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。

BACKGROUND & AIMS: :The neonatal hippocampus exhibits regularly recurring waves of synchronized neuronal activity in vitro. Because active sleep (AS), characterized by bursts of phasic motor activity in the form of myoclonic twitching, may provide conditions that are conducive to activity-dependent development of hippocampal circuits, we hypothesized that the waves of synchronous neuronal activity that have been observed in vitro would be associated with AS-related twitching. Using unanesthetized 1- to 12-d-old rats, we report here that the majority of neurons in CA1 and the dentate gyrus (DG) are significantly more active during AS than during either quiet sleep or wakefulness. Neuronal activity typically occurs in phasic bursts, during which most neurons are significantly cross-correlated both within and across the CA1 and DG fields. All AS-active neurons increase their firing rates during periods of myoclonic twitching of the limbs, and a subset of these neurons exhibit a burst of activity immediately after limb twitches, suggesting that the twitches themselves provide sensory feedback to the infant hippocampus, as occurs in the infant spinal cord and neocortex. Finally, the synchronous bursts of neuronal activity are coupled to the emergence of the AS-related hippocampal gamma rhythm during the first postnatal week, as well as the emergence of the AS-related theta rhythm during the second postnatal week. We hypothesize that the phasic motor events of active sleep provide the developing hippocampus with discrete sensory stimulation that contributes to the development and refinement of hippocampal circuits as well as the development of synchronized interactions between hippocampus and neocortex.

背景与目标： ：新生的海马体在体外表现出定期重复出现的同步神经元活动。由于活动性睡眠（AS）以肌阵挛性抽搐形式的阶段性运动活动爆发为特征，可能提供有利于活动依赖型海马回路发展的条件，因此我们假设已观察到同步神经元活动波体外会与AS相关的抽搐有关。使用未麻醉的1至12天大的大鼠，我们在此报告，在AS期间，CA1和齿状回（DG）中的大多数神经元比安静睡眠或清醒期间的神经元活跃得多。神经元活动通常发生在阶段性爆发中，在此期间，大多数神经元在CA1和DG场内和跨CA1和DG场都具有显着的互相关性。在四肢肌阵挛性抽搐期间，所有AS活跃神经元均会提高放电率，这些神经元的一部分在四肢抽搐后立即表现出爆发性活动，这表明抽搐本身会向婴儿海马提供感觉反馈，就像在四肢抽搐时一样。婴儿脊髓和新皮层。最后，神经元活动的同步爆发与产后第一周出现AS相关的海马γ节奏，以及产后第二周出现AS相关theta节奏有关。我们假设主动睡眠的阶段性运动事件为发展中的海马提供了离散的感觉刺激，从而促进了海马电路的发展和完善以及海马与新皮层之间同步相互作用的发展。

BACKGROUND & AIMS: :Post-traumatic stress disorder (PTSD) is characterized by memory disturbances following trauma. Acute predator threat has emerged as an ethological model of PTSD, yet the effects of predator odor on signaling cascades associated with long-term memory remain poorly understood. In this study, we exposed male and female Wistar rats to the synthetic predator odor 2,5-dihydro-2,4,5-trimethylthiazoline (TMT) to assess behavioral and physiological responses as well as rapid modulation of signal transduction cascades associated with learning and memory in the male and female hippocampus. During exposure to TMT in the homecage, both male and female animals displayed robust immobility, avoidance, and altered activity as a function of time. Physiologically, TMT exposure increased circulating corticosterone and blood glucose in both male and female rodents, suggesting that TMT evokes sex-independent behavioral and physiological responses. With respect to signal transduction, TMT exposure rapidly reduced phosphorylation of cyclic-adenosine monophosphate response element binding protein (CREB) in the male, but not the female hippocampus. Furthermore, TMT exposure reduced phosphorylation of extracellular signal-regulated kinase 1/2 and increased nuclear expression of the synapto-nuclear messenger protein Jacob in the male hippocampus, consistent with activation of the CREB shut-off pathway. In a follow-up behavioral experiment, post-training exposure to TMT did not affect spatial water maze performance of male rats. However, male rats re-introduced to the context in which TMT had previously been presented displayed avoidance and hyperactivity, but not freezing behavior or elevated corticosterone responses, suggesting that TMT exposure supports a form of contextual conditioning which is not characterized by immobility. Taken together, our findings suggest that TMT evokes similar behavioral and physiological responses in male and female Wistar rats, but affects distinct signaling cascades in the male and female hippocampus which may contribute to behavioral disruptions associated with predator exposure.

背景与目标： 创伤后应激障碍（PTSD）的特征是创伤后的记忆障碍。急性捕食者威胁已成为PTSD的一种行为学模型，但对捕食者气味对与长期记忆相关的信号级联反应的影响仍知之甚少。在这项研究中，我们将雄性和雌性Wistar大鼠暴露于合成的捕食性气味2,5-二氢-2,4,5-三甲基噻唑啉（TMT）中，以评估行为和生理反应以及与学习相关的信号转导级联的快速调节和雌性海马的记忆。在笼子中暴露于TMT期间，雄性和雌性动物均表现出强健的不动，回避和随时间变化的活动。从生理上讲，TMT暴露会增加雄性和雌性啮齿动物的循环皮质酮和血糖，这表明TMT引起了与性别无关的行为和生理反应。关于信号转导，TMT暴露可迅速减少雄性海马中环磷酸腺苷单磷酸反应元件结合蛋白（CREB）的磷酸化。此外，TMT暴露减少了雄性海马中细胞外信号调节激酶1/2的磷酸化并增加了突触核信使蛋白Jacob的核表达，这与CREB阻断途径的激活相一致。在一项后续的行为实验中，训练后暴露于TMT并没有影响雄性大鼠的空间水迷宫性能。然而，重新引入先前曾提出过TMT的情境的雄性大鼠表现出回避和过度活跃，但没有冰冻行为或皮质酮反应升高，这表明TMT暴露支持一种形式的情境调节，其特征是不动。两者合计，我们的发现表明TMT在雄性和雌性Wistar大鼠中引起相似的行为和生理反应，但会影响雄性和雌性海马中不同的信号传导级联，这可能导致与捕食者接触相关的行为破坏。

BACKGROUND & AIMS: BACKGROUND:Hippocampal functions are sensitive to sleep deficiency. Dopamine D1 receptor (D1R) in hippocampus can regulate the expression of cAMP response element binding protein (CREB) through PKA, MAPK and phosphoinositide pathway, but which pathway plays the major role in hippocampus during Chronic sleep deprivation (CSD) is unclear. METHODS:The CSD model was created, SKF rats were administered the D1R agonist (SKF38363), and hippocampus from each animal was dissected for following molecular detection. The gene and protein levels of CREB and key molecules in D1R pathways were measured by real-time PCR and western blotting, respectively. RESULTS:Both the gene and protein expression of CREB in hippocampus decreased by CSD and improved significantly by SKF38393 (p<0.05). Both the gene and protein expression of PKA in hippocampus decreased by CSD and improved significantly by SKF38393 (p<0.05). SKF38393 just significantly improved the gene level of CaMK IV and the protein level of p-CaMK IV (p<0.05) in CSD rats, but it cannot improve the protein expression of ERK1/2 and p-ERK1/2. DISCUSSION:CSD significantly decreased the expression of CREB in hippocampus. As the key molecules, PKA and CaMK IV play an important role during the improvement of hippocampus by the activation of D1R, and this process might be improved during CSD through the PKA and phosphoinositide pathway.

背景与目标： 背景：海马功能对睡眠不足敏感。海马中的多巴胺D1受体（D1R）可以通过PKA，MAPK和磷酸肌醇途径调节cAMP反应元件结合蛋白（CREB）的表达，但是在慢性睡眠剥夺（CSD）期间，该途径在海马中起主要作用尚不清楚。
方法：建立CSD模型，给SKF大鼠施用D1R激动剂（SKF38363），并解剖每只动物的海马体以进行分子检测。通过实时PCR和蛋白质印迹分别测量CR1和D1R途径中关键分子的基因和蛋白质水平。
结果：CSD降低海马CREB的基因和蛋白表达，SKF38393显着提高海马CREB的基因和蛋白表达（p <0.05）。 CSD使海马PKA的基因和蛋白表达均降低，而SKF38393则使PKA的基因和蛋白表达均显着提高（p <0.05）。 SKF38393可以显着改善CSD大鼠的CaMK IV基因水平和p-CaMK IV蛋白水平（p <0.05），但不能改善ERK1 / 2和p-ERK1 / 2的蛋白表达。
讨论：CSD可明显降低海马CREB的表达。作为关键分子，PKA和CaMK IV在D1R活化过程中改善海马过程中起着重要作用，并且在CSD期间可通过PKA和磷酸肌醇途径改善这一过程。

BACKGROUND & AIMS: :We examined the effect of transient forebrain ischemia of 2-, 3-, 4- and 5-min duration on the development of delayed neuronal death in field CA1 of the hippocampus in the gerbil whose brain temperature was maintained at 37 degrees C. Transient ischemia of 3- and 4-min duration caused almost the same maximal damage in field CA1 as observed in the gerbils subjected to 5-min ischemia. A detrimental factor inducing delayed neuronal death in field CA1 may be already set up during the first 3 min after the onset of ischemia in the gerbil whose brain temperature is maintained at normothermic levels.

背景与目标： ：我们研究了持续2分钟，3分钟，4分钟和5分钟的短暂性前脑缺血对大脑温度保持在37摄氏度的沙土鼠海马CA1区迟发性神经元死亡发展的影响。持续3分钟和4分钟的局部缺血在田野CA1中造成的最大损害几乎与遭受5分钟局部缺血的沙鼠所观察到的相同。沙鼠缺血发作后的前3分钟内，可能已经建立了导致CA1区域延迟神经元死亡的有害因素，其脑温保持在正常水平。

BACKGROUND & AIMS: :It has been suggested that stroke-prone spontaneously hypertensive rats (SHRSP) show vulnerability to neuronal damage following transient ischemia. To observe the effect of hydroxyl radicals on neuronal damage in the hippocampus of SHRSP during ischemia and recirculation, we measured the levels of 2,3-dihydroxybenzoic acid (2,3-DHBA), as a biological marker of hydroxyl radicals in the hippocampus of SHRSP, by high pressure liquid chromatography-electrochemical detection. The production of hydroxyl radicals in the hippocampus during the first 20 min of recirculation was a peak in all intervals. The changes in 2,3-DHBA levels during ischemia and recirculation in SHRSP were significantly higher than in Wistar-Kyoto rats. These results suggest that neuronal damage following ischemia and recirculation is, in part, caused by the increase in hydroxyl radicals during ischemia and recirculation.

背景与目标： ：已经表明，中风倾向性自发性高血压大鼠（SHRSP）在短暂性脑缺血后表现出对神经元损害的脆弱性。为了观察羟基自由基对SHRSP缺血和再循环过程中海马神经元损伤的影响，我们测量了2,3-二羟基苯甲酸（2,3-DHBA）的水平，该水平是大鼠海马中羟基自由基的生物学标记SHRSP，通过高压液相色谱-电化学检测。在再循环的前20分钟内，海马中的羟基自由基的产生在所有时间间隔内均达到峰值。 SHRSP缺血和再循环期间2,3-DHBA水平的变化显着高于Wistar-Kyoto大鼠。这些结果表明，缺血和再循环后的神经元损害部分是由于缺血和再循环期间羟自由基的增加所致。

BACKGROUND & AIMS: :Mesenchymal stem cells (MSCs) have been used in clinical studies to treat neurological diseases and damage. However, implanted MSCs do not achieve their regenerative effects by differentiating into and replacing neural cells. Instead, MSC secretome components mediate the regenerative effects of MSCs. MSC-derived extracellular vesicles (EVs)/exosomes carry cargo responsible for rescuing brain damage. We previously showed that EP4 antagonist-induced MSC EVs/exosomes have enhanced regenerative potential to rescue hippocampal damage, compared with EVs/exosomes from untreated MSCs. Here we show that EP4 antagonist-induced MSC EVs/exosomes promote neurosphere formation in vitro and increase neurogenesis and neuritogenesis in damaged hippocampi; basal MSC EVs/exosomes do not contribute to these regenerative effects. 2',3'-Cyclic nucleotide 3'-phosphodiesterase (CNP) levels in EP4 antagonist-induced MSC EVs/exosomes are 20-fold higher than CNP levels in basal MSC EVs/exosomes. Decreasing elevated exosomal CNP levels in EP4 antagonist-induced MSC EVs/exosomes reduced the efficacy of these EVs/exosomes in promoting β3-tubulin polymerization and in converting toxic 2',3'-cAMP into neuroprotective adenosine. CNP-depleted EP4 antagonist-induced MSC EVs/exosomes lost the ability to promote neurogenesis and neuritogenesis in damaged hippocampi. Systemic administration of EV/exosomes from EP4 -antagonist derived MSC EVs/exosomes repaired cognition, learning, and memory deficiencies in mice caused by hippocampal damage. In contrast, CNP-depleted EP4 antagonist-induced MSC EVs/exosomes failed to repair this damage. Exosomal CNP contributes to the ability of EP4 antagonist-elicited MSC EVs/exosomes to promote neurogenesis and neuritogenesis in damaged hippocampi and recovery of cognition, memory, and learning. This experimental approach should be generally applicable to identifying the role of EV/exosomal components in eliciting a variety of biological responses.

背景与目标： 间充质干细胞（MSCs）已用于临床研究中，以治疗神经系统疾病和损伤。但是，植入的MSC不能通过分化为神经细胞并替代神经细胞来实现其再生作用。取而代之的是，MSC分泌组的成分介导了MSC的再生作用。 MSC衍生的细胞外囊泡（EVs / exosome）携带负责挽救脑损伤的货物。我们以前表明，与未经处理的MSC产生的EVs /外泌体相比，EP4拮抗剂诱导的MSC EV /外泌体具有增强的修复海马损伤的再生潜能。在这里，我们显示EP4拮抗剂诱导的MSC EV /外来体在体外促进神经球形成，并增加受损海马中的神经发生和神经发生。基础MSC EV /外泌体对这些再生作用无贡献。 EP4拮抗剂诱导的MSC EV /外泌体中的2'，3'-环核苷酸3'-磷酸二酯酶（CNP）水平比基础MSC EV /外泌体中的CNP水平高20倍。在EP4拮抗剂诱导的MSC EV /外泌体中降低外泌体CNP水平升高，降低了这些EV /外泌体在促进β3-微管蛋白聚合以及将有毒的2'，3'-cAMP转化为神经保护腺苷中的功效。耗尽CNP的EP4拮抗剂诱导的MSC EV /外泌体丧失了在受损海马体中促进神经发生和神经发生的能力。来自EP4-拮抗剂衍生的MSC EV /外来体的EV /外来体的全身给药修复了海马损伤引起的小鼠的认知，学习和记忆缺陷。相反，CNP耗尽的EP4拮抗剂诱导的MSC EV /外泌体未能修复这种损害。外泌体CNP有助于EP4拮抗剂引起的MSC EV /外泌体在受损海马中促进神经发生和神经发生的能力，并恢复认知，记忆和学习能力。这种实验方法通常应适用于确定EV /外泌体成分在引发各种生物学反应中的作用。

BACKGROUND & AIMS: :The effects of a high estradiol dose on memory and on nitric oxide metabolites in hippocampal tissues were investigated. Sham-Est and OVX-Est Groups were treated with 4 mg/kg of estradiol valerate for 12 weeks. Time latency and path length were significantly higher in the Sham-Est and OVX-Est Groups than in the Sham and OVX Groups, respectively (p<0.001). The animals in the Sham-Est and OVX-Est Groups spent lower time in the target quadrant (Q1) than those of the Sham and OVX Groups during the probe trial test (p<0.05 and <0.001, respectively). Significantly lower nitric oxide metabolite levels in the hippocampi of the Sham-Est and OVX-Est Groups were observed than in the Sham and OVX ones (p<0.001). These results suggest that decreased nitric oxide levels in the hippocampus may play a role in the learning and memory deficits observed after treatment with a high dose of estradiol, although the precise underlying mechanisms remain to be elucidated.

背景与目标： ：研究了高雌二醇剂量对海马组织记忆力和一氧化氮代谢产物的影响。 Sham-Est和OVX-Est组分别用4 mg / kg的戊酸雌二醇处理12周。 Sham-Est和OVX-Est组的时间延迟和路径长度分别比Sham和OVX组高（p <0.001）。在探针试验过程中，Sham-Est和OVX-Est组的动物在目标象限（Q1）上花费的时间比Sham和OVX组的动物低（分别为p <0.05和<0.001）。与Sham和OVX组相比，Sham-Est和OVX-Est组海马中的一氧化氮代谢产物水平显着降低（p <0.001）。这些结果表明，海马中一氧化氮水平的下降可能在大剂量雌二醇治疗后观察到的学习和记忆障碍中起作用，尽管确切的潜在机制尚待阐明。

BACKGROUND & AIMS: :Chronic infusion of mice with a β2 adrenergic receptor (β2AR) analog was shown to cause long-term DNA damage in a pathway which involves β Arresin-1-mediated activation of Mdm2 and subsequent degradation of the tumor suppressor protein p53. The objective of the present study was to test whether a single acute stress, which manifests long lasting changes in behavior, affects the interaction of Mdm2 with p53, β2AR, and β Arrestin-1 in the dorsal and ventral hippocampal CA1. Adult rats were subject to underwater trauma, a brief forceful submersion under water and tested a month later for behavioral and biochemical changes. Elevated plus maze tests confirmed that animals that experienced the threat of drowning present heightened levels of anxiety one month after trauma. An examination of the CA1 hippocampal areas of the same rats showed that underwater trauma caused a significant increase in the association of Mdm2 with β2AR, β Arrestin-1, and p53 in the ventral but not dorsal CA1. Our results provide support for the idea that stress-related events may result in biochemical changes restricted to the ventral 'emotion-related' parts of the hippocampus.

背景与目标： ：用β2肾上腺素能受体（β2AR）类似物长期注入小鼠会在涉及βArresin-1介导的Mdm2活化以及随后的肿瘤抑制蛋白p53降解的途径中引起长期DNA损伤。本研究的目的是测试表现出长期持续行为改变的单个急性应激是否会影响Mdm2与背侧和腹侧海马CA1中的p53，β2AR和βArrestin-1的相互作用。成年大鼠遭受水下创伤，在水中短暂短暂浸入水中，一个月后对其行为和生化变化进行了测试。高架迷宫测试证实，遭受溺水威胁的动物在受伤一个月后表现出更高的焦虑水平。对同一只大鼠的海马区CA1的检查显示，水下创伤导致腹侧CA1中Mdm2与β2AR，βArrestin-1和p53的关联显着增加，而在背侧CA1中则没有。我们的研究结果支持这样一种观点，即与压力有关的事件可能导致生化变化仅限于海马腹侧“与情绪相关的”部分。

BACKGROUND & AIMS: :The human and rat hippocampus is highly susceptible to iron deficiency (ID) during the late fetal, early neonatal time period which is a peak time of regulated brain iron uptake and utilization. ID during this period alters cognitive development and is characterized by distinctive, long-term changes in hippocampal cellular growth and function. The fundamental processes underlying these changes are not entirely understood. In this study, ID-induced changes in expression of 25 genes implicated in iron metabolism, including cell growth and energy metabolism, dendrite morphogenesis, and synaptic connectivity were assessed from postnatal day (P) 7 to P65 in hippocampus. All 25 genes showed altered expression during the period of ID (P7, 15, and 30); 10 had changes on P65 after iron repletion. ID caused long-term diminished protein levels of four factors critical for hippocampal neuron differentiation and plasticity, including CamKII alpha, Fkbp1a (Fkbp12), Dlgh4 (PSD-95), and Vamp1 (Synaptobrevin-1). ID altered gene expression in the mammalian target of rapamycin (mTOR) pathway and in a gene network implicated in Alzheimer disease etiology. ID during late fetal and early postnatal life alters the levels and timing of expression of critical genes involved in hippocampal development and function. The study provides targets for future studies in elucidating molecular mechanisms underpinning iron's role in cognitive development and function.

背景与目标： ：人类和大鼠海马在胎儿晚期，新生儿早期（这是调节的脑铁摄取和利用的高峰时间）高度易患铁缺乏症（ID）。在此期间，ID会改变认知能力，其特征是海马细胞生长和功能的独特长期变化。这些变化所基于的基本过程尚未完全被理解。在这项研究中，从出生后第7天到第65天，评估了ID诱导的25个与铁代谢有关的基因表达的变化，包括细胞生长和能量代谢，树突形态发生和突触连接性。在ID期间（P7、15和30），所有25个基因的表达均发生了改变。铁补充后，P10的P65有变化。 ID导致长期降低海马神经元分化和可塑性的四个关键因素的蛋白质水平，包括CamKII alpha，Fkbp1a（Fkbp12），Dlgh4（PSD-95）和Vamp1（Synaptobrevin-1）。 ID改变了雷帕霉素（mTOR）途径的哺乳动物靶标和涉及阿尔茨海默病病因的基因网络中的基因表达。胎儿晚期和产后早期的内源性疾病改变了参与海马发育和功能的关键基因的表达水平和时间。该研究为阐明铁在认知发展和功能中的作用的分子机制提供了未来研究的目标。