神经可塑性与认知功能关系研究进展

认知是神经中枢的高级智能活动,其神经生理特性是中枢神经之高度可塑性,涵盖神经网络、神经再生及突触连接等层次的可塑性调节变化。因突触可塑性是神经元之间信息传递之中心枢纽,亦为神经可塑性之主要部位。故本文主要从与突触可塑性相关的LTP、突触素、相关神经递质及临床相关疾病等方面阐述突触可塑性对认知功能的影响。     

突触可塑性调节过程中蛋白质磷酸化修饰的研究进展

突触可塑性可以导致神经元传递效率的改变,是神经系统发育、学习记忆等脑的高级功能活动中细胞功能的重要基础。蛋白质磷酸化修饰通过蛋白激酶和蛋白磷酸酶之间的动态平衡对突触可塑性和突触传递的长期调节,参与各种脑疾病(包括精神疾病和神经退行性疾病)的发生发展。本文综述了磷酸化修饰和突触可塑性的关系,重点介绍了长时程增强和长时程抑制相关的离子型谷氨酸受体磷酸化修饰研究进展,以期为神经元突触可塑性改变相关的脑疾病研究提供新的思路。     

神经元的突触可塑性与学习和记忆

大量研究表明,神经元的突触可塑性包括功能可塑性和结构可塑性,与学习和记忆密切相关.最近,在经过训练的动物海马区,记录到了学习诱导的长时程增强(long term potentiation,LTP),如果用激酶抑制剂阻断晚期LTP,就会使大鼠丧失训练形成的记忆.这些结果指出,LTP可能是形成记忆的分子基础.因此,进一步研究哺乳动物脑内突触可塑性的分子机制,对揭示学习和记忆的神经基础有重要意义.此外,在精神迟滞性疾病和神经退行性疾病患者脑内记录到异常的LTP,并发现神经元的树突棘数量减少,形态上产生畸变或萎缩,同时发现,产生突变的基因大多编码调节突触可塑性的信号通路蛋白,故突触可塑性研究也将促进精神和神经疾病的预防和治疗.综述了突触可塑性研究的最新进展,并展望了其发展前景.     

脑内ATF4对学习记忆的调节作用

转录激活因子4(ATF4)属于碱性亮氨酸拉链结构域蛋白中的ATF/CREB转录因子家族,ATF4在脑内广泛表达,在应激、痛觉、突触可塑性和神经退行性变等中发挥重要作用。学习与记忆是脑的高级功能之一,学习是获取新信息的过程,记忆是将信息进行编码、储存及提取的过程,二者被认为是认知活动的基础。突触可塑性是突触在形态、结构和功能上的可变性和可修饰性,与神经系统的发育和学习记忆等脑的高级功能密切相关。突触可塑性的长时程增强和长时程抑制是学习和记忆形成的基础。近年来研究发现, ATF4与突触可塑性和学习记忆密切相关,其在神经退行性变、脑损伤和药物成瘾等疾病中扮演重要角色,有必要深入理解ATF4在学习记忆障碍相关疾病中发挥的作用,为相关疾病的治疗提供新靶点。     

突触可塑性与阿尔茨海默病

突触可塑性是指突触在神经元持续活动影响下发生的特异性数目、结构和功能的变化,它是学习记忆形成的基础,在神经功能中发挥重要的作用。突触可塑性包括突触传递和结构可塑性,二者与阿尔茨海默病(Alzheimer's disease,AD)发病有密切关系。本文从突触可塑性相关的长时程增强(longterm potentiation,LTP)、突触相关蛋白、神经递质以及神经受体和离子在AD脑内的改变,探讨突触可塑性在AD发病机制中的可能作用,为研究AD发病机制,预防和治疗提供新思路。     

SHH信号通路在海马神经可塑性及相关神经系统疾病中的作用

音猬因子（sonic hedgehog,SHH）是一种分泌蛋白质,可在发育过程中控制神经祖细胞、神经元和神经胶质细胞的形成。研究发现,海马是学习和记忆中至关重要的大脑区域,SHH在海马神经元回路的形成和可塑性中发挥重要作用,可介导海马神经的发生和突触的可塑性调节。海马神经元树突中SHH受体的激活是跨神经元信号通路的组成部分,该信号通路可加速轴突的生长并增强谷氨酸从突触前末端的释放。SHH信号通路转导受损可导致中枢神经系统损伤和相关疾病（如自闭症、抑郁症和神经退行性疾病等）发生。因此,控制SHH信号通路转导,如使用SHH通路抑制剂或激动剂可能有助于相关疾病的治疗。综述了SHH信号通路的海马神经可塑性及其在中枢神经系统发育和相关疾病中的影响,以期为阐明SHH信号转导受损导致的海马神经受损和中枢神经系统相关疾病的机制奠定一定的理论依据。     

多巴胺调节海马神经元可塑性的研究进展

多巴胺是脑内重要的信息传递物质,不仅可以作为递质释放到前额叶、伏隔核等脑区,直接进行信息传递,也可以作为调质调节其它突触递质的传递,并影响神经元可塑性。海马参与构成边缘系统,受多巴胺能神经支配,执行着有关学习记忆以及空间定位的功能。海马神经元的可塑性是学习记忆的细胞分子基础。研究表明,多巴胺对海马神经元的突触可塑性和兴奋性可塑性都具有重要的调节作用。本文扼要综述多巴胺对海马神经元突触可塑性和兴奋性可塑性的调节机制的研究进展,以期为DA系统参与海马区学习记忆功能的研究提供新思路,更深入地了解学习记忆的神经机制。     

短时程突触可塑性研究概况

突触可塑性是神经系统所具有的重要特征,也是神经系统实现其功能的重要保障。按照持续的时间划分,突触可塑性可分为短时程突触可塑性和长时程突触可塑性。短时程突触可塑性包括短时程增强和短时程压抑两种类型。与长时程突触可塑性不同,短时程突触可塑性的产生主要依赖于神经递质释放概率的变化,其往往决定神经回路的信息处理和反应模式,不仅直接参与了对输入信号的识别和处理,而且还可对长时程突触可塑性的表达产生重要影响。     

D2DR在纹状体突触可塑性及运动障碍中枢调控中的作用

多巴胺Ⅱ型受体在大脑基底神经节纹状体区域表达丰富,可反馈性调节突触前多巴胺合成并介导细胞信号转导。纹状体神经元突触可塑性受多巴胺Ⅱ型受体介导的cAMP/PKA和PLC信号通路调节,也是自主运动控制的神经基础。在运动性疲劳及以帕金森病为代表的运动功能障碍的中枢疾病中,多巴胺Ⅱ型受体通过平衡基底神经节直接通路和间接通路发挥重要作用。本文对多巴胺Ⅱ型受体在纹状体神经元突触可塑性和运动功能障碍中枢调控中的作用进行综述,为相关疾病的靶向干预和治疗提供理论基础。     

神经营养因子功能的“阴/阳”特性

神经营养因子是一类对神经元的营养、支持、分化及突触可塑性等具有重要作用的蛋白质。近年来研究发现神经营养因子合成中的前体分子产生相反的诱导神经元凋亡作用,并在中枢退行性疾病发生中扮演着重要的角色。本文综述了神经营养因子及其前体蛋白在合成代谢、受体调控和功能上的"阴/阳"特性,并讨论其在疾病过程中的可能作用,为进一步探索认识神经营养因子的功能、病理意义、疾病治疗价值提供新的视角。     

Digitalizing neuronal synapses with cryo-electron tomography and correlative microscopy

Synapses are the structural and functional joints of neuronal circuits, and brain function is fundamentally based on synaptic quantal transmission and plasticity. Precise mapping of key components within individual synapses in different states can reveal the principles governing synapse formation, transmission, and plasticity and improving understanding of the mechanisms of synapse-related diseases. Cryo-electron tomography (cryo-ET) and correlative microscopy are increasingly powerful tools that can dissect the molecular sociology of intact cells, including neuronal synapses. In this study, we discuss current progress made in cryo-ET studies assessing neuronal synapses, especially sample preparation, molecule identification, and correlative approaches for synaptic dynamics and functions.     

Interplay between Short- and Long-Term Plasticity in Cell-Assembly Formation

Various hippocampal and neocortical synapses of mammalian brain show both short-term plasticity and long-term plasticity, which are considered to underlie learning and memory by the brain. According to Hebb’s postulate, synaptic plasticity encodes memory traces of past experiences into cell assemblies in cortical circuits. However, it remains unclear how the various forms of long-term and short-term synaptic plasticity cooperatively create and reorganize such cell assemblies. Here, we investigate the mechanism in which the three forms of synaptic plasticity known in cortical circuits, i.e., spike-timing-dependent plasticity (STDP), short-term depression (STD) and homeostatic plasticity, cooperatively generate, retain and reorganize cell assemblies in a recurrent neuronal network model. We show that multiple cell assemblies generated by external stimuli can survive noisy spontaneous network activity for an adequate range of the strength of STD. Furthermore, our model predicts that a symmetric temporal window of STDP, such as observed in dopaminergic modulations on hippocampal neurons, is crucial for the retention and integration of multiple cell assemblies. These results may have implications for the understanding of cortical memory processes.     

Theoretical aspects of neuroplasticity.

The authors propose an integrative theory of the organization of neuroplastic processes. Neuroplasticity is assumed to be one of the essential characteristics of the nervous tissue which may be manifested comparatively rapidly and result in reversible changes (functional plasticity). It may also modulate the expression of genotype into phenotype (adaptation) and thus bring about long-lasting effects. Neuroplastic mechanisms are triggered by various natural or artificial stimuli, which may arise in the internal or external environment, and they may differ quantitatively or qualitatively. The effects of plasticity can lead to either positive or negative changes during development (evolutionary plasticity), after short-term exposition (reactive plasticity), after long-term or continuous stimuli (adaptational plasticity), and during functional or structural recovery of damaged neuronal circuits (reparation plasticity). Manifestations of plasticity have probably the same basis, irrespective of the cause which triggered them or the brain region where they were accomplished. Neuroplastic mechanisms are based on the modulation of signal transmission across synapses. They can be related to interneuronal relations. The resulting changes may occur in the communication between neurons (synaptic level), in the activity of local neuronal circuits (at the level of local circuits) or in the relations between individual functional brain systems (multimodular level).     

Normal protein composition of synapses in Ts65Dn mice: a mouse model of Down syndrome

Down syndrome (DS) is the most prevalent form of intellectual disability caused by the triplication of ∼230 genes on chromosome 21. Recent data in Ts65Dn mice, the foremost mouse model of DS, strongly suggest that cognitive impairment in individuals with DS is a consequence of reduced synaptic plasticity because of chronic over-inhibition. It remains unclear however whether changes in plasticity are tied to global molecular changes at synapses, or are due to regional changes in the functional properties of synaptic circuits. One interesting framework for evaluating the activity state of the DS brain comes from in vitro studies showing that chronic pharmacological silencing of neuronal excitability orchestrates stereotyped changes in the protein composition of synaptic junctions. In the present study, we use proteomic strategies to evaluate whether synapses from the Ts65Dn cerebrum carry signatures characteristic of inactive cortical neurons. Our data reveal that synaptic junctions do not exhibit overt alterations in protein composition. Only modest changes in the levels of synaptic proteins and in their phosphorylation are observed. This suggests that subtle changes in the functional properties of specific synaptic circuits rather than large-scale homeostatic shifts in the expression of synaptic molecules contribute to cognitive impairment in people with DS.     

Structural plasticity of dendritic spines: The underlying mechanisms and its dysregulation in brain disorders

Dendritic spines are specialized structures on neuronal processes where the majority of excitatory synapses are localized. Spines are highly dynamic, and their stabilization and morphology are influenced by synaptic activity. This extrinsic regulation of spine morphogenesis underlies experience-dependent brain development and information storage within the brain circuitry. In this review, we summarize recent findings that demonstrate the phenomenon of activity-dependent structural plasticity and the molecular mechanisms by which synaptic activity sculpt neuronal connections. Impaired structural plasticity is associated with perturbed brain function in neurodevelopmental disorders such as autism. Information from the mechanistic studies therefore provides important insights into the design of therapeutic strategies for these brain disorders.     

Progress in neural plasticity

The year 2009 marks the tenth anniversary of the founding of Institute of Neuroscience (ION) in the Shanghai campus of Chinese Academy of Sciences.     

Nicotinic modulation of synaptic transmission and plasticity in cortico-limbic circuits

Nicotine is the principle addictive agent delivered via cigarette smoking. The addictive activity of nicotine is due to potent interactions with nicotinic acetylcholine receptors (nAChRs) on neurons in the reinforcement and reward circuits of the brain. Beyond its addictive actions, nicotine is thought to have positive effects on performance in working memory and short-term attention-related tasks. The brain areas involved in such behaviors are part of an extensive cortico-limbic network that includes relays between prefrontal cortex (PFC) and cingulate cortex (CC), hippocampus, amygdala, ventral tegmental area (VTA) and the nucleus accumbens (nAcc). Nicotine activates a broad array of nAChRs subtypes that can be targeted to pre- as well as peri- and post-synaptic locations in these areas. Thereby, nicotine not only excites different types of neurons, but it also perturbs baseline neuronal communication, alters synaptic properties and modulates synaptic plasticity.In this review we focus on recent findings on nicotinic modulation of cortical circuits and their targets fields, which show that acute and transient activation of nicotinic receptors in cortico-limbic circuits triggers a series of events that affects cognitive performance in a long lasting manner. Understanding how nicotine induces long-term changes in synapses and alters plasticity in the cortico-limbic circuits is essential to determining how these areas interact in decoding fundamental aspects of cognition and reward.     

Dream contents and failing memories

Mentation during sleep states is thought to originate in an activation of brain circuits that encode inherited and experiential memories. Spontaneous degradation of the strengths of synapses occurs in all brain circuits because of "turnover" of molecules essential for synaptic function. In circuits employed frequently during waking, synaptic strengths are refreshed and maintained in their dedicated or functional ranges largely through use, by virtue of activity-dependent synaptic plasticity. In circuits employed infrequently during waking, synaptic strengths are refreshed largely during sleep, by circuit activations induced by spontaneous, self-generated, largely low-frequency brain waves, also by virtue of activity-dependent synaptic plasticity. The outputs of circuits activated during sleep do not necessarily rise to the level of 'unconscious' awareness. Such an absence of awareness of the outputs of individual circuits, that is, an absence of dreaming, is proposed to be the primitive condition in animals that sleep. On the other hand, temporal binding of these outputs is accompanied by the thoughts and perceptions of dreams, which is proposed to be the advanced condition. Linking or serial ordering of otherwise 'static' thoughts and perceptions gives rise to continuous, often narrative and veridical, dreams. In all cases, dream contents are derived from the memories--not necessarily veridical--encoded in the reinforced circuitry. In the absence of synaptic strength refreshments during sleep, synaptic strengths in infrequently used circuits would weaken and the circuits would become incompetent, with their encoded memories degraded or lost. Maintenance of synaptic strengths in infrequently used circuitry during sleep apparently does not always achieve perfection. Weakened synapses begin to occur in circuits in appreciable numbers in children after the age of about 5 years. When these 'incompetent' circuits (with weakened synapses) are activated during sleep, there are minimal influences on dream contents, namely, distortions that make some objects, such as animals, faces, and scenes, unrecognizable. As weakened synapses increase in numbers with age, the numbers of distorted objects in dreams also increase. In adults, people in as many as 80% of dreams may be unrecognizable. Besides the normal weakening of synaptic strengths, some synapses become defective, in consequence of deleterious, adventitious, exogenous influences, for example, radiation. As these faulty synapses accumulate in old memories, activation of circuits incorporating them during sleep leads to dreams with incoherent, bizarre, or impossible contents. The infrequent activation of such old, incompetent circuits in some waking conditions leads to false memories, delusions, or hallucinations.     

Intercellular protein-protein interactions at synapses

Chemical synapses are asymmetric intercellular junctions through which neurons send nerve impulses to communicate with other neurons or excitable cells. The appropriate formation of synapses, both spatially and temporally, is essential for brain function and depends on the intercellular protein-protein interactions of cell adhesion molecules (CAMs) at synaptic clefts. The CAM proteins link pre- and post-synaptic sites, and play essential roles in promoting synapse formation and maturation, maintaining synapse number and type, accumulating neurotransmitter receptors and ion channels, controlling neuronal differentiation, and even regulating synaptic plasticity directly. Alteration of the interactions of CAMs leads to structural and functional impairments, which results in many neurological disorders, such as autism, Alzheimer’s disease and schizophrenia. Therefore, it is crucial to understand the functions of CAMs during development and in the mature neural system, as well as in the pathogenesis of some neurological disorders. Here, we review the function of the major classes of CAMs, and how dysfunction of CAMs relates to several neurological disorders.