性A2拮抗剂8-SPT（8-（对-磺基苯基）茶碱）发现了相似的结果，表明DMPX对LTP的作用不是由于对细胞内中间体的直接作用。如果在破伤风后45分钟使用DMPX，则LTP的表达不会受到影响，这表明A2受体在LTP的维持阶段中没有重要作用。选择性的A2a受体激活不会改变电场EPSP。同样，选择性阻断A2a受体也不会干扰破伤风诱导的LTP。神经元放电速率的增加可导致细胞外腺苷浓度的升高。总之，这些结果表明，A2受体可能在诱导中起重要作用，尽管不是维持海马LTP的作用，并且该作用可能是由A2b受体介导的。

BACKGROUND & AIMS: :Neuronal death associated with cerebral ischemia and hypoglycemia is related to increased release of excitatory amino acids (EAA) and energy failure. The intrahippocampal administration of the glycolysis inhibitor, iodoacetate (IOA), induces the accumulation of EAA and neuronal death. We have investigated by microdialysis the role of exocytosis, glutamate transporters and volume-sensitive organic anion channel (VSOAC) on IOA-induced EAA release. Results show that the early component of EAA release is inhibited by riluzole, a voltage-dependent sodium channel blocker, and by the VSOAC blocker, tamoxifen, while the early and late components are blocked by the glutamate transport inhibitors, L-trans-pyrrolidine 2,4-dicarboxylate (PDC) and DL-threo-beta-benzyloxyaspartate (DL-TBOA); and by the VSOAC blocker 4,4'-dinitrostilbene-2,2'-disulfonic acid (DNDS). Riluzole, DL-TBOA and tamoxifen did not prevent IOA-induced neuronal death, while PDC and DNDS did. The VSOAC blockers 5-nitro-2-(3-phenylpropyl-amino) benzoic acid (NPPB) and phloretin had no effect either on EAA efflux or neuronal damage. Results suggest that acute inhibition of glycolytic metabolism promotes the accumulation of EAA by exocytosis, impairment or reverse action of glutamate transporters and activation of a DNDS-sensitive mechanism. The latest is substantially involved in the triggering of neuronal death. To our knowledge, this is the first study to show protection of neuronal death by DNDS in an in vivo model of neuronal damage, associated with deficient energy metabolism and EAA release, two conditions involved in some pathological states such as ischemia and hypoglycemia.

背景与目标： ：与脑缺血和低血糖有关的神经元死亡与兴奋性氨基酸（EAA）释放增加和能量衰竭有关。海马内糖酵解抑制剂碘乙酸盐（IOA）的给药可诱导EAA积累和神经元死亡。我们已经通过微透析研究了胞吐作用，谷氨酸转运蛋白和体积敏感性有机阴离子通道（VSOAC）对IOA诱导的EAA释放的作用。结果表明，EAA释放的早期组分被电压依赖性钠通道阻滞剂利鲁唑和VSOAC阻断剂他莫昔芬抑制，而谷氨酸转运抑制剂L-反式吡咯烷2则阻断了早期和晚期组分。 ，4-二羧酸盐（PDC）和DL-苏-β-苄氧基天冬氨酸（DL-TBOA）;通过VSOAC阻滞剂4,4'-二硝基二苯乙烯-2,2'-二磺酸（DNDS）。利鲁唑，DL-TBOA和他莫昔芬不能预防IOA诱导的神经元死亡，而PDC和DNDS可以预防。 VSOAC阻滞剂5-硝基-2-（3-苯基丙基-氨基）苯甲酸（NPPB）和荧光素对EAA流出或神经元损伤均无影响。结果表明，糖酵解代谢的急性抑制可通过胞吐作用，谷氨酸转运蛋白的损伤或逆作用以及DNDS敏感机制的激活来促进EAA的积累。最新消息实质上涉及神经元死亡的触发。据我们所知，这是第一个在体内神经元损伤模型中由DNDS保护神经元死亡的研究，该模型与能量代谢不足和EAA释放有关，这是某些病理状态（例如局部缺血和低血糖）的两个条件。

BACKGROUND & AIMS: :Given the paucity of data on the distribution of serotonin (5-HT) receptors of type 6 (5-HT(6)) in the human brain, the aim of this study was to investigate their distribution in postmortem human prefrontal cortex, striatum and hippocampus by either immunohistochemical or immunofluorescence techniques. The brain samples were obtained from 6 subjects who had died for causes not involving primarily or secondarily the CNS. The 5-HT(6) receptor distribution was explored by the [(125)I]SB-258585 binding to brain membranes followed by immunohistochemical and immunofluorescence evaluations. A specific [(125)I]SB-258585 binding was detected in all the regions under investigation, whilst the content in the hippocampus and cortex being about 10-30 times lower than in the striatum. Immunohistochemistry and double-label immunofluorescence microscopy experiments, carried out in the prefrontal cortex and hippocampus only, since data in the striatum were already published, showed the presence of 5-HT(6) receptors in both pyramidal and glial cells of prefrontal cortex, while positive cells were mainly pyramidal neurons in the hippocampus. The heterogeneous distribution of 5-HT(6) receptors provides a preliminary explanation of how they might regulate different functions in different brain areas, such as, perhaps, brain trophism in the cortex and neuronal firing in the hippocampus. This study, taking into account all the limitations due to the postmortem model used, represents the starting point to explore the 5-HT(6) receptor functionality and its sub-cellular distribution.

背景与目标： ：鉴于缺乏6型血清素（5-HT）受体（5-HT（6））在人脑中的分布的数据，本研究的目的是研究它们在死后人类前额叶皮层，纹状体中的分布免疫组织化学或免疫荧光技术检测海马和海马。脑样本是从6名因主要或次要不涉及CNS的原因死亡的受试者中获得的。通过[（125）I] SB-258585与脑膜的结合，然后进行免疫组织化学和免疫荧光评估，探索了5-HT（6）受体的分布。在所有研究区域中均检测到特定的[（125）I] SB-258585结合，而海马和皮质中的含量比纹状体低约10-30倍。仅在前额叶皮层和海马体中进行的免疫组织化学和双标记免疫荧光显微镜实验，因为纹状体中的数据已经发表，显示在前额叶皮层的锥体细胞和神经胶质细胞中都存在5-HT（6）受体，而阳性细胞主要是海马中的锥体神经元。 5-HT（6）受体的异质分布为它们如何在不同的大脑区域调节不同的功能提供了初步的解释，例如，大脑皮层的营养和海马神经元的放电。这项研究，考虑到由于使用死后模型的所有限制，代表了探索5-HT（6）受体功能及其亚细胞分布的起点。

BACKGROUND & AIMS: :Olfaction in rodents provides an excellent modality for the study of cellular mechanisms of information processing and storage, since a single occurrence of precisely timed stimuli has high survival value. We have followed up preliminary evidence of cytokine and proteinase involvement in normal (as opposed to pathologically-induced) brain plasticity by surveying for the presence of these factors in the olfactory circuitry of the rat. Genes for 25-30 common cytokines and their receptors, and over 30 cell matrix and adhesion molecules were found to be expressed across the olfactory bulb, insular cortex, amygdala, and dorsal hippocampus. We then measured by real-time PCR the transcriptional expression of seven of these genes following a one-time exposure to the novel odor of blueberry bars or cornnuts, in contrast to presentation of the familiar odor of lab chow. In the amygdala significant up-regulation of interleukin-1 receptor 1 (IL1r1), interleukin-4 receptor (IL4r), fibroblast growth factor 13 (FGF13), and cathepsin-H (CtsH) was observed in males in response to the odor of cornnuts only. Changes were less consistent and widespread in the hippocampus, but were again sex specific for three genes: cathepsin-L (CtsL), matrix metalloproteinase-14 (MMP-14) and MMP-16. Our results show that transcription for several specific cytokines, growth factors, and proteinases responds to a one-time exposure to a novel odor, in a manner that tends to be region- and sex-specific. This suggests considerable variation in the way that olfactory information is processed at the cellular level in different brain regions and by the two sexes.

背景与目标： ：啮齿动物的嗅觉为研究信息处理和存储的细胞机制提供了一种极好的方式，因为精确定时刺激的单次出现具有很高的生存价值。我们通过调查大鼠嗅觉回路中这些因素的存在，追踪了细胞因子和蛋白酶参与正常（而非病理性诱导）脑可塑性的初步证据。发现25-30种常见细胞因子及其受体的基因，以及30多种细胞基质和粘附分子的基因在嗅球，岛皮层，杏仁核和海马背侧表达。然后，我们通过实时PCR测量了这些基因中的七个基因在一次暴露于蓝莓条或玉米栗的新气味后的转录表达，这与呈现出熟悉的实验室食物气味相反。在杏仁核中，男性对白细胞介素1受体1（IL1r1），白细胞介素4受体（IL4r），成纤维细胞生长因子13（FGF13）和组织蛋白酶-H（CtsH）的表达明显上调，这是由于它们的气味引起的。仅玉米粒。变化在海马中的一致性较差且分布广泛，但又对三种基因具有性别特异性：组织蛋白酶-L（CtsL），基质金属蛋白酶-14（MMP-14）和MMP-16。我们的结果表明，几种特定的细胞因子，生长因子和蛋白酶的转录以一种倾向于区域和性别特异性的方式，对一次性暴露于一种新气味的反应。这表明嗅觉信息在不同大脑区域和由两个性别在细胞水平上处理的方式存在很大差异。

BACKGROUND & AIMS: :The short-term plasticity of synaptic transmission has usually been related to neurotransmitter release-dependent processes. In this work, we describe a calcium- and release-independent augmentation of the fiber volley (FVA) that appears during stimulation of the Wistar rat commissural/Schaffer collateral afferents at 10-Hz. Among the possible mechanisms involved in this phenomenon, an increment in sodium channel density or the facilitation of recovery from inactivation does not seem to be responsible for this effect since the depolarization rate of the somatic action potentials (APs) of CA3 pyramidal cells decreases during the 10-Hz stimulation. On the other hand, an increase in the synchronization of the APs can be observed during the very first pulses of the 10-Hz tetanus. However, the major part of the FVA occurs with any increase in synchronization of AP firing. Finally, a strong increase in the firing probability, with kinetics similar to that observed with the FVA, appears at 10-Hz stimulation when APs are induced at threshold intensities. This hyperexcitability seems to be mediated by a residual depolarization that persists for more than 100 ms after the AP. The nature of this post-spike depolarization is uncertain since it persists in the absence of extracellular calcium and was not blocked by the application of phenytoin (100 microM), and this excludes the implication of either calcium or sodium-persistent currents. Additionally, the increase of the stimulation strength did not alter this depolarization, which suggests that the presumed extracellular potassium accumulation produced after the synchronic stimulation of APs is not involved in the depolarization. Interestingly, the slow post-depolarization induced by both supra- and subthreshold pulses is well fitted by a single exponential decay with similar time constants, an indication that the tail depolarization may represent passive discharge of the membrane following an incomplete repolarization of the AP.

背景与目标： ：突触传递的短期可塑性通常与神经递质的释放依赖过程有关。在这项工作中，我们描述了在10-Hz刺激Wistar大鼠连合/ Schaffer侧支传入的过程中出现的纤维凌空（FVA）的钙依赖性和释放依赖性增强。在此现象的可能机制中，钠通道密度的增加或从失活中恢复的促进似乎与这种作用无关，因为CA3锥体细胞的体细胞动作电位（APs）的去极化速率会在此过程中降低。 10 Hz刺激。另一方面，可以在10 Hz的破伤风的第一个脉冲期间观察到AP的同步性增加。但是，FVA的主要部分是随着AP触发同步的增加而发生的。最后，当以阈值强度诱导AP时，在10 Hz刺激下，发射概率会大大增强，其动力学与FVA所观察到的相似。这种超兴奋性似乎是由残留的去极化介导的，该残留的去极化在AP后持续100毫秒以上。穗后去极化的性质尚不确定，因为它在不存在细胞外钙的情况下仍会持续存在，并且不受苯妥英（100 microM）的作用所阻止，并且不包括钙或钠持续电流。另外，刺激强度的增加并没有改变这种去极化，这表明在同步刺激APs之后产生的推测的细胞外钾积累不参与去极化。有趣的是，由超阈值脉冲和亚阈值脉冲引起的缓慢的去极化后，被具有相似时间常数的单个指数衰减很好地拟合，这表明尾部去极化可能代表了AP不完全极化后的被动放电。

BACKGROUND & AIMS: :Glutamate (GLU) and gamma-amino butyric acid (GABA) are essential amino acids (AA) for brain function serving as excitatory and inhibitory neurotransmitter respectively. Their tablets are available in market for improving gut function and muscle performance. Despite of having a major role during memory formation and processing, effects of these tablets on brain functioning like learning and memory have not been investigated. Therefore, present study is aimed to investigate the effects of orally supplemented GLU and GABA on learning and memory performance and further to monitor related effects of these orally supplemented GLU and GABA on brain levels of these AA. Three groups of rats were supplemented orally with drinking water (control group) or suspension of tablets of GABA and Glutamate, respectively for four weeks. Cognitive performance was determined using behavioral tests (Novel object recognition test, Morris water maze, Passive avoidance test) measuring recognition, spatial reference and aversive memory. Levels of GLU, GABA and acetylcholine (ACh) were estimated in rat hippocampus. Results showed that chronic oral administration of GLU and GABA tablets has a significant impact on brain function and can alter GLU and GABA content in rat hippocampus. Compared to GABA, GLU supplementation specifically enhances memory performance via increasing ACh. Thus, GLU can be suggested as a useful supplement for improving learning and memory performance and neurochemical status of brain and in future could be effective in the treatment of neurological disorders affecting learning and memory performance.

背景与目标： ：谷氨酸（GLU）和γ-氨基丁酸（GABA）是大脑功能所必需的氨基酸（AA），分别充当兴奋性和抑制性神经递质。他们的片剂在市场上可用于改善肠道功能和肌肉性能。尽管在记忆形成和加工过程中起主要作用，但尚未研究这些片剂对大脑功能（如学习和记忆）的作用。因此，本研究旨在研究口服补充GLU和GABA对学习和记忆能力的影响，并进一步监测这些口服补充GLU和GABA对这些AA的脑水平的相关影响。向三组大鼠分别口服饮用水（对照组）或GABA和谷氨酸盐片剂的悬浮液，持续4周。使用行为测试（小说对象识别测试，莫里斯水迷宫，被动回避测试）来测量认知，空间参考和厌恶记忆，从而确定认知能力。估计大鼠海马中的GLU，GABA和乙酰胆碱（ACh）的水平。结果表明，长期口服GLU和GABA片剂对脑功能有显着影响，并且可以改变大鼠海马中GLU和GABA的含量。与GABA相比，GLU补充剂通过增加ACh来专门增强记忆力。因此，GLU可被建议作为改善学习和记忆性能以及大脑神经化学状态的有用补充剂，将来可能有效治疗影响学习和记忆性能的神经系统疾病。

BACKGROUND & AIMS: :A rapid elevation in the level of endogenous corticosterone (CORT) functions in the stress response associated with the hypothalamus-pituitary-adrenal axis, and it has been well documented that high levels of CORT play neurotoxic roles in the hippocampus. Both aging and the circadian rhythm possibly affect the sensitivity to CORT, although their endogenous modifications in the CORT-mediated events remain unclear. To explore the influence of age or circadian time on hippocampal vulnerability to excess CORT, we examined the relative mRNA expression of bcl-2 and bax in the dentate gyrus (DG) and the CA1 subfield, compared with the CA3 as an internal standard, after acute CORT administration using in situ RT-PCR. Male rats aged 10 weeks (young) or 6 months (adult) were treated with CORT at 0800 or 2000 h. The bcl-2 to bax mRNA ratio in the dentate gyrus (DG) was significantly decreased 2h after CORT exposure in the young rats treated at 0800 or 2000 h. In the adult rats, the treatment with CORT at 0800 h significantly decreased the bcl-2 to bax ratio, whereas the treatment at 2000 h was ineffective; the discrepancy between the treatment time points was apparent in adult rats, but not in young rats. Our results emphasize the importance of circadian time as well as age as a factor influencing the stress paradigm.

背景与目标： ：内源性皮质酮（CORT）水平的快速升高在下丘脑-垂体-肾上腺轴相关的应激反应中起作用，并且有充分的文献证明高水平的CORT在海马中发挥神经毒性作用。衰老和昼夜节律都可能影响对CORT的敏感性，尽管它们在CORT介导的事件中的内源性修饰尚不清楚。为了探讨年龄或昼夜节律时间对海马对过量CORT易损性的影响，我们比较了齿状回（DG）和CA1子域中bcl-2和bax的相对mRNA表达，并比较了CA3作为内标。使用原位RT-PCR进行急性CORT给药。将10周龄（年轻）或6个月龄（成年）的雄性大鼠在0800或2000 h进行CORT治疗。在0800或2000 h处理的年轻大鼠中，CORT暴露2h后，齿状回（DG）中bcl-2与bax mRNA的比例显着降低。在成年大鼠中，在0800 h用CORT处理可显着降低bcl-2与bax的比率，而在2000 h处理则无效。治疗时间点之间的差异在成年大鼠中很明显，而在年轻大鼠中则没有。我们的结果强调了昼夜节律的重要性以及年龄是影响压力范式的重要因素。

BACKGROUND & AIMS: OBJECTIVE:The effects of melatonin on antioxidant status were examined in pinealectomized rats using enzymatic, histological and immunohistochemical techniques. The aim of this study is to investigate the effects of melatonin on hippocampal apoptosis. MATERIALS AND METHODS:Male Wistar rats (n=21) were divided into 3 groups: Group I and group II were designated as control (sham-pinealectomy) and pinealectomized rats, respectively. Rats in group III were pinealectomized and injected daily with melatonin (1 mg/kg) for 3 months beginning at day 7 after surgery. At the end of experimental period, all rats were killed by decapitation. The brains of the rats were removed and the hippocampus tissue was obtained from all brain specimens. The right hippocampal specimens of all rats were used for determination of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA) levels. The left hippocampus tissue specimens of all animals were used for immunohistochemical and histological evaluation. RESULTS:The levels of SOD and GSH-Px were significantly decreased, and MDA levels were significantly increased in pinealectomized rats compared to the controls. In the histological and immunohistochemical evaluation of this group, increase of pyknotic cells, vacuolar degeneration and apoptosis were observed. However, increased SOD and GSH-Px enzyme activities, and decreased MDA levels were detected in the rats administered melatonin after pinealectomy. Furthermore, histological and apoptotic changes in hippocampus caused by pinealectomy were lost in the rats treated with melatonin. CONCLUSIONS:The results of our study revealed that pinealectomy-induced oxidative damage and morphological changes in the hippocampal tissue were suppressed by melatonin.

背景与目标： 目的：采用酶法，组织学和免疫组化技术研究褪黑激素对松果体切除大鼠的抗氧化状态的影响。这项研究的目的是研究褪黑激素对海马细胞凋亡的影响。
材料与方法：雄性Wistar大鼠（n = 21）分为3组：将I组和II组分别作为对照组（假松果体切除术）和松果体切除的大鼠。从手术后第7天开始，对第三组的大鼠进行松果体切除术，并每天注射褪黑激素（1 mg / kg），持续3个月。在实验期结束时，所有大鼠被斩首处死。取出大鼠的大脑，并从所有脑标本中获得海马组织。所有大鼠的右海马标本用于测定超氧化物歧化酶（SOD），谷胱甘肽过氧化物酶（GSH-Px）和丙二醛（MDA）水平。所有动物的左海马组织标本用于免疫组织化学和组织学评估。
结果：与对照组相比，松果体切除的大鼠的SOD和GSH-Px水平显着降低，MDA水平显着升高。在该组的组织学和免疫组织化学评价中，观察到了泌尿生殖细胞的增加，液泡变性和细胞凋亡。然而，在松果体切除术后施用褪黑激素的大鼠中检测到SOD和GSH-Px酶活性增加，而MDA水平降低。此外，褪黑素治疗的大鼠失去了由松果体切除术引起的海马组织学和凋亡的改变。
结论：我们的研究结果表明，褪黑素能抑制松果体切除术引起的海马组织氧化损伤和形态变化。

BACKGROUND & AIMS: :Diabetes mellitus (DM) may give rise to cognitive impairment, but the pathological mechanism involved was still unknown. We employed streptozotocin (STZ)-induced diabetic rats and test their capacity for learning and memory by three-arm radial maze. We determined the expression level of growth-associated protein-43 (GAP-43) and mitogen activated protein kinase phosphatase-1 (MKP-1) in the hippocampus by immunohistochemistry. MKP-1 mRNA level in the CA1 and dentate gyrus (DG) Hippocampal area is further determined by RT-PCR method. We also observed the ultrastructures of Hippocampal neurons by transmission electron microscopy (TEM). All data were analyzed by the independent samples t-test. Four weeks after STZ induction, the diabetic rats showed decreased capacity for learning and memory as indicated by the increase in the error number and reaction time in three-arm radial maze test. TEM results showed the ultrastructures of diabetic hippocampus, including area CA1 and DG, neurons were characterized by swollen mitochondria, increased heterochromatin accumulation and reduced synaptic contacts. The optical density as well as the positive neuron number for GAP-43 and MKP-1 decreased significantly in the CA1 and DG Hippocampal area in diabetic rats (P<0.01). RT-PCR results also showed MKP-1 mRNA in the CA1 and DG Hippocampal area was decreased in the diabetic rats. These results indicated that DM could down-regulate GAP-43 and MKP-1 expression in Hippocampal area that is in charge of memory and cognition. As indicated by our study, the changes in GAP-43 and MKP-1 expression in hippocampus may play a role in the pathogenesis of diabetic dementia.

背景与目标： ：糖尿病（DM）可能引起认知障碍，但涉及的病理机制仍不清楚。我们采用了链脲佐菌素（STZ）诱导的糖尿病大鼠，并通过三臂radial骨迷宫测试了它们的学习和记忆能力。我们通过免疫组织化学测定了海马中的生长相关蛋白43（GAP-43）和有丝分裂原活化蛋白激酶磷酸酶1（MKP-1）的表达水平。通过RT-PCR方法进一步测定CA1和齿状回（DG）海马区中的MKP-1 mRNA水平。我们还通过透射电子显微镜（TEM）观察了海马神经元的超微结构。所有数据均通过独立样本t检验进行分析。诱导STZ后四周，糖尿病大鼠的学习和记忆能力下降，这是通过三臂放射状迷宫测试中错误数和反应时间的增加来表明的。 TEM结果显示，糖尿病海马的超微结构包括CA1区和DG区，神经元的特征在于线粒体肿胀，异染色质积累增加和突触接触减少。糖尿病大鼠CA1区和DG海马区的GAP-43和MKP-1的光密度以及阳性神经元数量均显着下降（P <0.01）。 RT-PCR结果还显示，糖尿病大鼠CA1和DG海马区的MKP-1 mRNA降低。这些结果表明DM可以下调负责记忆和认知的海马区GAP-43和MKP-1的表达。正如我们的研究所表明的，海马区GAP-43和MKP-1表达的变化可能在糖尿病性痴呆的发病机理中起作用。

BACKGROUND & AIMS: :Intermittent hypoxia, such as that associated with obstructive sleep apnea, can cause neuronal death and neurobehavioral dysfunction. The cellular and molecular mechanisms through which hypoxia alter hippocampal function are incompletely understood. This study used in vitro [(35)S]guanylyl-5'-O-(gamma-thio)-triphosphate ([(35)S]GTP gamma S) autoradiography to test the hypothesis that carbachol and DAMGO activate hippocampal G proteins. In addition, this study tested the hypothesis that in vivo exposure to different oxygen (O(2)) concentrations causes a differential activation of G proteins in the CA1, CA3, and dentate gyrus (DG) regions of the hippocampus. G protein activation was quantified as nCi/g tissue in CA1, CA3, and DG from rats housed for 14 days under one of three different oxygen conditions: normoxic (21% O(2)) room air, or hypoxia (10% O(2)) that was intermittent or sustained. Across all regions of the hippocampus, activation of G proteins by the cholinergic agonist carbachol and the mu opioid agonist [D-Ala(2), N-Met-Phe(4), Gly(5)] enkephalin (DAMGO) was ordered by the degree of hypoxia such that sustained hypoxia > intermittent hypoxia > room air. Carbachol increased G protein activation during sustained hypoxia (38%), intermittent hypoxia (29%), and room air (27%). DAMGO also activated G proteins during sustained hypoxia (52%), intermittent hypoxia (48%), and room air (43%). Region-specific comparisons of G protein activation revealed that the DG showed significantly less activation by carbachol following intermittent hypoxia and sustained hypoxia than the CA1. Considered together, the results suggest the potential for hypoxia to alter hippocampal function by blunting the cholinergic activation of G proteins within the DG.

背景与目标： ：间歇性缺氧，例如与阻塞性睡眠呼吸暂停有关的缺氧，可能导致神经元死亡和神经行为功能障碍。缺氧改变海马功能的细胞和分子机制尚不完全清楚。这项研究使用体外[（35）S]胍基-5'-O-（γ-硫代）-三磷酸（[（35）S] GTPγS）放射自显影，以检验卡巴胆碱和DAMGO激活海马G蛋白的假说。此外，这项研究检验了以下假设：体内暴露于不同的氧气（O（2））浓度会导致海马CA1，CA3和齿状回（DG）区域中G蛋白的差异激活。 G蛋白活化被量化为在以下三种不同氧气条件之一下饲养14天的大鼠在CA1，CA3和DG中的nCi / g组织：常氧（21％O（2））室内空气或低氧（10％O（ 2））是断断续续的或持续的。在海马的所有区域，胆碱能激动剂卡巴胆碱和μ阿片类激动剂[D-Ala（2），N-Met-Phe（4），Gly（5）]脑啡肽（DAMGO）激活G蛋白的顺序是：缺氧程度，使持续缺氧>间歇性缺氧>室内空气。在持续缺氧（38％），间歇性缺氧（29％）和室内空气（27％）期间，卡巴胆碱会增加G蛋白的活化。 DAMGO还可以在持续性缺氧（52％），间歇性缺氧（48％）和室内空气（43％）期间激活G蛋白。 G蛋白活化的区域特异性比较显示，间歇性缺氧和持续性缺氧后DG所显示的DG活化程度明显低于CA1。综合考虑，结果表明缺氧可能通过减弱DG中G蛋白的胆碱能激活来改变海马功能。

BACKGROUND & AIMS: :Dendrotoxins, important pharmacological tools for studying K(+) channels, are potently convulsant in the central nervous system and evidence suggests that different members of the dendrotoxin family may act at pre- or post-synaptic sites. Using a combination of intrahippocampal infusion, microdialysis and electroencephalograph (EEG) recording, we have compared the effects of alpha-dendrotoxin and dendrotoxin K on extracellular levels of excitatory amino acids in anaesthetised rats. Our findings show that although infusion of 35 pmol of both peptides was associated with elevated extracellular aspartate and glutamate, these increased levels were more sustained with dendrotoxin K. Furthermore, there was EEG evidence of an associated transient functional change consistent with an action on pre-synaptic K(+) channels. In contrast, infusion of alpha-dendrotoxin produced only a brief effect on amino acid levels and no evidence of a functional consequence.

背景与目标： ：Dendrotoxins是研究K（）通道的重要药理工具，在中枢神经系统中很强惊厥，证据表明树突毒素家族的不同成员可能在突触前或突触后部位起作用。使用海马内输注，微透析和脑电图（EEG）记录的组合，我们比较了α-树突毒素和树突毒素K对麻醉大鼠兴奋性氨基酸细胞外水平的影响。我们的发现表明，尽管输注35 pmol的两种肽都与升高的细胞外天冬氨酸和谷氨酸有关，但树突毒素K可使这些升高的水平更持久。突触K（）通道。相反，输注α-树突毒素仅对氨基酸水平产生短暂影响，而没有功能后果的证据。

BACKGROUND & AIMS: :The 5-hydroxytryptamine (5-HT; serotonin) transporter (5-HTT) is important in terminating serotonergic neurotransmission and is a primary target for many psychotherapeutic drugs. Study of the regulation of 5-HTT activity is therefore important in understanding the control of serotonergic neurotransmission. Using high-speed chronoamperometry, we have demonstrated that local application of 5-HT(1B) antagonists into the CA3 region of the hippocampus prolongs the clearance of 5-HT from extracellular fluid (ECF). In the present study, we demonstrate that the 5-HT(1B) antagonist cyanopindolol does not produce this effect by increasing release of endogenous 5-HT or by directly binding to the 5-HTT. Dose-response studies showed that the potency of cyanopindolol to inhibit clearance of 5-HT was equivalent to that of the selective 5-HT reuptake inhibitor fluvoxamine. Local application of the 5-HT(1A) antagonist WAY 100635 did not alter 5-HT clearance, suggesting that the effect of cyanopindolol to prolong clearance is not via a mechanism involving 5-HT(1A) receptors. Finally, the effect of low doses of cyanopindolol and fluvoxamine to inhibit clearance of 5-HT from ECF was additive. These data are consistent with the hypothesis that activation of terminal 5-HT(1B) autoreceptors increases 5-HTT activity.

背景与目标： ：5-羟色胺（5-HT; 5-羟色胺）转运蛋白（5-HTT）在终止5-羟色胺能神经传递中很重要，并且是许多心理治疗药物的主要靶标。因此，研究5-HTT活性的调节对理解5-羟色胺能神经传递的控制是重要的。使用高速计时电流分析法，我们已经证明将5-HT（1B）拮抗剂局部应用到海马CA3区可以延长5-HT从细胞外液（ECF）的清除。在本研究中，我们证明了5-HT（1B）拮抗剂氰基吲哚洛尔不会通过增加内源性5-HT的释放或直接与5-HTT结合而产生这种作用。剂量反应研究表明，氰基吲哚醇抑制5-HT清除的效力与选择性5-HT再摄取抑制剂氟伏沙明的效力相当。 5-HT（1A）拮抗剂WAY 100635的局部应用不会改变5-HT的清除率，这表明氰基吲哚洛尔延长清除率的作用不是通过涉及5-HT（1A）受体的机制进行的。最后，低剂量的氰基吲哚洛尔和氟伏沙明抑制5-HT从ECF清除的作用是加和的。这些数据与终端5-HT（1B）自身受体激活增加5-HTT活性的假设是一致的。

BACKGROUND & AIMS: :The dentate gyrus of the hippocampus continues generating new neurons throughout life. These neurons originate from radial astrocytes within the subgranular zone (SGZ). Here, we find that Sox1, a member of the SoxB1 family of transcription factors, is expressed in a subset of radial astrocytes. Lineage tracing using Sox1-tTA;tetO-Cre;Rosa26 reporter mice shows that the Sox1-expressing cells represent an activated neural stem/progenitor population that gives rise to most if not all newly born granular neurons, as well as a small number of mature hilar astrocytes. Furthermore, a subpopulation of Sox1-marked cells have long-term neurogenic potential, producing new neurons 3 months after inactivation of tetracycline transactivator. Remarkably, after 8 weeks of labeling and a 12-week chase, as much as 44% of all granular neurons in the dentate gyrus were derived from Sox1 lineage-traced adult neural stem/progenitor cells. The fraction of Sox1-positive cells within the radial astrocyte population decreases with age, correlating with a decrease in neurogenesis. However, expression profiling shows that these cells are transcriptionally stable throughout the lifespan of the mouse. These results demonstrate that Sox1 is expressed in an activated stem/progenitor population whose numbers decrease with age while maintaining a stable molecular program.

背景与目标： 海马的齿状回在整个生命中继续产生新的神经元。这些神经元起源于颗粒下带（SGZ）内的星形星形胶质细胞。在这里，我们发现Sox1，SoxB1家族的转录因子家族的成员，在radial状星形胶质细胞的子集中表达。使用Sox1-tTA; tetO-Cre; Rosa26报告基因小鼠的谱系追踪显示，表达Sox1的细胞代表一个激活的神经干/祖细胞群，该群体会产生大多数（如果不是全部）新生的颗粒神经元，以及少数成熟的神经元。肺门星形胶质细胞。此外，Sox1标记的细胞亚群具有长期的神经源性潜力，在灭活四环素反式激活剂后3个月会产生新的神经元。值得注意的是，标记8周和追踪12周后，齿状回中多达44％的所有颗粒神经元均来自Sox1谱系追踪的成年神经干/祖细胞。星形星形胶质细胞群中Sox1阳性细胞的比例随年龄的增长而降低，这与神经发生的减少有关。但是，表达谱显示这些细胞在小鼠的整个生命周期中都是转录稳定的。这些结果表明，Sox1在活化的茎/祖细胞中表达，其数量随着年龄的增长而减少，同时保持稳定的分子程序。

BACKGROUND & AIMS: Hippocampal GABAergic interneurons are responsible for controlling the output and efficacy of synaptic input of large principal cell populations and, thereby, determine the oscillatory discharge patterns and synaptic plasticity in the hippocampus. Single interneurons are able to prevent repetitive firing of postsynaptic pyramidal cells (R. Miles, K. Tóth, A.I. Gulyás, N. Hájos, and T.F. Freund. Neuron, 16815-823, 1996), whereas on occasion a single pyramidal cell may be able to activate an interneuron under in vitro conditions (A.I. Gulyás, R. Miles, A. Sik, K. Tóth, N. Tamamaki, and T.F. Freund.

Nature (London), 366683-687, 1993). Inhibition is therefore extremely powerful. Transient suppression of interneuronal activity allows the precise timing and synchronization of inhibitory postsynaptic potentials arriving at principal cells.

A rhythmic suppression or modulation of interneuron discharge may be brought about by input from at least two major sources(i) from other local interneurons or (ii) from subcortical centers. Of the possible local sources, in the present review particular attention will be paid to GABAergic neurons specialized to innervate other interneurons. Subcortical pathways known to modulate specific inhibitory functions in the hippocampus, i.e., the GABAergic and cholinergic septohippocampal and the serotonergic raphe hippocampal pathways, will also be reviewed. Roles of these control mechanisms may include the generation of theta and higher frequency oscillations and the selective removal of inhibition from the termination zone of specific excitatory afferents, thereby increasing their efficacy and (or) plasticity.

背景与目标： 海马GABA能性神经元负责控制大量主细胞群的输出和突触输入的功效，从而确定海马中的振荡放电模式和突触可塑性。单个中间神经元能够阻止突触后锥体细胞的反复发射（R. Miles，K.Tóth，AIGulyás，N.Hájos和TF Freund。Neuron，16815-823，1996），而有时单个锥体细胞可能是能够在体外条件下激活中间神经元（AIGulyás，R.Miles，A.Sik，K.Toth，N.Tamamaki和TF Freund。

Nature（London），366683-687，1993） 。因此抑制作用非常强大。神经元间活动的瞬时抑制可以使到达主细胞的抑制性突触后电位的精确定时和同步。

至少从两个主要来源（i）的输入可以实现对神经元放电的节律性抑制或调节。其他局部中间神经元；或（ii）来自皮层下中心。在可能的本地来源中，在本综述中，将特别关注专门用于支配其他中间神经元的GABA能神经元。也将审查已知可调节海马中特定抑制功能的皮层下途径，即GABA能和胆碱能的海马途径和血清素能的罗非鱼海马途径。这些控制机制的作用可能包括产生theta和更高频率的振荡，以及选择性地消除特定兴奋性传入传入末端区域的抑制作用，从而提高其功效和（或）可塑性。

BACKGROUND & AIMS: Previously, we demonstrated that transection of the fimbria/fornix blocked the excitatory effect of corticotropin-releasing hormone (CRH) on startle (CRH-enhanced startle), suggesting that the hippocampus and its efferent target areas that communicate via the fimbria may be critically involved in CRH-enhanced startle. The bed nucleus of the stria terminalis (BNST) receives direct projections from the ventral hippocampus via the fimbria/fornix. Therefore, the role of the ventral hippocampus, the BNST, and the amygdala in CRH-enhanced startle was investigated. NMDA lesions of the BNST completely blocked CRH-enhanced startle, whereas chemical lesions of the ventral hippocampus and the amygdala failed to block CRH-enhanced startle. However, the same amygdala-lesioned animals showed a complete blockade of fear-potentiated startle, a conditioned fear response sensitive to manipulations of the amygdala. In contrast, BNST-lesioned rats had normal fear-potentiated startle. This indicates a double dissociation between the BNST and the amygdala in two different paradigms that enhance startle amplitude. Microinfusions of CRH into the BNST, but not into the ventral hippocampus, mimicked intracerebroventricular CRH effects. Furthermore, infusion of a CRH antagonist into the BNST blocked CRH-enhanced startle in a dose-dependent manner. Control studies showed that this blockade did not result from either leakage of the antagonist into the ventricular system or a local anesthetic effect caused by infusion of the antagonist into the BNST. The present studies strongly suggest that CRH in the CSF can activate the BNST, which could lead to activation of brainstem and hypothalamic BNST target areas involved in anxiety and stress responses.

背景与目标： 先前，我们证明了横隔纤维/穹ni横断阻止了促肾上腺皮质激素释放激素（CRH）对惊吓（CRH增强的惊吓）的兴奋作用，这表明海马及其通过突触进行沟通的目标区域可能受到了严重影响。令CRH惊呆了。末端纹状体的床核（BNST）通过腹膜/穹receives从腹侧海马接受直接投射。因此，研究了腹侧海马，BNST和杏仁核在CRH增强惊吓中的作用。 BNST的NMDA损伤完全阻断了CRH增强的惊吓，而腹侧海马和杏仁核的化学损伤未能阻断CRH增强的惊吓。然而，相同的扁桃体病变动物表现出对恐惧增强惊吓的完全阻断，这是一种对杏仁核的操纵敏感的条件化恐惧反应。相反，BNST损伤的大鼠具有正常的恐惧增强惊吓。这表明BNST和杏仁核之间在两种不同的范式之间双重解离，从而增强了惊吓幅度。将CRH微量注入BNST，但不注入腹侧海马区，模仿了脑室内CRH效应。此外，将CRH拮抗剂输注到BNST中以剂量依赖的方式阻断了CRH增强的惊吓。对照研究表明，这种阻断作用不是由拮抗剂渗入心室系统引起的，也不是由将拮抗剂注入BNST引起的局部麻醉作用引起的。本研究强烈表明，CSF中的CRH可以激活BNST，这可能导致涉及焦虑和压力反应的脑干和下丘脑BNST目标区域激活。