Episodic memory meets working memory in the frontal lobe: functional neuroimaging studies of encoding and retrieval

Recent functional-neuroimaging studies have provided a wealth of new information suggesting that regions of the prefrontal cortex play a role in episodic memory encoding and retrieval. This review seeks to evaluate the results of these studies in the context of one general model that has proposed that the left prefrontal cortex is preferentially involved in episodic memory encoding, whereas the right prefrontal cortex is preferentially involved in episodic memory retrieval, irrespective of the type (e.g., modality) of information being remembered. The origins of this framework are considered in some detail and then all relevant functional-neuroimaging studies are critically reviewed. The results of this review fail to provide support for the functional-asymmetry model, suggesting instead that episodic memory encoding and retrieval may actually involve similar regions of the lateral prefrontal cortex when all factors relating to the type of stimulus material (i.e., modality), are appropriately controlled.     

Synaptic and non-synaptic mechanisms underlying low calcium bursts in the in vitro hippocampal slice

Summary 1. The epileptiform activity generated by lowering extracellular [Ca⁺⁺] was studied in the CA1 subfield of rat hippocampal slices maintained in vitro at 32° C. Extracellular and intracellular recordings were performed with NaCl and KCl filled microelectrodes. 2. Synaptic potentials evoked by stimulation of the stratum radiatum and alveus were blocked upon perfusion with artificial cerebrospinal fluid (ACSF) containing 0.2 mM Ca⁺⁺, 4 mM Mg⁺⁺. Blockade of synaptic potentials was accompanied by the appearance of synchronous field bursts which either occurred spontaneously or could be induced by stimulation of the alveus. 3. Both spontaneous and stimulus-induced low Ca⁺⁺ bursts recorded extracellularly in stratum pyramidale consisted of a negative potential shift with superimposed population spikes. This extracellular event was closely associated with intracellularly recorded action potentials rising from a prolonged depolarization shift. Steady hyperpolarization of the cell membrane potential decreased the amplitude of the depolarizing shift suggesting that synaptic conductance were not involved in the genesis of the low Ca⁺⁺ burst. 4. Spontaneous depolarizing inhibitory potentials recorded in normal ACSF with KCl filled microelectrodes were reduced in size in low Ca⁺⁺ ACSF. However, small amplitude potentials could still be observed at a time when low Ca⁺⁺ bursts were generated by hippocampal CA1 pyramidal neurons. 5. Bicuculline methiodide, an antagonist of -aminobutyric acid (GABA), was capable of modifying the frequency of occurrence and the shape of synchronous field bursts. The effects evoked by bicuculline methiodide were, however, not observed when 81–100% of NaCl was replaced with Na-Methylsulphate. Hence, it was concluded that in low Ca⁺⁺ ACSF even though large release of transmitter such as those following electrical activation of stratum radiatum or alveus cannot be observed, small spontaneous release of the inhibitory transmitter GABA seems to persist. 6. Substitution of NaCl with Na-Methylsulphate also caused changes in the synchronous field bursts which were different from those observed following application of bicuculline methiodide. These findings suggest that in low Ca⁺⁺ ACSF, in addition to residual GABAergic Cl^- mechanisms, non-synaptic Cl^- conductances might play a role in controlling the excitability of hippocampal neurons.Supported by grants from the MRC of Canada (MA-8109) and Sick Children Foundation to MA     

Synaptic GABAergic and glutamatergic mechanisms underlying alcohol sensitivity in mouse hippocampal neurons

This study was designed to examine the neuronal mechanisms of ethanol sensitivity by utilizing inbred short sleep (ISS) and inbred long sleep (ILS) mouse strains that display large differences in sensitivity to the behavioural effects of ethanol. Comparisons of whole-cell electrophysiological recordings from CA1 pyramidal neurons in hippocampal slices of ISS and ILS mice indicate that ethanol enhances GABA_A receptor-mediated inhibitory postsynaptic currents (GABA_A IPSCs) and reduces NMDA receptor-mediated excitatory postsynaptic currents (NMDA EPSCs) in a concentration- and strain-dependent manner. In ILS neurons, these receptor systems are significantly more sensitive to ethanol than those in ISS neurons. To further examine the underlying mechanisms of differential ethanol sensitivities in these mice, GABA_B activity and presynaptic and postsynaptic actions of ethanol were investigated. Inhibition of GABA_B receptor function enhances ethanol-mediated potentiation of distal GABA_A IPSCs in ILS but not ISS mice, and this blockade of GABA_B receptor function has no effect on the action of ethanol on NMDA EPSCs in either mouse strain. Thus, subregional differences in GABA_B activity may contribute to the differential ethanol sensitivity of ISS and ILS mice. Moreover, analysis of the effects of ethanol on paired-pulse stimulation, spontaneous IPSC events, and brief local GABA or glutamate application suggest that postsynaptic rather than presynaptic mechanisms underlie the differential ethanol sensitivity of these mice. Furthermore, these results provide essential information to focus better on appropriate target sites for more effective drug development for the treatment of alcohol abuse.     

Aging-related changes of neural mechanisms underlying visual-spatial working memory

Capacities of the prefrontal cortex (PFC) such as working memory (WM) are known to decline with increasing age. However, it is unclear which neurofunctional mechanisms may underlie this aging-related cognitive decline. The finding that PFC activity tends to be less lateralized in older subjects has led to the assumption of a hemispheric asymmetry reduction in the PFC associated with aging (HAROLD). Using functional magnetic resonance imaging (fMRI), we here investigated aging-related neurofunctional alterations during the performance of a visual-spatial WM task with differential levels of difficulty. Older volunteers activated dorsolateral PFC regions bilaterally while young subjects recruited these areas only in the left hemisphere. These data corroborate the hemispheric asymmetry reduction in the PFC associated with aging (HAROLD) account. However, we also observed functional reorganizations in parieto-occipital areas, and with increasing WM demands, an aging-related reversed hemispheric asymmetry of prefrontal activations. Importantly, neither PFC nor parieto-occipital reorganizations prevented older participants from showing worse WM performance than young volunteers. We conclude that frontal-parietal functional reorganizations may reflect compensational mechanisms related to aging, but do not obviate diminished visual-spatial WM performance in older people.     

Frontal cortex, laterality, and memory: encoding versus retrieval

The cerebral hemispheres differ in their capabilities and response to verbal versus nonverbal visual material. A priori, it might thus be expected that the right hemisphere would be best activated during a mnemonic task with fMRI when using nonverbalizable images, and the left hemisphere with verbal material. However, previous psychological tests had shown a high degree of similarity in measures of memory for these disparate items. It was thus hypothesized that extensive commonality in the areas activated would prevail when this previously tested material was employed with fMRI. Six subjects underwent fMRI with four types of trials in blocks: fixating; passively viewing 12 words and 12 nonverbalizable images; endeavoring to remember (encoding) another set of 12 words and images; endeavoring to recognize (retrieve) previously viewed words or images. Passive viewing produced small islands of activation in left versus right frontal cortex for words and images, respectively. Endeavoring to remember enlarged the areas of activation and produced some bilaterality. Retrieval greatly augmented activation as well as bilaterality, and some 20% of the activated frontal volume was shared by words and images. Thus, on the one hand, the distribution of activation upon retrieval differed substantially for words versus images, but on the other, as predicted, there was considerable commonality. Predominant laterality of activation in some areas shifted between encoding and retrieval (HERA), importantly involving different regions for words versus images. Of course, processes other than memory per se are undoubtedly involved in these distributions of fMRI activation in frontal cortex, yet the nature of the to-be-remembered items is clearly a major factor, in accord with the asymmetric lateralization in their basic representation.     

What is remembered? Role of attention on the encoding and retrieval of hippocampal representations

The hippocampus is critically involved in storing explicit memory such as memory for space. A defining feature of explicit memory storage is that it requires attention both for encoding and retrieval. Whereas, a great deal is now known about the mechanisms of storage, the mechanisms whereby attention modulates the encoding and retrieval of space and other hippocampus-dependent memory representations are not known. In this review we discuss recent studies, including our own, which show on the cellular level that attention is critical for the stabilization of spatial and reward-associated odour representations. Our findings support the view that in the hippocampus attention selects the reference frame for task-relevant information. This mechanism is in part mediated by dopamine acting through D1/D5 receptors and involves an increase in neuronal synchronization in the gamma band frequency. We propose that synchronous activity leads to enhancements in synaptic strength that mediate the stabilization of hippocampal representations.     

Exercise improves memory acquisition and retrieval in the Y-maze task: relationship with hippocampal neurogenesis

Enhanced physical activity is associated with improvements in cognitive function in rodents as well as in humans. The authors examined in detail which aspects of learning and memory are influenced by exercise, using a spatial Y-maze test combined with a 14-day exercise paradigm at different stages of learning. The authors show that 14 days of wheel running promotes memory acquisition, memory retention, and reversal learning. The exercise paradigm that was employed also significantly increased the number of maturing neurons, suggesting that an increase in neurogenesis underlies the positive effects of exercise on Y-maze performance. Finally, the authors show that memory acquisition in itself does not have a major impact on the number of immature neurons. However, memory retention testing and reversal learning both cause a significant reduction in the number of doublecortin and Ser133- phosphorylated pCREB-positive cells, indicating that a decrease in neurogenesis might be a prerequisite for optimal memory retrieval.     

肿瘤细胞中双微体形成机制的研究进展

基因扩增是肿瘤细胞中癌基因激活的主要途径之一,扩增的基因可使肿瘤细胞获得生长优势,进而生存下来或产生耐药性.双微体(DMs)是细胞遗传学上最主要的基因扩增表现形式.研究表明DMs存在于多种类型的肿瘤细胞内,且DMs中扩增基因的拷贝数与肿瘤细胞的恶性演进过程相关,因此,深入研究其形成机制对于治疗肿瘤具有重要意义.本文综述了DMs的形成分子机制,希望为肿瘤治疗提供新的方向.     

Allocentric spatial memory activation of the hippocampal formation measured with fMRI

Hippocampal activation was investigated, comparing allocentric and egocentric spatial memory. Healthy participants were immersed in a virtual reality circular arena, with pattern-rendered walls. In a viewpoint-independent task, they moved toward a pole, which was then removed. They were relocated to another position and had to move to the prior location of the pole. For viewpoint-dependent memory, the participants were not moved to a new starting point, but the patterns were rotated to prevent them from indicating the final position. Hippocampal and parahippocampal activation were found in the viewpoint-independent memory encoding phase. Viewpoint-dependent memory did not result in such activation. These results suggest differential activation of the hippocampal formation during allocentric encoding, in partial support of the spatial mapping hypothesis as applied to humans.     

Different underlying mechanisms for deficits in concept formation in dementia.

We investigated the different mechanisms that may underlie deficits in verbal concept formation among patients with Alzheimer's disease (AD) and ischaemic vascular dementia (IVD) associated with periventricular and deep white matter alterations. Concept formation was assessed with the WAIS-R Similarities subtest (SIM). Two types of errors were re-coded from the 0-point responses as scored by the WAIS-R manual. In set errors (e.g., dog-lion "they're alive") were coded when patients reported a very vague superordinate concept for the word pair. Out of set responses (e.g., dog-lion "the lion roars and the dog barks") were coded when a response was clearly out of mental set, i.e., when participants were unable to provide a superordinate concept for the word pair. Between-group comparisons demonstrated no difference in SIM test performance according to the scoring system described in the WAIS-R manual. Nonetheless, AD patients produced a greater proportion of in set errors, while IVD patients produced a greater proportion of out of set errors. Out of set errors were highly associated with measures of executive function, while in set errors were associated with measures related to delayed recognition memory and semantic intrusion errors. We conclude that the underlying deficits that contribute to poor concept formation differ between AD and IVD patients. In IVD impaired concept formation is related to deficits in the executive systems necessary to monitor responses and sustain mental set. In AD, by contrast, the deficit appears to be secondary to impaired verbal response selection.     

锌缺乏对小鼠海马长时程增强的影响

目的探讨锌缺乏对小鼠海马区域锌离子含量以及长时程增强(LTP)的影响。方法 3周龄CD-1小鼠饲以低锌饲料(0.85mg/kg)和去离子水5周进行实验。应用金属自显影技术(AMG)检测低锌饲料喂养对小鼠海马游离锌离子含量的影响;在小鼠海马齿状回的苔藓纤维层插入刺激电极,在CA3区锥体细胞层插入记录电极,记录高频刺激后海马苔藓纤维CA3区引起的峰电位(PS)和兴奋性突触后电位(f-EPSP)的变化,分析锌缺乏对小鼠海马LTP形成的影响。结果 AMG结果显示锌缺乏小鼠海马CA1,CA3和齿状回区域的锌离子含量明显降低(P<0.05-0.01);电生理检测结果表明锌缺乏小鼠在高频刺激后海马苔藓纤维的PS和f-EPSP均显著下降(P<0.01),提示锌缺乏抑制小鼠海马长时程增强的形成。结论锌缺乏使小鼠海马游离锌离子含量下降,参与对海马长时程增强形成的抑制。     

Functional connectivity reveals load dependent neural systems underlying encoding and maintenance in verbal working memory

One of the main challenges in working memory research has been to understand the degree of separation and overlap between the neural systems involved in encoding and maintenance. In the current study we used a variable load version of the Sternberg item recognition test (two, four, six, or eight letters) and a functional connectivity method based on constrained principal component analysis to extract load-dependent neural systems underlying encoding and maintenance, and to characterize their anatomical overlap and functional interaction. Based on the pattern of functional connectivity, constrained principal component analysis identified a load-dependent encoding system comprising bilateral occipital (Brodmann's area (BA) 17, 18), bilateral superior parietal (BA 7), bilateral dorsolateral prefrontal (BA 46), and dorsal anterior cingulate (BA 24, 32) regions. For maintenance, in contrast, constrained principal component analysis identified a system that was characterized by both load-dependent increases and decreases in activation. The structures in this system jointly activated by maintenance load involved left posterior parietal (BA 40), left inferior prefrontal (BA 44), left premotor and supplementary motor areas (BA 6), and dorsal cingulate regions (BA 24, 32), while the regions displaying maintenance-load-dependent activity decreases involved bilateral occipital (BA 17, 18), posterior cingulate (BA 23) and rostral anterior cingulate/orbitofrontal (BA 10, 11, 32) regions. The correlation between the encoding and maintenance systems was strong and negative (Pearson's r = -.55), indicting that some regions important for visual processing during encoding displayed reduced activity during maintenance, while subvocal rehearsal and phonological storage regions important for maintenance showed a reduction in activity during encoding. In summary, our analyses suggest that separable and complementary subsystems underlie encoding and maintenance in verbal working memory, and they demonstrate how constrained principal component analysis can be employed to characterize neuronal systems and their functional contributions to higher-level cognition.     

Molecular-cellular mechanisms of the formation of long-term memory in the edible snail

This short review, based mainly on our own studies, summarizes data on the molecular-cellular mechanisms of non-associative and associative forms of learning (sensitization and classical conditioning) in the edible snail. A hypothesis is proposed which suggests that learning in defensive behavior command neurons in the edible snail is activated by a complex metabolic response specific for the type of conditioned habit. Excitation arriving at the neuron, in addition to activating second messenger systems, initiates the synthesis of short-lived (1–3 h) protein molecules which are specific (in the case of conditioning) or relatively specific (in the case of sensitization) for particular synaptic inputs. When training is inadequate, its effect can disappear from the point at which these proteins are degraded. When learning is better fixed, its effects last for several days (for sensitization) or significantly longer periods of time (for conditioning). Prolonged retention of habits should correspond to the situation of self-maintaining synthesis of long-lived protein molecules, which control the synthesis of synapse-specific short-lived regulator molecules. P. K. Anokhin Science Research Institute of Normal Physiology, Russian Academy of Medical Sciences, Moscow. Translated from Fiziologicheskii Zhurnal im. I. M. Sechenova, Vol. 81, No. 8, pp. 18–23, August, 1995.     

大鼠海马结构在空间辨别性学习记忆时突触素表达的变化

目的:探讨空间辨别性学习记忆活动与突触可塑性的关系。方法:用免疫组织化学方法对具有空间辨别性学习记忆功能的模型大鼠与对照组大鼠海马结构内突触素I的表达进行对比研究。结果:(1)对照组大鼠海马结构内未见明显的突触素颗粒产物;在模型组,经水迷宫训练1周的大鼠海马切片上见到齿状回、CA4和CA3区出现深染的颗粒分布,CA2和CA1区颗粒较少;训练2周的大鼠海马结构内的染色显示颗粒与训练1周的比较无明显差异,但染色加深;(2)模型组大鼠的突触素反应产物的光密度值明显大于对照组(P＜0.05);模型组大鼠海马结构内突触素光密度值在训练的1~2周内随训练时间增加而增加,训练2~3周则增加不明显;模型组大鼠海马结构CA3、CA4区和齿状回突触素反应产物的光密度值较CA1和CA2区的大,差异有显著(P＜0.05)。结论:(1)大鼠经水迷宫训练获得空间辨别性学习记忆功能时在海马结构内有新突触形成;(2)海马结构的CA3、CA4区和齿状回与空间辨别性学习记忆的关系密切。     

Signaling mechanisms underlying group I mGluR-induced persistent AHP suppression in CA3 hippocampal neurons

Activation of group I metabotropic glutamate receptors (mGluRs) leads to a concerted modulation of spike afterpotentials in guinea pig hippocampal neurons including a suppression of both medium and slow afterhyperpolarizations (AHPs). Suppression of AHPs may be long-lasting, in that it persists after washout of the agonist. Here, we show that persistent AHP suppression differs from short-term, transient suppression in that distinct and additional signaling processes are required to render the suppression persistent. Persistent AHP suppression followed DHPG application for 30 min, but not DHPG application for 5 min. Persistent AHP suppression was temperature dependent, occurring at 30–31°C, but not at 25–26°C. Preincubation of slices in inhibitors of protein synthesis (cycloheximide or anisomycin) prevented the persistent suppression of AHPs by DHPG. Similarly, preincubation of slices in an inhibitor of p38 MAP kinase (SB 203580) prevented persistent AHP suppression. In contrast, a blocker of p42/44 MAP kinase activation (PD 98059) had no effect on persistent AHP suppression. Additionally, we show that the mGluR5 antagonist MPEP, but not the mGluR1 antagonist LY 367385, prevented DHPG-induced persistent AHP suppression. Thus persistent AHP suppression by DHPG in hippocampal neurons requires activation of mGluR5. In addition, activation of p38 MAP kinase signaling and protein synthesis are required to impart persistence to the DHPG-activated AHP suppression.