胚胎皮层神经元的迁移及其相关分子机制

在中枢神经系统发育中,皮层神经元的迁移是一个复杂而又被精确调控的过程。胚胎皮层神经元主要有两种迁移方式：来源于背侧端脑的锥体神经元主要采用放射状迁移;而来源于腹侧端脑的中间神经元则采用切线方向迁移进入皮层。其中,在皮层发育早期,锥体神经元直接以胞体位移运动向表面迁移;而在发育晚期,皮层相对较厚时,锥体神经元需借助放射状胶质细胞突起的导向作用迁移到目的部位。     

新皮质的发育与片层化构筑的形成

新皮质由神经上皮经过增殖、分化和神经细胞的迁移后逐步发育而来,新增殖的有丝分裂后神经元沿着放射状胶质细胞按照由内向外的迁移原则在皮质板定居下来。Cajal-Retzius细胞在新皮质发育及片层化过程中起着关键作用,Cajal-Retzius细胞分泌的reelin是迁移中神经元的终止信号和化学趋向信号,reelin的这些功能使得从大脑皮质的细胞构筑和纤维构筑得以形成。     

星型胶质细胞对神经元调控的研究进展

神经系统的细胞主要由神经元和神经胶质细胞组成。人脑中神经元的总数约为1010~1012个。在脑内,神经元被神经胶质细胞紧紧包围,神经胶质细胞数量是神经元的10~50倍,约占据脑体积的一半,其中主要是星型胶质细胞(astrocytes,AS)。在视皮层,AS占整个神经胶质细胞的61·5%;在丘脑占     

Notch在脊椎动物神经发育中作用的研究进展

Notch具有高度保守性,从无脊椎动物到脊椎动物的多个物种中均有表达。在脊椎动物胚胎发育过程中,Notch信号控制神经前体细胞的分化方向、影响神经元突起的延伸、调节神经元迁移和脑区形成。Notch在脊椎动物神经系统中的研究越来越引起人们的重视,尤其是其在哺乳动物新皮质形成过程中的作用研究将有可能从根本上揭示出脊椎动物端脑发育进化的分子机制。     

小鼠放射状胶质细胞和小脑皮质的发育

目的探讨小鼠小脑皮质发育过程中放射状胶质细胞的分化。方法应用免疫荧光及5-溴脱氧尿嘧啶核苷(BrdU)检测技术,标记小鼠胚胎8d至生后180d小脑(57例,分为19组,每组3只)的神经干细胞、放射状胶质细胞、普肯耶细胞及颗粒细胞。结果放射状胶质细胞于胚胎13d的神经上皮出现,尔后该细胞分化为各种神经元和贝格曼胶质细胞,并在小脑皮质层状结构的形成中起着重要作用。结论放射状胶质细胞来源于神经上皮细胞,是神经细胞和神经胶质细胞的前体细胞。在小脑皮质的发育过程中,放射状胶质细胞能分化为普肯耶细胞和颗粒细胞,并为神经细胞的迁移提供路径和支架。     

新皮质神经元移行障碍发病机理的研究进展

神经元移行障碍（neuron migration disorder，NMD）是皮质发育障碍（disorder of cortical developments DCDs）的一种类型，表现为在大脑的不适当位置出现单个或多处神经元和神经胶质细胞形成的灰质块，常出现在脑室周围、深部白质、皮质下白质和软脑膜。其表面的大脑皮质可正常或者表现为细胞层次或细胞结构的紊乱。临床表现主要为难治性癫痫、智力障碍和精神发育迟缓。     

新生儿皮质第一层PV免疫反应Cajal-Retzius和非Cajal-Retzius神经元的分布

目的　研究Cajal Retzius(CR)和非Cajal Retzius(NCR)神经元在新生儿大脑 13个皮质区的分布、相应密度和可能的亚型。方法　采用免疫组织化学方法检测新生儿大脑皮质神经元数目及分布。结果　 (1)PV免疫反应阳性CR细胞见于所有的新皮质区 ,这些区域在第一层深部也发现PV ir水平纤维丛。 (2 )许多PV irCR细胞显示退行性变的明显标志。 (3)除大的CR细胞外 ,小的PV irNCR神经元也出现在新皮质区。它们包括不同的形态学种类 ,可以区分为几种亚型。结论　NCR细胞高密度地出现于第一感觉区 3、1、17和 4 1区。由于PV irNCR细胞密度在各区的差异 ,PV irCR与PV irNCR的比率在第一感觉区相对较低。目前对出生早期大鼠躯体感觉皮质的研究报道第一层存在复杂的相关的神经元间自发作用的时空模式。一个很大的可能性就是区域多样的神经元活性可能在不同脑区皮质环路中起主要作用。     

成年大鼠去皮层血管引起前脑室下区祖细胞增殖迁移并形成迁移路至损伤部位(二)来自背外侧脑室下区的祖细胞形成迁移路经胼胝体至损伤部位

近年来很多实验证明各种脑损伤和中枢神经疾病都能促进神经干细胞或祖细胞向非嗅球区域迁移,本研究将成年大鼠一侧大脑皮层血管去除,用免疫组化方法标记前脑室下区正在分裂的细胞、神经元祖细胞和胶质细胞祖细胞。结果证明:损伤侧及对侧的背外侧脑室下区各类祖细胞明显增多并向胼胝体迁移,在胼胝体内它们分别形成迁移路至损伤部位;迁移路内的各种祖细胞具有典型的不成熟的迁移细胞特点,胞体细长,一般首尾各有一突起,其引导突皆朝向损伤区。本研究结果提示去皮层血管增殖的前脑室下区神经元祖细胞和胶质细胞祖细胞通过放射状迁移路至损伤部位可能参与修复机制。     

bHLH转录因子与大脑皮质祖细胞分化

在大脑新皮质发育过程中 ,bHLH转录调控因子 (basichelix loop helixtranscripitionfactor)参与调节大脑皮质多能祖细胞的分化。前神经bHLH因子 (Mash1,Neurogenin1,andNeurogenin2 )活性增强和Hes、Id因子的活性相应的减弱引起皮质多能祖细胞由增殖状态向神经生成转变。神经元形成后 ,Hes因子的激活促进星形胶质细胞的分化 ,而前神经bHLH因子Ngn抑制星形胶质细胞的分化。bHLH因子Olig1和Olig2活性的增加和Id活性的减弱启动了少突胶质细胞的形成。     

缺氧致新生小鼠脑发育异常的形态学研究

目的:建立新生小鼠缺氧模型,观察缺氧后大脑中认知相关脑区主要神经细胞类型在发育期的变化特征。方法:新生2 d的仔鼠在10%氧环境连续饲养5 d,之后放回正常氧环境,并在发育阶段不同时间点取材。利用免疫荧光组织化学比较小鼠缺氧后胼胝体(CC)和运动皮质(M1)中少突胶质细胞密度、成熟少突胶质细胞的比率、髓鞘蛋白水平的变化,以及前扣带回皮质(ACC)、海马(Hippo)、感觉皮质(S1)中兴奋性神经元、抑制性神经元的表达变化。进一步比较ACC中不同类型抑制性中间神经元、小胶质细胞、星形胶质细胞的密度变化特征。同时,还检测了缺氧对突触蛋白表达的影响。结果:免疫荧光定量检测结果显示：与对照组相比,缺氧小鼠CC、M1中髓鞘蛋白表达水平,成熟少突胶质细胞的比率均降低;ACC中兴奋性神经元的数量无显著差异,而ACC、Hippo以及S1的γ-氨基丁酸(GABA)标记的抑制性神经元的数量显著降低;ACC中小清蛋白阳性(PV⁺)神经元、生长抑素阳性(SST⁺)神经元和血管活性肠多肽阳性(VIP⁺)神经元的数量均显著减少;缺氧小鼠ACC中囊泡...     

Dual origin of the mammalian neocortex and evolution of the cortical plate

Summary A Golgi study of the structural organization of the early developmental stages of the cerebral cortex of the cat has been presented. It has been demonstrated that the structural organization of the mammalian neocortex undergoes a series of fundamental transformations in the course of its early embryonic development. A clear understanding of these early structural changes is essential to comprehend the multi-layered nature of the mammalian cerebral cortex. In order of appearance the following basic transformations have been recognized in mammalian cortical ontogenesis. A. The first recognizable change in the undifferentiated neuroepithelial structure of the cerebral vesicle is the arrival and penetration of corticipetal fibers through its superficial region. The penetration of these afferent fibers into the cerebral vesicle forms a clear plexiform region under the pial surface just above the matrix zone. This clear plexiform region corresponds to the classical marginal zone and is composed, at first, of corticipetal fibers and their collaterals. B. The arrival of these corticipetal fibers induces maturation of some neurons. Primitive-looking and still-developing neurons begin to appear scattered among the afferent fibers without forming any distinct lamination. This combination of an external white matter of afferent fibers with scattered neurons among the fibers has been named the primordial plexiform layer of the mammalian cerebral cortex. Its structure represents a primitive type of nervous organization which is reminiscent of the amphibian brain. In mammalian cortical ontogenesis this primitive plexiform layer has a short duration and it is established as a distinct structure prior to the appearance of the cortical plate. C. The appearance and the formation of the cortical plate within the primordial plexiform layer results in the separation of its neurons and fibers into a superficial and a deep plexiform lamination. Structural and functional interrelationships soon start to develop between the neuronal elements of the superficial and the deep plexiform laminations establishing the primordial neocortical organization, which is characterized by specific types of neurons and fibers. Its structural organization resembles somewhat that of the cerebral cortex of some reptiles. It is important to emphasize that the neurons and fibers of this primordial neocortical organization persist and become components of the adult cerebral cortex. The superficial plexiform becomes layer I and the deep lamination becomes layer VII of the adult mammalian cerebral cortex. Therefore, the cortical plate represents the primordium of only layers VI, V, IV, III, and II of the adult cerebral cortex. The cortical plate is considered to be a distinct mammalian structure of a more recent phylogenetic origin. D. The last significant transformation consists of the sequential growth and maturation of the cortical plate which follows an inside-out progression. The maturation of the neurons of the cortical plate and hence the formation of its laminations seems to be due to the sequential and progressive arrival of corticipetal fibers which takes place during the late embryonic stages of development.According to these observations the mammalian cerebral cortex has a double origin and a possible dual nature. A new interpretation of the basic structural organization of the mammalian neocortex based primarily on this dual nature is introduced and analyzed in this communication. It proposes new ideas concerning the origin, the embryonic development, and the phylogenetic evolution of the mammalian cerebral cortex which differ somewhat from the classical conceptions of cortical development.This work has been supported by the National Institute of Child Health and Human Development Grant no. 09274.     

Reelin, Rap1 and N-cadherin orient the migration of multipolar neurons in the developing neocortex

Projection neurons migrate from the ventricular zone to the neocortical plate during the development of the mouse brain. Their overall movement is radial, but they become multipolar and move nonradially in the intermediate zone. Here we show that Reelin, the Rap1 GTPase and N-cadherin (NCad) are important for multipolar neurons to polarize their migration toward the cortical plate. Inhibition and rescue experiments indicated that Reelin regulates migration through Rap1 and Akt, and that the Rap1-regulated GTPases RalA, RalB, Rac1 and Cdc42 are also involved. We found that Rap1 regulated the plasma membrane localization of NCad and NCad rescued radial polarization when Rap1 was inhibited. However, inhibition of Rap1 or NCad had little effect on glia-dependent locomotion. We propose a multistep mechanism in which Reelin activates Rap1, Rap1 upregulates NCad, and NCad is needed to orient cell migration.     

Reelin在中枢神经系统进化过程中的作用

目的探讨Reelin在中枢神经系统进化过程中所起的作用及其调节机制。方法取Reelin基因缺失小鼠(Reeler)和野生小鼠(WT),胚龄16d(E16)至出生30d(P30)各年龄点,共192例。利用免疫荧光技术与5’-溴脱氧尿嘧啶核苷(Brd U)法,检测两组小鼠中大脑皮质、海马、脊髓发育过程中放射状胶质细胞、神经干细胞、增殖细胞及星形胶质细胞的表达,并使用Nissl染色技术,分别对脊髓、海马、大脑皮质的组织学特征进行观察。结果脊髓发育过程中,神经细胞仅发生1次迁移,并形成套层,套层进而衍变成呈H型脊髓灰质。与野生型小鼠相比,同年龄Reelin基因缺失小鼠(Reeler小鼠)在形态结构、细胞迁移方面与野生型小鼠基本类似,但增殖的神经细胞数目明显减少。在第1次迁移的基础上,海马的形成还需经历第2次神经细胞迁移,最终形成了双"C"字型结构的锥体细胞层和颗粒细胞层;与野生型小鼠相比,在形态上Reeler小鼠锥体细胞层明显扩散劈裂为两层,齿状回颗粒层细胞明显增殖并向门区迁移以致颗粒层与门区的界限消失,形成鼓槌状结构;同时,增殖的神经细胞数目减少,放射状胶质细胞排列紊乱。新皮质的形成也需经历两次迁移,但第2次神经细胞迁移所形成的皮质板按照由内向外的迁移方式继续发育为界限清晰的6层结构;与野生型小鼠相比,同年龄点Reeler小鼠新皮质片层化结构紊乱,增殖的神经细胞和放射状胶质细胞数目均有所减少,并且放射状胶质细胞排列紊乱。结论脊髓、海马和新皮质分别代表了进化过程中的管状神经、古皮质和新皮质,Reelin可能是皮质进化的关键分子。Reelin参与了第2次迁移以及新皮质皮质板的继续分层,Reelin缺失可以引起上述皮质形态和结构的变化,尤其是古皮质和新皮质。     

The evolution of the mammalian Y chromosome

There is a predominant theory for the evolution of the mammalian Y chromosome. This theory hypothesizes that genes for sex determination and male-specific traits, as well as sequences for X-Y meiotic pairing, are conserved on the mammalian Y chromosome across all lineages and that all other Y chromosomal genes or sequences have been or will be lost in each mammalian lineage. There are effects of mouse Y chromosomal genes on behaviors and other traits that are not male specific. Under the predominant theory, these Y chromosomal genes could be the same as the conserved genes for sex determination or malespecific traits, or they could be genes that have been lost from the Y chromosomes of other mammalian lineages and that will eventually be lost from the Y chromosome of the rodent lineage. Recently, the evolution of the primate and rodent Y chromosomes has been studied at the DNA level. These studies are summarized and reviewed in this article. The findings of these studies are not fully consistent with the predominant theory for the evolution of the mammalian Y chromosome. Also, they imply that there are other possibilities for the phylogenetic history of Y chromosomal genes of mice with effects on behavior. These are that Y chromosomal genes with effects on mouse behaviors or other traits could be conserved genes other than those for sex determination or malespecific traits or that they could be novel genes on the Y chromosome of the rodent orMus lineage.     

Quantitative mapping of the local and extrinsic sources of GABA and Reelin to the layer Ia neuropil in the adult rat neocortex

Inputs to apical dendritic tufts have been considered to be crucial for associative learning, attention and similar ‘‘feedback’’ interactions and are located in neocortical layer Ia. Excitatory thalamic projections to apical tufts in layer Ia have been well characterized and their role in the cortical circuit has been emphasized. In addition, the neuropil and the extracellular matrix surrounding apical tufts are highly reactive to GABA and to the glycoprotein Reelin, respectively. Recently it has been shown that the GABA inhibition on apical dendrites can reduce the output of pyramidal cells in layer V, however, the origin of 89 % of the symmetric synapses in layer I still remains unknown. In the present study we have systematically analyzed the origin of the GABAergic neuropil in neocortical layer Ia in a qualitative and quantitative manner, and investigated the possible extrinsic origin of the rich extracellular Reelin content of the same layer. We show that the inhibitory inputs in a given spot in layer I come from cortical projections and arise mainly from Martinotti cells located directly under that same spot. Double bouquet and bipolar cells may also project to layer Ia although to a lesser extent and the external globus pallidus and zona incerta provide the remaining inhibitory inputs. Finally, our results suggest that Martinotti cells are also the main source of Reelin in layer Ia. The present data will help in the understanding of the cortical circuit and why it changes in pathological conditions.     

Morphomolecular neuronal phenotypes in the neocortex reflect phylogenetic relationships among certain mammalian orders

The cytoarchitecture of the cerebral cortex in mammals has been traditionally investigated using Nissl, Golgi, or myelin stains and there are few comparative studies on the relationships between neuronal morphology and neurochemical specialization. Most available studies on neuronal subtypes identified by their molecular and morphologic characteristics have been performed in species commonly used in laboratory research such as the rat, mouse, cat, and macaque monkey, as well as in autopsic human brain specimens. A number of cellular markers, such as neurotransmitters, structural proteins, and calcium-buffering proteins, display a highly specific distribution in distinct classes of neocortical neurons in a large number of mammalian species. In this article, we present an overview of the morphologic characteristics and distribution of three calcium-binding proteins, parvalbumin, calbindin, and calretinin, and of a component of the neuronal cytoskeleton, nonphosphorylated neurofilament protein in the neocortex of various species, representative of the major subdivisions of mammals. The distribution of these neurochemical markers defined several species- and order-specific patterns that permit assessment of the degree to which neuronal morphomolecular specialization, as well as the regional and laminar distribution of distinct cell types in the neocortex, represents derived or ancestral features. In spite of the remarkable diversity in morphologic and cellular organization that occurred during mammalian neocortical evolution, such patterns identified several associations among taxa that closely match their phylogenetic relationships.     

The functional anatomy and evolution of the mammalian humero-ulnar articulation

Major stages in the structural and functional evolution of the mammalian humero-ulnar joint are described on the basis of paleontological and cineradiograhic evidence. In pelycosaurs (the earliest known fossil reptiles with mammalian affinities), the humerus projected laterad and more or less horizontally; locomotor movements were principally rotation about its proximodistal axis. Because the forearm moved in a plane perpendicular to this axis, the flexed elbow was subjected to substantial torque. The humero-ulnar joint consisted of two pairs of facets that engaged upon humeral rotation and was principally a stabilizing rather than a flexion-extension mechanism. Cynodonts (advanced mammal-like reptiles ancestral to mammals) possessed an ulnar condyle rather than a trochlea. A condylar humero-ulnar articulation, usually with a spiral configuration, was retained by early mammals and persists in slightly modified form among modern prototherians. The spiral joint allows the ulna to extend in a sagittal plane as the humerus rotates, adducts, and elevates. The primitive therian trochlea evolved by enlargement of the intercondylar groove separating the ulnar and radial condyles and by retention of part of the ulnar condyle mechanism. Cineradiography demonstrates the relationship of diverse types of mammalian humero-ulnar joints to limb posture and excursion characteristics.     

Electrophysiological and gene expression profiling of neuronal cell types in mammalian neocortex

It is a challenging question to understand how different neuronal types are organized into a complex architecture in the cortex, an architecture which is also adapted in different regions to subserve very different functions. Recent developments in genetic and molecular techniques have opened up the possibility of using gene expression profiling for neuronal cell typing, with the aim of uncovering novel cell types and the underlying mechanisms which generate and maintain neuronal heterogeneity in the cortex. This review introduces some current ideas about neuronal cell types in the cortex and describes recent approaches to expression profiling for defining cortical neuronal cell types.