Memory corticalization triggered by REM sleep: mechanisms of cellular and systems consolidation

Once viewed as a passive physiological state, sleep is a heterogeneous and complex sequence of brain states with essential effects on synaptic plasticity and neuronal functioning. Rapid-eye-movement (REM) sleep has been shown to promote calcium-dependent plasticity in principal neurons of the cerebral cortex, both during memory consolidation in adults and during post-natal development. This article reviews the plasticity mechanisms triggered by REM sleep, with a focus on the emerging role of kinases and immediate-early genes for the progressive corticalization of hippocampus-dependent memories. The body of evidence suggests that memory corticalization triggered by REM sleep is a systemic phenomenon with cellular and molecular causes.     

The rodent hippocampus and spatial memory: from synapses to systems

Although its operations are not limited to the spatial domain, there is a near consensus that the hippocampus plays a critical role in memory for place. This review aims to explore this role, with a particular emphasis on the functions performed by distinct hippocampal subregions. The use of innovative lesioning techniques, localized pharmacological treatments, and molecular genetic interventions is offering increasingly precise brain-regional specificity and temporal control. Together with the electrophysiological recording of neuronal activity, these techniques are beginning to shed light on the functioning of specific components of the hippocampal circuitry in the different phases of memory – encoding, storage, consolidation, and retrieval. In view of these developments, we examine the involvement of the hippocampus in the encoding versus retrieval of spatial memory, before turning to the issue of long-term information storage and the role of ‘cellular’ and ‘systems’ consolidation processes in the formation of lasting memories. Received 17 July 2006; received after revision 24 October 2006; accepted 16 November 2006     

Memory processes during sleep: beyond the standard consolidation theory

Two-step theories of memory formation suggest that an initial encoding stage, during which transient neural assemblies are formed in the hippocampus, is followed by a second step called consolidation, which involves re-processing of activity patterns and is associated with an increasing involvement of the neocortex. Several studies in human subjects as well as in animals suggest that memory consolidation occurs predominantly during sleep (standard consolidation model). Alternatively, it has been suggested that consolidation may occur during waking state as well and that the role of sleep is rather to restore encoding capabilities of synaptic connections (synaptic downscaling theory). Here, we review the experimental evidence favoring and challenging these two views and suggest an integrative model of memory consolidation.     

Memory formation and the regulation of gene expression

On a cellular level, formation of memory is based on a selective change in synaptic efficacy that is both fast and, in case of important information, long-lasting. Rapidity of cellular changes is achieved by modifying preexisting synaptic molecules (receptors, ion channels), which instantaneously alters the efficacy of synaptic transmission. Endurance, that is the formation of long-term memory (LTM), is based on transient and perhaps also long-lasting changes in protein synthesis. A number of different methods exist to interfere with the synthesis of specific proteins or proteins in general. Other methods, in turn, help to identify proteins whose synthesis is changed following learning. These mostly molecular methods are briefly described in the present review. Their successful application in a variety of memory paradigms in invertebrates and vertebrates is illustrated. The data support the importance of selective changes in gene expression for LTM. Proteins newly synthesized during memory consolidation are likely to contribute to restructuring processes at the synapse, altering the efficiency of transmission beyond the scope of STM. Increased or, less often, decreased synthesis of proteins appears during specific time windows following learning. Recent evidence supports older data suggesting that two or even more waves of protein synthesis exist during the consolidation period. It is expected that the new molecular methods will help to identify and characterize molecules whose expression changes during LTM formation even in complex vertebrate learning paradigms.     

Protein kinases: which one is the memory molecule?

Encoding of new experiences is likely to induce activity-dependent modifications in the brain. Studies in organisms far apart on the phylogenetic scale have shown that similar, sometimes identical, signal transduction pathways subserve plasticity in neuronal systems, and they may play pivotal roles in the formation of long-term memories. It has become evident that phosphorylation/dephosphorylation reactions are critical for the initiation of cellular mechanisms that embody, retain and modify information in neural circuits. Although physiological investigations on synaptic plasticity have had a major impact, we have concentrated our review on behavioural studies that provide direct or indirect evidence for a role of kinases in mechanisms underlying memory formation. From these, it appears that the learning event induces activation of a variety of kinases with specific time courses. For instance, the calcium/calmodulin-dependent protein kinase II seems to participate in an early phase of memory formation. Apparently, activation of both protein tyrosine kinases and mitogen-activated protein kinases is required for much longer and may thus have a particular function during transformation from short-term into long-term memory. Quite different time courses appear for protein kinase C (PKC) and protein kinase A (PKA), which may function at two different time points, shortly after training and again much later. This suggests that PKC and PKA might play a role at early and late stages of memory formation. However, we have considered some examples showing that these signalling pathways do not function in isolation but rather interact in an intricate intracellular network. This is indicative of a more complex contribution of each kinase to the fine tuning of encoding and information processing. To decipher this complexity, pharmacological, biochemical and genetic investigations are more than ever necessary to unravel the role of each kinase in the syntax of learning and memory formation.     

Memory

The molecular mechanisms underlying the induction and maintenance of memory are highly dynamic and comprise distinct phases covering a time window from seconds to even a lifetime. Neuronal networks, which contribute to these processes, have been extensively characterized on various levels of analysis, and imaging techniques allow monitoring of both gross brain activity as well as functional changes in defined brain areas during the time course of memory formation. New techniques developed in honeybees and fruit flies even allow for manipulation of neuronal networks and molecular cascades in a short temporal domain while a living animal under observation acquires new associative memories. These advantages make honeybees and flies ideal organisms to study transient molecular events underlying dynamic memory processing in vivo. In this review we will focus on the temporal features of molecular processes in learning and memory formation, summarize recent knowledge and present an outlook on future developments.     

Issues surrounding sleep-dependent memory consolidation and plasticity

There is a growing body of evidence in support of sleep-dependent memory consolidation and plasticity. However, there are also examples of memory development and plasticity in the absence of sleep, casting doubt on an exclusive sleep-dependent memory hypothesis. As a result, polarized stances have arisen within the field. Here we reflect on these findings, and explore how they maybe reconcilable in a unified approach to understanding the roles of wake, sleep and specific sleep stages in successful memory processing and brain plasticity.Received 6 August 2004; received after revision 28 September 2004; accepted 5 October 2004     

塑料排水板堆载预压软基处理变形观察分析

采用塑料排水板堆载预压法对某软土路基工程进行处理,对路基变形及孔隙水压力等进行了严密观测;同时采取浅层沉降监测、深层沉降监测、孔隙水压力监测、地下水位观测等手段,以及地表沉降、孔隙水压力等变化规律,推算出预压荷载下的最终沉降量和固结度,深入分析塑料排水板堆载预压软土地基处理方法的加固效果。分析结果表明,该方法能有效地加快软基的固结沉降,提高地基土的稳定性和承载力,可供软土地基处理设计与施工参考。     

The role of Ca2+/calmodulin-stimulable adenylyl cyclases as molecular coincidence detectors in memory formation

Evidence from systems as diverse as mollusks, insects and mammals has revealed that adenylyl cyclase, cyclic adenosine 3′,5′-monophosphate (cAMP) cascade, cAMP-dependent protein kinases and their substrates are required for the cellular events underlying the short-term and long-term forms of memory. In Aplysia and Drosophila models, the coincident activation of independent paths converge to produce a synergistic activation of Ca²⁺/calmodulin-stimulable adenylyl cyclase, thereby enhancing the cAMP level that appears as the primary mediator of downstream events that strengthen enduring memory. In mammals, in which long-term memories require hippocampal function, our understanding of the role of adenylyl cyclases is still fragmentary. Of the differently regulated isoforms present in the hippocampus, the susceptibility of type 1 and type 8 to stimulation by the complex Ca²⁺/calmodulin and their expression in the hippocampus suggest a role for these two isoforms as a molecular coincidence device for hippocampus-related memory function. Here, we review the key features of Ca²⁺/calmodulin stimulable adenylyl cyclases, as well as the involvement of cAMP-regulated signaling pathway in the processes of learning and memory.     

Facilitation of avoidance conditioning by reticular stimulation in the cat]

Learning is facilitated in Cats by posttrial reticular stimulation. It has been pointed out that this stimulation has no immediate anterograde effect and does not evoke any change in the cortical, motor or autonomic functions during its delivery. Moreover this stimulation has no effect on the time course of cortical and autonomic responses to the conditioned stimulus. Therefore, these results suggest that reticular stimulation has a specific action on memory consolidation or information processing.     

一款用于多媒体处理的异构多核系统芯片的可测试性设计

随着集成电路工艺的发展,系统芯片（SoC）集成已成为超大规模集成电路的主流设计方法.SoC设计具有强调自顶向下设计、突出设计重用性、重视低功耗的特点,给集成电路的可测试性设计带来了严峻的挑战.本文针对一款用于多媒体处理的异构多核系统芯片DPU-m,提出了一套完整的可测试性设计方案,支持3种工作模式：功能模式、存储器内建自测试模式以及扫描测试模式,并进行了设计实现和评估.针对逻辑电路的可测试性设计,采用自顶向下的模块化设计思想,提出并实现了一种分布式与多路选择器相结合的测试访问机制,实验结果表明,DPU-m逻辑电路单固定型故障的测试覆盖率为98.58%,满足设计方要求;针对实速时延测试的需求,设计并实现了基于片上时钟生成器的时钟控制单元,可在片上支持不同时钟域、6种时钟频率的实速时延测试;针对存储器电路的自测试,设计并实现了串并行结合的存储器内建自测试结构,在最大测试功耗的约束下有效地减少了测试时间;进一步设计了顶层测试结果输出电路,满足了设计方要求的诊断分辨率,若以100 MHz的频率进行测试,测试时间为14 ms.     

The unique features of follicular T cell subsets

The germinal center (GC) reaction is critical for humoral immunity, but also contributes adversely to a variety of autoimmune diseases. While the major protective function of GCs is mediated by plasma cells and memory B cells, follicular helper T (TFH) cells represent a specialized T cell subset that provides essential help to the antigen-specific B cells in the form of membrane-bound ligands and secreted factors such as IL-21. Recent studies have revealed that TFH cells are capable of considerable functional diversity as well as possessing the ability to form memory cells. The molecular basis of this plasticity and heterogeneity is only now emerging. It has also become apparent that several other populations of follicular T cells exist, including natural killer T cells and regulatory T cells. In this review we will discuss the function of follicular T cells and interaction of these populations within the GC response.     

Sleep and sleep disturbances: biological basis and clinical implications

Sleep is a neurochemical process involving sleep promoting and arousal centers in the brain. Sleep performs an essential restorative function and facilitates memory consolidation in humans. The remarkably standardized bouts of consolidated sleep at night and daytime wakefulness reflect an interaction between the homeostatic sleep need that is manifested by increase in sleep propensity after sleep deprivation and decrease during sleep and the circadian pacemaker. Melatonin, the hormone produced nocturnally by the pineal gland, serves as a time cue and sleep-anticipating signal. A close interaction exists between the sleep-wake, melatonin, core temperature, blood pressure, immune and hormonal rhythms leading to optimization of the internal temporal order. With age the robustness of the circadian system decreases and the prevalence of sleep disorders, particularly insomnia, increases. Deviant sleep patterns are associated with increased risks of morbidity, poor quality of life and mortality. Current sleep pharmacotherapies treat insufficient sleep quantity, but fail to improve daytime functioning. New treatment modalities for sleep disorders that will also improve daytime functioning remain a scientific and medical challenge.     

A study of granulated metrial gland cell differentiation in pregnant, macrophage-deficient, osteopetrotic (op/op) mice.

A population of uterine natural killer (NK) cells, commonly called granulated metrial gland (GMG) cells, differentiates in the mouse uterus during normal pregnancy. Little is known regarding the process of differentiation of GMG cells or of other NK cell subsets. It has been suggested that macrophage precursors, under the combined influences of the cytokine growth factors colony stimulating factor-1 (CSF-1) and interleukin-2, become NK-cell like in morphology, pattern of target cell lysis and surface antigen phenotype. Mice expressing the mutation osteopetrosis (op/op) are unable to produce the cytokine CSF-1. To determine whether CSF-1 is required for the successful differentiation of uterine NK cells, implantation sites in pregnant, op/op mice were studied histologically. GMG cell differentiation appeared to progress normally in op/op mice studied between days 7 and 14 of gestation. Thus, the growth factor CSF-1 is not required for differentiation of the uterine NK cell subset known as GMG cells and probably GMG cells do not differentiate from macrophage precursor cells which are deficient in op/op mice.     

Is it a short‐memory,long‐memory,or permanently Granger‐causation influence?

Exploring the Granger‐causation relationship is an important and interesting topic in the field of econometrics. In the traditional model we usually apply the short‐memory style to exhibit the relationship, but in practice there could be other different influence patterns. Besides the short‐memory relationship, Chen (2006) demonstrates a long‐memory relationship, in which a useful approach is provided for estimation where the time series are not necessarily fractionally co‐integrated. In that paper two different relationships (short‐memory and long‐memory relationship) are regarded whereby the influence flow is decayed by geometric, or cutting off, or harmonic sequences. However, it limits the model to the stationary relationship. This paper extends the influence flow to a non‐stationary relationship where the limitation is on ?0.5 ≤ d ≤ 1.0 and it can be used to detect whether the influence decays off (?0.5 ≤ d < 0.5) or is permanent (0.5 ≤ d ≤ 1.0). Copyright © 2008 John Wiley & Sons, Ltd.     

A study of granulated metrial gland cell differentiation in pregnant,macrophage-deficient,osteopetrotic (op/op) mice

A population of uterine natural killer (NK) cells, commonly called granulated metrial gland (GMG) cells, differentiates in the mouse uterus during normal pregnancy. Little is known regarding the process of differentiation of GMG cells or of other NK cell subsets. It has been suggested that macrophage precursors, under the combined influences of the cytokine growth factors colony stimulating factor-1 (CSF-1) and interleukin-2, become NK-cell like in morphology, pattern of target cell lysis and surface antigen phenotype. Mice expressing the mutation osteopetrosis (op/op) are unable to produce the cytokine CSF-1. To determine whether CSF-1 is required for the successful differentiation of uterine NK cells, implantation sites in pregnant,op/op mice were studied histologically. GMG cell differentiation appeared to progress normally inop/op mice studied between days 7 and 14 of gestation. Thus, the growth factor CSF-1 is not required for differentiation of the uterine NK cell subset known as GMG cells and probably GMG cells do not differentiate from macrophage precursor cells which are deficient inop/op mice.     

非线性薄膜方程的差分迭代求解

对类似于非线性薄膜一类的非线性偏微分方程提出一种新的算法.该法首先略去非线性部分的影响,或给予非线性部分莱一初值,使非线性部分成为已知,从而将原非线性方程转化为线性方程,并按差分法或其它方法求得其线性解.再将所得线性解代入非线性部分使其成为已知,再次求得其解.这样反复迭代直至收敛,进而求得原非线性方程的非线性解.