Chemical modulation of memory formation in larval zebrafish

Whole organism-based small-molecule screens have proven powerful in identifying novel therapeutic chemicals, yet this approach has not been exploited to identify new cognitive enhancers. Here we present an automated high-throughput system for measuring nonassociative learning behaviors in larval zebrafish. Using this system, we report that spaced training blocks of repetitive visual stimuli elicit protein synthesis-dependent long-term habituation in larval zebrafish, lasting up to 24 h. Moreover, repetitive acoustic stimulation induces robust short-term habituation that can be modulated by stimulation frequency and instantaneously dishabituated through cross-modal stimulation. To characterize the neurochemical pathways underlying short-term habituation, we screened 1,760 bioactive compounds with known targets. Although we found extensive functional conservation of short-term learning between larval zebrafish and mammalian models, we also discovered several compounds with previously unknown roles in learning. These compounds included a myristic acid analog known to interact with Src family kinases and an inhibitor of cyclin dependent kinase 2, demonstrating that high-throughput chemical screens combined with high-resolution behavioral assays provide a powerful approach for the discovery of novel cognitive modulators.     

Distinct kinetics of synaptic structural plasticity,memory formation,and memory decay in massed and spaced learning

Long-lasting memories are formed when the stimulus is temporally distributed (spacing effect). However, the synaptic mechanisms underlying this robust phenomenon and the precise time course of the synaptic modifications that occur during learning remain unclear. Here we examined the adaptation of horizontal optokinetic response in mice that underwent 1 h of massed and spaced training at varying intervals. Despite similar acquisition by all training protocols, 1 h of spacing produced the highest memory retention at 24 h, which lasted for 1 mo. The distinct kinetics of memory are strongly correlated with the reduction of floccular parallel fiber–Purkinje cell synapses but not with AMPA receptor (AMPAR) number and synapse size. After the spaced training, we observed 25%, 23%, and 12% reduction in AMPAR density, synapse size, and synapse number, respectively. Four hours after the spaced training, half of the synapses and Purkinje cell spines had been eliminated, whereas AMPAR density and synapse size were recovered in remaining synapses. Surprisingly, massed training also produced long-term memory and halving of synapses; however, this occurred slowly over days, and the memory lasted for only 1 wk. This distinct kinetics of structural plasticity may serve as a basis for unique temporal profiles in the formation and decay of memory with or without intervals.During learning, memories are formed in a specific population of neuronal circuits and are consolidated for persistence (1, 2). These memory processes are supported by discrete subcellular events such as reversible modifications in the efficacy of synaptic transmission (3–5) or persistent structural modifications in the size and number of synaptic connections (6–8). However, how these synaptic modifications relate to the dynamics of formation and decay of memories in behaving animals remains elusive. Memory formation and its persistence are also sensitive to the temporal features of stimulus presentation, as observed in the well-known “spacing effect.” Training trials that include resting intervals between them (spaced training) produce stronger and longer-lasting memories than do the same number of trials with no intervals (massed training) (9). The spacing effect has been observed in a variety of explicit and implicit memory tasks (10–13), and the molecular mechanisms supporting this phenomenon have been reported (14–18). Various intracellular signaling molecules such as CREB (19), mitogen-activated protein (MAP) kinase (20, 21), and PKA (22, 23) underlie the spacing effect and are implicated in the remodeling of neuronal structures (23). In vitro studies showed that spaced stimuli induced the protrusion of new filopodia (20) and the recruitment of new synapses (24) in hippocampal neurons. However, despite the existence of numerous behavioral and molecular studies, no conjoint study has elucidated the synaptic correlates that underpin the expression of the spacing effect during learning. Here we studied the temporal evolution and decay of memory and its correlation with synaptic modifications during learning with distinct temporal patterns of training.We used an adaptation of the horizontal optokinetic response (HOKR), which is a simple model of cerebellum-dependent motor learning. It is a compensatory eye movement for stabilization of the visual image on the retina during horizontal motion of the surroundings. A surrounding that oscillates horizontally at a given frequency causes retinal slips in naive animals and facilitates HOKR 1 h after training (HOKR adaptation) (25–27). The amount of adaptation can be quantitatively monitored, and the flocculus (Fl), which is a phylogenetically preserved cerebellar lobule, is involved in the adaptation of the HOKR (28, 29). These features render this paradigm as an experimental model, useful for investigating neural correlates and mechanisms involved in motor learning. In a previous study, we showed that the short-term adaptation of HOKR induced by 1-h training was accompanied by a rapid and transient reduction (28%) in the number of AMPA receptors (AMPARs) in parallel fiber (PF) to Purkinje cell (PC) synapses, whereas the long-term adaptation induced by repeated 1-h training over 5 d was accompanied by a slowly developing reduction (45%) of PF–PC synapses (30). Despite recent controversies on the role of long-term depression (LTD) and a postulated role of long-term potentiation in cerebellar motor learning (31–33), this study first showed that LTD as a form of reduced AMPARs in PF–PC synapses does occur in physiological learning.In the present study, we further examined how the spacing effect is correlated with the structural plasticity in PF–PC synapses. We showed that spaced training including 1-h intervals induced stable long-lasting memories within 4 h after the training, which was accompanied by a rapid and long-lasting (>1 mo) reduction of PF–PC synapses after a transient reduction in AMPAR density and shrinkage of PF–PC synapses and PC spines. One hour of massed training also induced a gradual reduction of the PF–PC synapses, which reached the same level as that observed for the spaced training 5 d later but recovered faster within 10 d. The time course corresponded well with the slower establishment and quicker decay of long-lasting memory induced by massed training. The tight correlation observed between the structural modifications and the kinetics of long-lasting memory pinpoints the distinct temporal regulation of synaptic connections as a mechanism underlying the spacing effect.     

Dynamics of dendritic spines in the mouse auditory cortex during memory formation and memory recall

Long-lasting changes in synaptic connections induced by relevant experiences are believed to represent the physical correlate of memories. Here, we combined chronic in vivo two-photon imaging of dendritic spines with auditory-cued classical conditioning to test if the formation of a fear memory is associated with structural changes of synapses in the mouse auditory cortex. We find that paired conditioning and unpaired conditioning induce a transient increase in spine formation or spine elimination, respectively. A fraction of spines formed during paired conditioning persists and leaves a long-lasting trace in the network. Memory recall triggered by the reexposure of mice to the sound cue did not lead to changes in spine dynamics. Our findings provide a synaptic mechanism for plasticity in sound responses of auditory cortex neurons induced by auditory-cued fear conditioning; they also show that retrieval of an auditory fear memory does not lead to a recapitulation of structural plasticity in the auditory cortex as observed during initial memory consolidation.Mammalian brains are characterized by a tremendous level of plasticity. This plasticity is believed to underlie the ability to extract and store information about past experiences and is crucial for animals and humans to interact adaptively in a changing environment. Therefore, detection and localization of a physical representation of a memory has been an intriguing aspect for a long time (1). Plastic changes in synapses are believed to be substrates of memory (2). The development of imaging techniques that allow chronic monitoring of dendritic spines, the morphological correlates of excitatory synapses on pyramidal neurons, in the living animal has provided valuable insights in the dynamics of neuronal circuits (3–5). It has recently been shown that not only chronic perturbations of sensory inputs (6, 7), but also temporally restricted learning experiences, impact the turnover of synaptic structures in the motor cortex and frontal association cortex of the mouse (8–10) and the high vocal center in zebra finches (11).Auditory-cued fear conditioning (ACFC) is an associative learning paradigm that has been widely used to analyze mechanisms of learning in the auditory modality (12). During a conditioning session, subjects quickly learn to associate a previously neutral sound cue [the conditional stimulus (CS)] with an aversive stimulus like a mild foot shock [unconditional stimulus (US)]. It is well established that memory traces after initial formation undergo several processes at different time scales that lead to their consolidation and render them to a stable state that is, e.g., resistant to trauma introduced by an electroconvulsive shock (13). Interestingly, similar molecular cascades are triggered not only during memory formation, but also when a memory trace is retrieved (14, 15). Furthermore, memory traces that were recently retrieved become sensitive again to manipulations like electroconvulsive shock (16), blockade of NMDA receptors (17), or blockade of protein synthesis (18). These similarities have been suggested to reflect remodeling of memory traces following recall (14, 19). However, data on the dynamics of synaptic structures during memory recall is lacking up to date.A number of brain structures have been identified mediating the formation of a memory induced by ACFC (12). Whereas inputs via the auditory cortex (ACx) to the amygdala, an essential brain structure for this learning paradigm, appear to be always sufficient to support fear conditioning (20), their necessity can depend on the spectrotemporal properties of the auditory CS (21, 22). The ACx as the primary sensory cortical area for the auditory modality has been extensively analyzed in the past during classical conditioning to sound stimuli (23–25) or pairing of sounds with artificial stimulation of the cholinergic system, which can substitute for aspects of the US (26–28). These paradigms lead to changes in the receptive fields of ACx neurons that are specific to the conditioned sound. There is evidence based on local pharmacological or optogenetic manipulations that plasticity of the ACx itself is necessary for experience-induced alterations in sound responses and does not simply reflect plasticity elsewhere in the auditory pathway (29, 30). Indeed, there is evidence based on electrophysiological recordings that synaptic plasticity at intracortical synapses can be induced by pairing of a sound with stimulation of the cholinergic system in vivo (28). Structural plasticity following ACFC has been observed in the frontal association cortex (10). However, it remains elusive if plasticity in sound responses in the ACx induced by ACFC (23–25) also has a structural correlate at the synaptic level.In this study, we asked two major questions: Does ACFC in behaving mice induce structural plasticity in synaptic circuits of the ACx? To what extent do memory formation and memory recall share similarities at the level of synaptic structures? We addressed these questions by combining sound-cued fear conditioning and memory testing with chronic in vivo imaging of dendritic spines in the ACx.     

PDGF signaling is required for epicardial function and blood vessel formation in regenerating zebrafish hearts

A zebrafish heart can fully regenerate after amputation of up to 20% of its ventricle. During this process, newly formed coronary blood vessels revascularize the regenerating tissue. The formation of coronary blood vessels during zebrafish heart regeneration likely recapitulates embryonic coronary vessel development, which involves the activation and proliferation of the epicardium, followed by an epithelial-to-mesenchymal transition. The molecular and cellular mechanisms underlying these processes are not well understood. We examined the role of PDGF signaling in explant-derived primary cultured epicardial cells in vitro and in regenerating zebrafish hearts in vivo. We observed that mural and mesenchymal cell markers, including pdgfrβ, are up-regulated in the regenerating hearts. Using a primary culture of epicardial cells derived from heart explants, we found that PDGF signaling is essential for epicardial cell proliferation. PDGF also induces stress fibers and loss of cell-cell contacts of epicardial cells in explant culture. This effect is mediated by Rho-associated protein kinase. Inhibition of PDGF signaling in vivo impairs epicardial cell proliferation, expression of mesenchymal and mural cell markers, and coronary blood vessel formation. Our data suggest that PDGF signaling plays important roles in epicardial function and coronary vessel formation during heart regeneration in zebrafish.     

A cellular model of memory reconsolidation involves reactivation-induced destabilization and restabilization at the sensorimotor synapse in Aplysia

The memory reconsolidation hypothesis suggests that a memory trace becomes labile after retrieval and needs to be reconsolidated before it can be stabilized. However, it is unclear from earlier studies whether the same synapses involved in encoding the memory trace are those that are destabilized and restabilized after the synaptic reactivation that accompanies memory retrieval, or whether new and different synapses are recruited. To address this issue, we studied a simple nonassociative form of memory, long-term sensitization of the gill- and siphon-withdrawal reflex in Aplysia, and its cellular analog, long-term facilitation at the sensory-to-motor neuron synapse. We found that after memory retrieval, behavioral long-term sensitization in Aplysia becomes labile via ubiquitin/proteasome-dependent protein degradation and is reconsolidated by means of de novo protein synthesis. In parallel, we found that on the cellular level, long-term facilitation at the sensory-to-motor neuron synapse that mediates long-term sensitization is also destabilized by protein degradation and is restabilized by protein synthesis after synaptic reactivation, a procedure that parallels memory retrieval or retraining evident on the behavioral level. These results provide direct evidence that the same synapses that store the long-term memory trace encoded by changes in the strength of synaptic connections critical for sensitization are disrupted and reconstructed after signal retrieval.     

Learning and memory in young and aged Fischer 344 rats

Changes in learning and memory processes that occur with senescence were investigated in male and female Fischer 344 rats, 3-26 mth of age. Age-related impairments were seen in retention of inhibitory avoidance learning, acquisition of a Y-maze discrimination task, and in a swim escape task with short intertrial training intervals. In contrast, old animals performed better than the young rats in an active avoidance task. No age differences were observed in either open field activity or in flinch or jump thresholds to footshock. These results indicate that impairments in learning and memory processes of aged rats are task-specific, and that memory deficits in old rats are best seen following one-time-only events or with weak training. The behavioral baselines described will help in the design of further research to correlate memory and neurobiological changes observed during the aging process in the rat.     

Drosophila Orb2 targets genes involved in neuronal growth,synapse formation,and protein turnover

In the study of long-term memory, how memory persists is a fundamental and unresolved question. What are the molecular components of the long-lasting memory trace? Previous studies in Aplysia and Drosophila have found that a neuronal variant of a RNA-binding protein with a self-perpetuating prion-like property, cytoplasmic polyadenylation element binding protein, is required for the persistence of long-term synaptic facilitation in the snail and long-term memory in the fly. In this study, we have identified the mRNA targets of the Drosophila neuronal cytoplasmic polyadenylation element binding protein, Orb2. These Orb2 targets include genes involved in neuronal growth, synapse formation, and intriguingly, protein turnover. These targets suggest that the persistent form of the memory trace might be comprised of molecules that maintain a sustained, permissive environment for synaptic growth in an activated synapse.     

Melatonin reduces memory changes and neural oxidative damage in mice treated with D-galactose

To investigate the role of melatonin in D-galactose-induced amnesic mice, the avoidance/escape and water maze tests were performed to evaluate their learning and memory function. Spectrophotometry was employed to determine the content of thiobarbituric acid-reactive substances (TBARS) and the activities of antioxidative enzymes in the brain. The present results demonstrate that D-galactose-induced amnesic mice had significantly decreased learning and memory function. The reduced activities of superoxide dismutase and glutathione peroxidase and increased levels of TBARS were found in brain tissue of the amnesic mice. Melatonin, administered (ig) at doses of 0.1, 1, or 10 mg/kg to the D-galactose-treated mice for 3 months, was sufficient to block these changes. These data suggest that D-galactose is involved in accelerating the brain aging process by elevating free radical generation and reducing antioxidative enzyme activities in vivo. Furthermore, the antioxidative activity of melatonin on the D-galactose-treated mice may account for, at least partially, the improvement of learning and memory function in the aging and amnesic model.     

Efficient associative memory storage in cortical circuits of inhibitory and excitatory neurons

Many features of synaptic connectivity are ubiquitous among cortical systems. Cortical networks are dominated by excitatory neurons and synapses, are sparsely connected, and function with stereotypically distributed connection weights. We show that these basic structural and functional features of synaptic connectivity arise readily from the requirement of efficient associative memory storage. Our theory makes two fundamental predictions. First, we predict that, despite a large number of neuron classes, functional connections between potentially connected cells must be realized with <50% probability if the presynaptic cell is excitatory and >50% probability if the presynaptic cell is inhibitory. Second, we establish a unique relation between probability of connection and coefficient of variation in connection weights. These predictions are consistent with a dataset of 74 published experiments reporting connection probabilities and distributions of postsynaptic potential amplitudes in various cortical systems. What is more, our theory explains the shapes of the distributions obtained in these experiments.     

有氧运动对血管性脑痴呆小鼠学习记忆能力的影响

目的探讨有氧运动对血管性脑痴呆小鼠记忆能力的影响及其作用机制。方法暴露小鼠双侧颈总动脉,重复夹闭动脉3次,尾静脉放血建立血管性脑痴呆小鼠模型,小鼠随机分为三组:假手术组、模型组和有氧运动组。术后第二天开始进行有氧运动,连续7周。训练结束后进行行为学检测,术后30天收集小鼠脑组织样本(海马、前额叶、全脑和血清)。HE染色观察海马CA1区的病理学变化、TUNEL法检测海马CA1区神经细胞凋亡、Western blot和紫外分光光度计检测Bcl-2、Bax、丙二醛(MDA)、超氧化物歧化酶(SOD)、生长相关蛋白(GAP-43)、脑源性神经营养因子(BDNF)、乙酰胆碱合成酶(ACHE)、乙酰胆碱转移酶(CHAT)、突触素(SYP)、神经细胞黏附分子(NCAM)及神经细胞黏附分子受体(NR2B)的变化。结果与假手术组相比,模型组小鼠的僵直时间显著缩短,CA1区神经元细胞病变严重,凋亡细胞增加,MDA和ACHE蛋白的表达明显上升,SYP、NCAM、NR2B、SOD、BDNF、CHAT、GAP-43和Bcl-2蛋白表达降低,Bax蛋白表达没有明显变化。与模型组相比,有氧运动组小鼠的僵直时间显著延长,海马区的组织病变情况改善,且凋亡细胞减少,MDA和ACHE蛋白的表达明显降低,SYP、NCAM、NR2B、SOD、BDNF、CHAT、GAP-43和Bcl-2蛋白的表达升高,Bax蛋白表达没有明显变化。结论有氧训练可能通过上调Bcl-2、SOD、BDNF、CHAT、GAP-43、SYP、NCAM及NR2B蛋白表达,下调MDA和ACHE蛋白表达,减少自由基损伤和海马区神经元细胞凋亡,从而改善血管性痴呆小鼠的学习记忆功能。     

咪达唑仑多次使用对小鼠学习记忆的影响

目的观察不同剂量的咪达唑仑多次使用对小鼠学习记忆的影响。方法100只KM小鼠分层随机区组设计,分为M1、M2、M3、M4组和生理盐水（NS）组,每组20只,各组再随机选取10只,参加跳台实验或避暗实验。M1、M2、M3和M4组分别以咪达唑仑0.5、1、2和4 mg/kg,NS组以10 ml/kg生理盐水腹腔注射,3次/d,连续10 d后,进行训练,24 h后进行记忆测验,以潜伏期和错误次数作为记忆成绩的指标。结果M1、M2、M3、M4组与NS组比较,M2、M3和M4组与M1组比较,M3和M4组与M2组比较,潜伏期缩短、错误次数次数增多（P〈0.05）;但M3组与M4组比较,潜伏期和错误次数相似（P〉0.05）。结论多次使用咪达唑仑对记忆的影响有一定剂量依赖性,但其记忆抑制作用有封顶效应。     

美金刚对癫痫大鼠空间学习记忆能力及钙结合蛋白-D28K表达的影响

目的探讨美金刚（MEM）对戊四氮（PTZ）点燃癫痫大鼠空间学习记忆能力及钙结合蛋白-D28K（Ca-28）表达的影响。方法将大鼠分为正常对照组、PTZ组和MEM干预组,采用PIZ慢性点燃癫痫模型,应用Morris水迷宫试验观察各组大鼠空间学习记忆能力,RT—PCR方法测定Ca-28mRNA表达,Western blot方法测定Ca-28表达。结果PTZ组大鼠空间学习记忆能力受损,Ca-28mRNA表达较正常对照组降低,Ca-28水平较正常对照组减少（P均〈0．05）;与PTZ组比较,MEM干预组空间学习记忆能力好转,Ca-28mRNA及蛋白表达升高（P均〈0．05）。结论PTZ点燃癫痫大鼠空间学习记忆能力受损,同时存在海马Ca-28表达异常;MEM可以改善癫痫大鼠的学习记忆能力,提高Ca-28的表达。     

Differential roles of the dopamine 1-class receptors,D1R and D5R,in hippocampal dependent memory

Activation of the hippocampal dopamine 1-class receptors (D1R and D5R) are implicated in contextual fear conditioning (CFC). However, the specific role of the D1R versus D5R in hippocampal dependent CFC has not been investigated. Generation of D1R- and D5R-specific in situ hybridization probes showed that D1R and D5R mRNA expression was greatest in the dentate gyrus (DG) of the hippocampus. To identify the role of each receptor in CFC we generated spatially restricted KO mice that lack either the D1R or D5R in DG granule cells. DG D1R KOs displayed significant fear memory deficits, whereas DG D5R KOs did not. Furthermore, D1R KOs but not D5R KOs, exhibited generalized fear between two similar but different contexts. In the familiar home cage context, c-Fos expression was relatively low in the DG of control mice, and it increased upon exposure to a novel context. This level of c-Fos expression in the DG did not further increase when a footshock was delivered in the novel context. In DG D1R KOs, DG c-Fos levels in the home cage was higher than that of the control mice, but it did not further increase upon exposure to a novel context and remained at the same level upon a shock delivery. In contrast, the levels of DG c-Fos expression was unaffected by the deletion of DG D5R neither in the home cage nor upon a shock delivery. These results suggest that DG D1Rs, but not D5Rs, contribute to the formation of distinct contextual representations of novel environments.The hippocampus is crucial for aversive Pavlovian conditioning, such as contextual fear conditioning (CFC) (1, 2). In CFC, the conditioned stimulus (context) is paired with the unconditioned stimulus (footshock), and after pairing, the context serves as a cue to predict a potential footshock (3, 4). Although the role of dopamine has been studied in the context of reward learning (5), evidence suggests that midbrain dopaminergic neurons are also important for aversive Pavlovian conditioning (6–9). In line with this evidence, hippocampal encoding of novel and contextual information is linked to dopamine release via excitation of dopamine neurons of the midbrain (5, 10, 11). Additionally, delivery of aversive stimuli, such as a footshock, results in increased dopaminergic neuron activity (12). Moreover, inactivation of hippocampal D1Rs and D5Rs attenuates contextual fear memory (13). Thus, it follows that delivery of an aversive stimulus activates midbrain dopamine neurons that project to the hippocampus, which is crucial for encoding novel contextual cues (12, 14, 15). Activation of hippocampal D1Rs and D5Rs may then strengthen the encoding of novel contextual information during CFC.The precise role of subregion-specific D1R or D5R activation in hippocampal-dependent learning and memory is unknown. This is in part due to the inability to discriminate between and spatially restrict D1R from D5R function (16–18), which is an important caveat because each receptor is involved in modulating distinct neuronal processes (19–22). Indeed, there is a lack of consensus of D1R and D5R expression patterns in the rodent hippocampus (23–27). Moreover, pharmacological findings are at odds with D1R and D5R global KO studies, which show that neither D1Rs nor D5Rs are required for fear conditioning (16, 17). Therefore, to reconcile these disparate findings and to test the necessity of D1R and D5R activation for CFC, it is necessary to functionally isolate and spatially restrict hippocampal D1R and D5R activity.In this study, we found that D1Rs and D5Rs exhibit overlapping expression in dentate gyrus (DG) granule cells. DG D1R activation is necessary to increase c-Fos expression in the DG and CA3 to enhance novel contextual encoding. Moreover, DG D1R activation decreases generalization of the conditioned fear response to novel contexts. However, we found no role for DG D5Rs in modulating DG c-Fos expression or contextual fear learning and memory. In using our subregion-specific KO mice, we show that the hippocampal dopamine signal plays a definitive role in CFC.     

Gain in sensitivity and loss in temporal contrast of STDP by dopaminergic modulation at hippocampal synapses

Spike-timing-dependent plasticity (STDP) is considered a physiologically relevant form of Hebbian learning. However, behavioral learning often involves action of reinforcement or reward signals such as dopamine. Here, we examined how dopamine influences the quantitative rule of STDP at glutamatergic synapses of hippocampal neurons. The presence of 20 μM dopamine during paired pre- and postsynaptic spiking activity expanded the effective time window for timing-dependent long-term potentiation (t-LTP) to at least −45 ms, and allowed normally ineffective weak stimuli with fewer spike pairs to induce significant t-LTP. Meanwhile, dopamine did not affect the degree of t-LTP induced by normal strong stimuli with spike timing (ST) of +10 ms. Such dopamine-dependent enhancement in the sensitivity of t-LTP was completely blocked by the D1-like dopamine receptor antagonist {"type":"entrez-protein","attrs":{"text":"SCH23390","term_id":"1052733334","term_text":"SCH23390"}}SCH23390, but not by the D2-like dopamine receptor antagonist sulpiride. Surprisingly, timing-dependent long-term depression (t-LTD) at negative ST was converted into t-LTP by dopamine treatment; this conversion was also blocked by {"type":"entrez-protein","attrs":{"text":"SCH23390","term_id":"1052733334","term_text":"SCH23390"}}SCH23390. In addition, t-LTP in the presence of dopamine was completely blocked by the NMDA receptor antagonist 2-amino-5-phosphonovaleric acid, indicating that D1-like receptor-mediated modulation appears to act through the classical NMDA receptor-mediated signaling pathway that underlies STDP. These results provide a quantitative and mechanistic basis for a previously undescribed learning rule that depends on pre- and postsynaptic ST, as well as the global reward signal.     

槲皮素对衰老小鼠学习记忆行为的影响

目的　检测槲皮素 (1 0mg·kg- 1 ·d- 1 )对衰老小鼠学习记忆行为的影响。方法　开场行为实验、避暗法实验和Morris水迷宫实验。结果　在开场行为实验中 ,槲皮素作用组在新异环境中自发行为有显著增加 ,其爬格子数、站立 /贴壁次数、梳洗次数比衰老模型组分别增加了 38.88%(P <0 .0 5)、57.2 3 % (P <0 .0 1 )和 2 8.49% (P <0 .0 5) ;在避暗法实验中 ,槲皮素作用组记忆保持能力显著增加 ,其电击 2 4小时后的步入潜伏期比衰老模型组升高了 55 .72 % (P <0 .0 1 ) ;在水迷宫实验中 ,槲皮素作用组空间学习记忆能力显著增加 ,在第 4天第 4轮训练中的逃避潜伏期比衰老模型组下降了 53 .7% (P <0 .0 1 ) ,而 5mg·kg- 1 ·d- 1 槲皮素灌喂组有相似结果 ,但表现剂量效应。结论　槲皮素可增加衰老小鼠的学习记忆能力。     

慢性脑缺血大鼠学习记忆损害与海马磁共振波谱分析

目的探讨慢性脑缺血对大鼠空间学习记忆功能及海马区神经细胞代谢物水平的影响及后两者的相关性。方法雄性10月龄SD大鼠30只,随机分为缺血组、假手术组和对照组,每组10只。行Morris水迷宫实验及质子磁共振波谱(~1H-MRS)扫描,计算左侧海马区N-乙酰天冬氨酸(NAA)/总肌酸(Cr)、胆碱复合物(Cho)/Cr的积分面积比值。结果缺血组大鼠定位航行的平均逃逸时间较假手术组和对照组明显延长,停留于平台所在区域的时间及穿越平台区域次数均较假手术组和对照组明显减少(P0.01)。缺血组大鼠左侧海马区Cho/Cr、NAA/Cr水平较假手术组和对照组明显降低(P0.05,P0.01)。各组大鼠左侧海马NAA/Cr、Cho/Cr水平与对应停留时间、穿越平台区域次数的变化趋势呈正相关。结论持续性低血流灌注可导致大鼠海马区神经元的功能代谢水平降低及学习记忆能力明显受损,海马区神经元的功能活性下降是认知障碍的重要机制之一。     

颞叶癫痫大鼠学习记忆障碍与海马病理变化的相关性研究

目的 探讨大鼠颞叶癫痫发作后不同时问学习、记忆障碍程度与海马病理变化的相关性。方法 采用立体定向技术在大鼠右侧海马注射红藻氨酸诱发颡叶癫痫发作,观察其行为学表现、脑电图变化,Morris水迷宫评价不同时间段学习、记忆障碍程度,以及海马、皮质病理变化。结果 注射红藻氨酸大鼠出现颞叶癫痫发作,随发作时间延长出现不同程度学习、记忆障碍,定位航行实验示逃避潜伏期延长,空间搜索实验示原平台象限内游泳时问百分比下降,与对照组比较均有显著性差异（P〈0．05）,发作后2个月达到高峰。右侧海马锥体细胞逐渐出现变性、坏死,由CA3区向CA4、CA2、CA1区扩展,2个月达到高峰;对侧海马锥体细胞也出现变性、坏死。但程度明显低于注射侧。结论 大鼠颡叶癫痫发作后,其学习、记忆障碍程度与海马变性、坏死程度具有一定相关性。     

Postsynaptic dysfunction is associated with spatial and object recognition memory loss in a natural model of Alzheimer's disease

Alzheimer's disease (AD) is an age-related neurodegenerative disorder associated with progressive memory loss, severe dementia, and hallmark neuropathological markers, such as deposition of amyloid-β (Aβ) peptides in senile plaques and accumulation of hyperphosphorylated tau proteins in neurofibrillary tangles. Recent evidence obtained from transgenic mouse models suggests that soluble, nonfibrillar Aβ oligomers may induce synaptic failure early in AD. Despite their undoubted value, these transgenic models rely on genetic manipulations that represent the inherited and familial, but not the most abundant, sporadic form of AD. A nontransgenic animal model that still develops hallmarks of AD would be an important step toward understanding how sporadic AD is initiated. Here we show that starting between 12 and 36 mo of age, the rodent Octodon degus naturally develops neuropathological signs of AD, such as accumulation of Aβ oligomers and phosphorylated tau proteins. Moreover, age-related changes in Aβ oligomers and tau phosphorylation levels are correlated with decreases in spatial and object recognition memory, postsynaptic function, and synaptic plasticity. These findings validate O. degus as a suitable natural model for studying how sporadic AD may be initiated.     

艾灸关元、足三里穴对不同月龄大鼠空间学习记忆能力的影响

目的 研究艾灸关元、足三里穴对不同月龄大鼠空同学习记忆能力的改善作用.方法 分别将10月龄及12月龄雌性大鼠各28只,随机分为对照组及灸治组,每组14只,观察不同月龄大鼠在Morris水迷宫中的学习记忆能力,并用定量分析的方法比较不同月龄、不同分组大鼠在定位航行及空间搜索试验中的学习记忆能力,评价不同月龄大鼠在灸治前后的行为学改变.结果 与青年组比较10月龄及12月龄雌性大鼠在定位航行及空间搜索试验中的学习记忆能力均明显下降,其中12月龄平均逃避潜伏期时间最长,通过平台的次数、在原平台象限停留时间最短,而不同月龄灸治组与对照组比较逃避潜伏期缩短,通过平台的次数、在原平台象限停留时间增加,以10月龄大鼠表现尤为明显(P＜0.05).结论 保健灸法可以提高不同月龄大鼠空间定位及探索能力,以10月龄保健灸组大鼠的疗效更为显著,采用灸治方法增强学习记忆能力,应提早进行.