基于忆阻器实现多样化STDP学习规则的突触电路设计

忆阻器作为一种具有记忆效应的非线性电路元件,它受到电流刺激后的电导变化与人脑中神经突触的权重变化类似,可用于模拟人脑学习、记忆过程中的突触行为.本文提出了一种基于忆阻器所搭建的突触电路,包含了由运放、逻辑门、模拟开关等器件构成的增强模块和抑制模块,以及由忆阻器和模拟开关构成的忆阻突触模块.通过对增强和抑制模块输入直流脉...     

慢性酒精中毒小鼠小脑的超微结构实验研究

目的 探讨慢性酒精中毒导致神经系统损伤的机制.方法 建立小鼠慢性酒精中毒动物模型,观察动物行为学的改变,测量血浆酒精浓度,通过透射电镜了解小脑的超微结构变化.结果 酒精处理组的血浆酒精浓度为101.4±20.5 mg/dL,与对照组和配对对照组比较,酒精处理组小鼠行动欠灵活,小脑线粒体形状多样、大小多变、数量增加和平均横断面面积显著减小;突触的数量减少、突触后膜致密物质厚度变薄、突触活性区长度变短及突触间隙宽度变宽,突触前结构内附着于突触的囊泡较多.结论 酒精对线粒体和突触结构、功能的损害可能是慢性酒精中毒的神经系统损伤机制之一.     

大鼠T_(10)脊髓半横断损伤模型的制备及评价

目的通过制备大鼠T10脊髓半横断动物模型,模拟脊髓损伤,研究其病理生理变化,为研究急性脊髓损伤的机制及治疗提供基础。方法成年雌性SD大鼠24只,随机分为两组:脊髓损伤组和假手术组,每组各12只。脊髓损伤组咬除棘突及相应椎板,横向半切断T10脊髓,假手术组仅行椎板切除术。分别于术后1、3、5、7、14、21、28 d进行BBB运动功能评分,同时于术后7、14、21、28 d分别检测其运动诱发电位和体感诱发电位,记录N1和P1波潜伏期,进而评估神经传导通路的完整性。结果脊髓损伤组大鼠术后BBB运动功能评分较低,在术后各时间点与假手术组相比具有统计学意义(P0.05)。神经电生理检测结果表明,与假手术组相比,脊髓损伤组运动诱发电位和体感诱发电位潜伏期均具有统计学意义(P0.05)。结论通过本实验方法建立大鼠急性脊髓损伤模型,制作过程简单,易于复制,可用于脊髓损伤的相关研究。     

基于STDP规则和忆阻桥突触的神经网络及图像处理

忆阻器是具有记忆和类突触特性的非线性电路元件.基于此特性,文中提出了一个基于STDP（spike-time-dependent plasticity）学习规则的忆阻桥突触电路,它具有可以作为人工神经网络突触的优势.根据此优势,将这个新的电路与其他电路和网络结合,构成全新的电路和网络.首先将该忆阻桥突触电路和3个附加的晶体管结合在一起,实现神经网络的突触运算,并构建完整的忆阻桥突触神经网络.然后再将它与细胞神经网络结合用于图像去噪、边缘提取、角检测和汉字识别.最后,通过一系列的仿真实验证实了该方案的可行性,说明基于STDP学习规则的忆阻桥突触神经网络更具仿生特性,而且集成度更高、模板更易更换,有望解决实时的复杂的智能问题.     

学习和记忆的神经基础

学习和记忆是脑是基本的高级功能,是我们每时每刻都在经历着的事情。学习和记忆过程中脑内发生了什么？在过去的２０多年中,有关学习和记忆的神经机制研究取得了重大进展。     

成年大鼠脊髓损伤后Sonic Hedgehog信号通路成分的动态表达

目的观察Sonic Hedgehog(Shh)信号通路中Shh、Gli-1在成年大鼠脊髓损伤后的动态表达,探讨Shh信号通路对大鼠脊髓损伤后的调控作用。方法将64只健康SD大鼠随机分为正常组(n=8),假手术组(n=8),脊髓损伤12h、1d、3d、7d、14d和21d组(n=8),共8组。构建大鼠脊髓损伤模型,观察损伤后大鼠行为学的改变,并应用实时荧光定量PCR技术(Real-Time Quantitative PCR)和蛋白免疫印迹法(Western Blotting)检测Shh、Gli-1 mRNA和相关蛋白表达水平的变化。结果行为学观察表明,大鼠脊髓损伤后运动功能下降,RT-PCR和免疫印迹法表明,Shh、Gli-1在正常组织少量表达,脊髓损伤后Shh、Gli-1表达均明显增高,损伤后第7天达到峰值,损伤21天后仍有高水平的表达。结论脊髓损伤可以上调Shh信号通路成分的表达并表现出一定的动态变化规律,提示Shh信号通路可能参与了脊髓损伤后神经细胞的调控作用。     

成年大鼠脊髓损伤后内源性神经前体细胞的增殖与分化规律的研究

目的观察成年大鼠脊髓损伤后内源性神经前体细胞的增殖与分化,探讨内源性神经前体细胞的自然变化规律。方法制作脊髓压迫损伤模型,Brdu腹腔注射标记神经前体细胞,免疫荧光法(Immunofluoreseence)检测大鼠脊髓Brdu、GFAP、MBP阳性细胞数的变化。结果 1)正常组可观察到少量Brdu阳性细胞,脊髓损伤后Brdu阳性细胞显著增加(p0.05),并在第7天达到最大值,21天时仍高水平表达。2)正常组可见少量Brdu/GFAP和Brdu/MBP阳性细胞,脊髓损伤后Brdu/GFAP,Brdu/MBP双标阳性细胞数显著增加(p0.05)。结论脊髓损伤后神经前体细胞的数量在第7天达到最大值,我们认为,一周内可能是神经前体细胞增殖分化调控的关键时期。此外,新生星形胶质细胞和少突胶质细胞大量增殖,并与神经前体细胞的迁移、后肢功能恢复表现出一定的同步性,提示新生胶质细胞可能参与了脊髓损伤后神经功能的修复作用。     

bFGF的产生机制及其在临床疾病中的作用

碱性成纤维细胞生长因子(bFGF)有着广泛的生物学活性,在多种临床疾病中起着重要的作用。研究发现,许多受体激活后都对bFGF的产生起调控作用,主要通过PLC/IP3/Ca~(2+)/钙调蛋白依赖性蛋白激酶、cAMP/PKA和MEK/MAPK信号传导通路,而bFGF反过来又对受体的数量和活性产生影响。本文就bFGF的产生机制及其在疼痛、抑郁、肿瘤、骨折和心梗中的作用进行综述。     

D-半乳糖致衰老小鼠学习记忆能力和睾丸的改变及延衰合剂的治疗作用

目的研究D-半乳糖所致亚急性衰老小鼠学习记忆能力和睾丸的变化,并观察延衰合剂对其的治疗作用。方法选昆明系雄性小鼠,用D-半乳糖建立亚急性衰老模型。应用Morris水迷宫实验测试衰老小鼠学习记忆能力的变化;电镜技术观察延衰合剂治疗后衰老小鼠睾丸的形态学改变;酶联免疫分析法检测血清睾酮的变化。结果衰老小鼠学习记忆能力下降,睾丸重量减少,生精细胞减少,结构紊乱,功能障碍,血清睾酮含量明显降低。在改变学习记忆能力上延衰合剂高剂量组作用明显优于延衰合剂低剂量纽（P〈0．05）,但与补肾益寿胶囊纽及延衰舍剂中荆量组差畀无显著性（P〉0．05）。结论延衰舍剂可以提高衰老小鼠学习记忆能力,改善睾丸生精小管的超微结构,抑制衰老小鼠血清睾酮含量的下降,具有一定的延缓衰老作用。     

行为学评价大鼠急性脊髓损伤模型脊髓节段选择的研究

目的通过行为学评价观察不同脊髓损伤节段选择的特点及对脊髓功能恢复的影响。方法选取不同脊髓损伤节段建立大鼠急性脊髓损伤模型。BBB评分法和斜板试验观察1d、3d、5d、7d、14d、21d和28d脊髓功能恢复情况。结果通过BBB评分法和斜板试验观察显示,脊髓损伤组(T8、T9、T10)大鼠相比假手术组大鼠各时间点均有显著差异(P0.01),整体趋势随时间呈现跳跃式变化。BBB评分结果显示,第5d开始,T10组的评分值高于T8组(P0.05),第7d到21d,T10组的评分值明显高于T8组(P0.01),第14d和21d,T10组的评分值高于T9组(P0.05),在第28d,T10组评分相比T8组和T9组无统计学差异(P0.05)。斜板实验结果显示,第5d到28d,T10组的评分值高于T8组(P0.05)。第5d到14d,T10组评分值高于T9组(P0.05),而第21d和28d,T10组的评分值相比T9组无统计学差异(P0.05)。评分值标准化为百分制后进行横向比较,假手术组大鼠两种评分值之间的一致性较好,脊髓损伤组大鼠两种评分值之间的差异较大,在术后1d、3d、28d时,无统计学差异(P0.05),在第7d、14d可观察到差异非常显著(P0.01)。结论通过BBB评分和斜板试验发现,T10组实验结果所反映的组间差异在术后各时间点较T8、T9差异更加显著,跨度更大,在实验过程中更有利于观察其变化,在损伤后第5d到第21d尤为明显,建立脊髓损伤模型选择T10损伤节段要优于T8和T9损伤节段。     

Memory

Our understanding of the cellular and molecular mechanisms underlying learning and memory formation derives from studies of species as diverse as worms, mollusks, insects, birds and mammals. Despite the quite different brain structures and neuronal networks, the studies support the current notion that neuronal activity leads to changes in synaptic connections as the neural substrate of behavioral plasticity. The analysis of the mechanisms underlying learning and memory formation reveals a surprisingly high conservation between invertebrates and mammals, both at the behavioral as well as the molecular level. This special issue provides an overview of the current knowledge on cellular and molecular processes underlying memory formation. The contributing reviews summarize the findings in different organisms, such as Aplysia, Drosophila, honeybees and mammals, and discuss new approaches, developments and hypotheses all aimed at understanding how the nervous system acquires, stores and retrieves information.     

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.     

Involvement of extrasynaptic glutamate in physiological and pathophysiological changes of neuronal excitability

Glutamate is the most abundant neurotransmitter of the central nervous system, as the majority of neurons use glutamate as neurotransmitter. It is also well known that this neurotransmitter is not restricted to synaptic clefts, but found in the extrasynaptic regions as ambient glutamate. Extrasynaptic glutamate originates from spillover of synaptic release, as well as from astrocytes and microglia. Its concentration is magnitudes lower than in the synaptic cleft, but receptors responding to it have higher affinity for it. Extrasynaptic glutamate receptors can be found in neuronal somatodendritic location, on astroglia, oligodendrocytes or microglia. Activation of them leads to changes of neuronal excitability with different amplitude and kinetics. Extrasynaptic glutamate is taken up by neurons and astrocytes mostly via EAAT transporters, and astrocytes, in turn metabolize it to glutamine. Extrasynaptic glutamate is involved in several physiological phenomena of the central nervous system. It regulates neuronal excitability and synaptic strength by involving astroglia; contributing to learning and memory formation, neurosecretory and neuromodulatory mechanisms, as well as sleep homeostasis.The extrasynaptic glutamatergic system is affected in several brain pathologies related to excitotoxicity, neurodegeneration or neuroinflammation. Being present in dementias, neurodegenerative and neuropsychiatric diseases or tumor invasion in a seemingly uniform way, the system possibly provides a common component of their pathogenesis. Although parts of the system are extensively discussed by several recent reviews, in this review I attempt to summarize physiological actions of the extrasynaptic glutamate on neuronal excitability and provide a brief insight to its pathology for basic understanding of the topic.     

Alzheimer’s disease risk factor lymphocyte-specific protein tyrosine kinase regulates long-term synaptic strengthening, spatial learning and memory

The lymphocyte-specific protein tyrosine kinase (Lck), which belongs to the Src kinase-family, is expressed in neurons of the hippocampus, a structure critical for learning and memory. Recent evidence demonstrated a significant downregulation of Lck in Alzheimer’s disease. Lck has additionally been proposed to be a risk factor for Alzheimer’s disease, thus suggesting the involvement of Lck in memory function. The neuronal role of Lck, however, and its involvement in learning and memory remain largely unexplored. Here, in vitro electrophysiology, confocal microscopy, and molecular, pharmacological, genetic and biochemical techniques were combined with in vivo behavioral approaches to examine the role of Lck in the mouse hippocampus. Specific pharmacological inhibition and genetic silencing indicated the involvement of Lck in the regulation of neuritic outgrowth. In the functional pre-established synaptic networks that were examined electrophysiologically, specific Lck-inhibition also selectively impaired the long-term hippocampal synaptic plasticity without affecting spontaneous excitatory synaptic transmission or short-term synaptic potentiation. The selective inhibition of Lck also significantly altered hippocampus-dependent spatial learning and memory in vivo. These data provide the basis for the functional characterization of brain Lck, describing the importance of Lck as a critical regulator of both neuronal morphology and in vivo long-term memory.     

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.     

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 glycinergic control of spinal pain processing

Alterations in synaptic transmission within the spinal cord dorsal horn play a key role in the development of pathological pain. While N-methyl-D-aspartate (NMDA) receptors and activity-dependent synaptic plasticity have been the focus of research for many years, recent evidence attributes very specific functions to inhibitory glycinergic and γ-aminobutyric acid (GABA)-ergic neurotransmission in the generation of inflammatory and neuropathic pain. The central component of inflammatory pain originates from a disinhibition of dorsal horn neurons, which are relieved from glycinergic neurotransmission by the inflammatory mediator prostaglandin E₂ (PGE₂). PGE₂ activates prostaglandin E receptors of the EP2 subtype and leads to a protein kinase A-dependent phosphorylation and inhibition of glycine receptors containing the α3 subunit (GlyRα3). This GlyRα3 is distinctly expressed in the superficial dorsal horn, where nociceptive afferents terminate. Other but probably very similar disinhibitory mechanisms may well contribute to abnormal pain occurring after peripheral nerve injury.Received 11 March 2005; received after revision 1 April 2005; accepted 19 April 2005     

AMPAR trafficking in synapse maturation and plasticity

Glutamate ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPARs) mediate most fast excitatory synaptic transmission in the central nervous system. The content and composition of AMPARs in postsynaptic membranes (which determine synaptic strength) are dependent on the regulated trafficking of AMPAR subunits in and out of the membranes. AMPAR trafficking is a key mechanism that drives nascent synapse development, and is the main determinant of both Hebbian and homeostatic plasticity in mature synapses. Hebbian plasticity seems to be the biological substrate of at least some forms of learning and memory; while homeostatic plasticity (also known as synaptic scaling) keeps neuronal circuits stable by maintaining changes within a physiological range. In this review, we examine recent findings that provide further understanding of the role of AMPAR trafficking in synapse maturation, Hebbian plasticity, and homeostatic plasticity.     

Antiepileptic drugs and the developing brain

Epilepsy is the most common neurological disorder in young humans. Antiepileptic drugs (AEDs) which are used to treat seizures in infants, children and pregnant women can cause cognitive impairment, microcephaly and birth defects. Ion channels, neurotransmitters and second messenger systems constitute molecular targets of AEDs. The same targets regulate brain processes essential both for propagation of seizures and for learning, memory and emotional behavior. Thus, AEDs can influence brain function and brain development in undesired ways. Here we review mechanisms of action of AEDs, examine clinical evidence for their adverse effects in the developing human brain, and present studies on cognitive and behavioral effects in animal models. Furthermore, we discuss mechanisms responsible for adverse effects of AEDs in the developing mammalian brain, including interference with cell proliferation and migration, axonal arborization, synaptogenesis, synaptic plasticity and physiological apoptotic cell death. Received 3 August 2005; received after revision 13 October 2005; accepted 1 November 2005     

Chemokines in neuron–glial cell interaction and pathogenesis of neuropathic pain

Neuropathic pain resulting from damage or dysfunction of the nervous system is a highly debilitating chronic pain state and is often resistant to currently available treatments. It has become clear that neuroinflammation, mainly mediated by proinflammatory cytokines and chemokines, plays an important role in the establishment and maintenance of neuropathic pain. Chemokines were originally identified as regulators of peripheral immune cell trafficking and were also expressed in neurons and glial cells in the central nervous system. In recent years, accumulating studies have revealed the expression, distribution and function of chemokines in the spinal cord under chronic pain conditions. In this review, we provide evidence showing that several chemokines are upregulated after peripheral nerve injury and contribute to the pathogenesis of neuropathic pain via different forms of neuron–glia interaction in the spinal cord. First, chemokine CX3CL1 is expressed in primary afferents and spinal neurons and induces microglial activation via its microglial receptor CX3CR1 (neuron-to-microglia signaling). Second, CCL2 and CXCL1 are expressed in spinal astrocytes and act on CCR2 and CXCR2 in spinal neurons to increase excitatory synaptic transmission (astrocyte-to-neuron signaling). Third, we recently identified that CXCL13 is highly upregulated in spinal neurons after spinal nerve ligation and induces spinal astrocyte activation via receptor CXCR5 (neuron-to-astrocyte signaling). Strategies that target chemokine-mediated neuron-glia interactions may lead to novel therapies for the treatment of neuropathic pain.