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1、脑发育与神经细胞发生,Part I 脑发育 Brain Development,一、外胚层（ectoderm）神经管（neural tube）,在受精后第18天，胚胎植入子宫壁，这时胚胎由外胚层、中胚层和内胚层组成。外胚层增厚形成神经盘(b)在第 20 天神经槽形成,(c)在第 22 天神经槽闭合形成神经管(d)在第 24 天形成：端脑（telencephalon）、间脑（diencephalon）、中脑（mesencephalon）、菱脑（rhombencephalon）,The neural plate is induced by signals from adjacent mesoder
2、mThe neural plate is patterned along its dorso-ventral axis by signals from adjacent non-neural cells The ventral NT the notochord The dorsal NT the epidermal ectoderm,neural plate,neural groove,neural fold,neural tube,neural tube,神经管形成的扫描电镜图,脑起源于神经管的头段1.脑泡的形成和外形的演变 第4周末，神经管头段形成三个膨大的脑泡(brain vesicle
3、)，分别为前脑泡、中脑泡和菱脑泡。,二、脑的发生,前脑泡 头端：向两侧膨大，形成左右两个端脑 尾端：形成间脑中脑泡 中脑菱脑泡 头段：形成后脑，演化为脑桥和小脑 末段：形成末脑，演化为延髓,第6周 端脑 间脑 中脑 后脑 末脑,神经管管腔的演变：前脑泡腔 两侧的侧脑室和间脑的第3脑室中脑泡腔 中脑导水管菱脑泡腔 第4脑室,注意沟（sulci和回（gyri）的出现时间,脑发育动态过程,三、脑发育畸形（brain malformation）,脑小畸形,无脑畸形,无脑回畸形,脑穿通畸形,巨脑回畸形,Part II 胚胎和胎儿阶段脑内神经发生Neural Development in Embryo a
4、nd Fetus,增殖（Proliferation）迁移（Migration）分化（Differentiation）聚集（Aggregation）突触形成（Synaptogenesis）神经元死亡（Neuron Death）突触重排（Synapse Rearrangement）髓鞘化（Myelination）,神经发生的八个阶段,1.增殖（Proliferation）,在室管带（ventricular zone）发生增殖速率：250000个/分钟,Begins with neural tube closure,2.迁移（Migration）,当细胞在室管带增殖后，迁移就开始了；迁移的细胞是不成
5、熟的，没有轴突和树突之分；迁移的同时出现细胞分化。,A:神经细胞迁移过程中,有领先突起。领先突起有分枝,动态竞争,其中一枝成为主干,带领细胞体的移动,其后,又不断重复分枝竞争,决定细胞移动方向。B:迁移的神经细胞也可以原来领先突起的生长锥消失,在细胞体完全相反的一边长出新的突起,导致细胞180度转向。,迁移的神经细胞,鼠脑室管膜下带细胞：肌动蛋白丝染绿色微管红色,神经管内迁移的两种类型：(1)放射状迁移(2)水平迁移,迁移的两种方法：(1)胞体迁移（Somal migration）(2)胶质细胞介导的迁移（Glial-mediated migration）,Migration-放射胶质细胞（R
6、adial Glia）,Radial glial cells act as guide wires for the migration of neurons,Radial Glial Cells:Are They Really Glia?,PS:软膜表面;MZ:边缘带;CP:皮质板;SP:底板;IZ:中间带;SVZ:亚室管膜层;VZ:室管膜层;RG:辐射状神经胶质细胞,细胞迁移与大脑皮层的形成（inside-outside）,以小鼠为例。皮层发育时先形成内层,后形成靠近边缘的外层,皮层神经细胞迁移模式,3.分化（Differentiation）,细胞分化：细胞表现出神经元特征的过程。神经前体细
7、胞（neuroblast）首先发出突起（neurites），在它到达最终固定位置时已经分化完成。树突数目在后期具有可变性，这有赖于环境的变化。,Cortical progenitor cells follow an intrinsic developmental sequence both in vivo and in vitro.,A,astrocyte;N,neuron;O,oligodendrocyte;P,progenitor cell,神经元命运的确定lateral inhibition跨膜蛋白Delta和Notch的相互作用在神经元命运确定中起关键作用。二者相互作用后，Notch通
8、过一系列反应抑制Neuro D和Neurogenin的表达。Neurogenin是激活Delta表达所必需的。,诱导细胞分化的因素,4.聚集（Aggregation）,Like neurons move together and form layers,5.突触形成（Synaptogenesis）,1 neuron makes up to 1000 synapses with other neurons,Synapse Formation,Synapse junction between axon and another neuron(where neurotransmission takes
9、 place)composed of presynaptic terminal,synaptic gap and postsynaptic site,(Prokop et al.,1996),Yoshimura,T.et al.J.Neurosci.2006;26:10626-10630,伪足形成（Lamellipodia）短小突起形成轴突（axon）形成树突（dendrites）形成突触形成,神经突起(Neurite),生长锥（Growth Cones）,Growth cones crawl forward as they elaborate the axons training behin
10、d them.Their extension is controlled by cues in their outside environment that ultimately direct them toward their appropriate targets,生长锥的形成是由骨架网格所含运动蛋白actin 和 肌球蛋白（myosin）介导,Major elements of the cytoskeleton：microtubules tubulin polymers provide structure support and act as conveyers microfilamen
11、ts actin polymers predominantly in growth cone neurofilaments support radial growthMAPs(MAP2,tau)promote assembly and stabilize microtubules,(Sanes,Reh,and Harris,2006),Cytoskeletal components of axons and dendrites differ,During development in primary neuronal cultures:Tau gradually segregates into
12、 axons MAP2 segregates into dendrites a combination of protein stability,differential protein sorting,and dendrite-specific transport of MAP2 mRNA are responsible for spatial segregation,courtesy of P.Lein,调节突起生长的外界因子,ECM-associatedlamininfibronectinheparin sulfates,CAMsN-cadherinNCAML1,Neurotrophic
13、 factors NGFBDNFGDNFNT-3,4BMP,InhibitoryCSPGsNG2MAGNogo,Guidingsemaphorinsephrinsnetrinsslits,Permissive,(Yoshimura,T.et al.J.Neurosci.2006;26:10626-10630),细胞外基质(ECMs)调节突起生长的细胞内分子机制,Factors regulating synapse formation,(Goda and Davis,2003),during neurite outgrowth genes encoding pre and postsynapti
14、c proteins expressed,priming factors released by neurons and glia(e.g.FGF,Wnts,NTs,cholesterol)cell adhesion molecules(e.g.N-CAM,SynCAM)stabilize contact sitesdifferentiation into pre and postsynaptic elements promoted by signaling of neurolignin and Wnt-7 via neurixin and frizzled.Active zone eleme
15、nts(vesicles,receptors)accumulate.synaptic vesicles docked and receptors embedded in PSD scaffold.,Synaptogenesis the formation of synapses The number of synapses reaches a maximum at about 2 years of age;After this,pruning begins;By 16,only half of the original synapses remain.,(Sanes,Reh,and Harri
16、s,2006),(Fletcher et al.,J.Neurosci.,1994),synapse formation in primary hippocampal cells,synapse formation in cat visual cortex,Synapse Formation Characterization and Assessment,Microscopic assessment of synapses(Use of pre and postsynaptic proteins as markers),(Abcam 2007),SYNAPSIN,presynaptic ves
17、icle protein,postsynaptic density protein,PSD,Genesis of connection:for example,The three phases of pathway formation Pathway selection pathTarget selection structureAddress selection cellThe three phases depends on:Direct cell-to-cell contractContract between cells and extracellular secretions of o
18、ther cellCommunication via action potentials and synaptic transmission,About 100 billion neurons in brain-remarkably precise interconnection among them-to perform the functions of the brain.,Axons locate their target tissues by using chemical attractants(blue)and repellants(orange)located around or
19、on the surface of guide cells.Left:An axon begins to grow toward target tissue.Guide cells 1 and 3 secrete attractants that cause the axon to grow toward them,while guide cell 2 secretes a repellant.Surfaces of guide cells and target tissues also display attractant molecules(blue)and repellant molec
20、ules(orange).Right:A day later,the axon has grown around only guide cells 1 and 3.,Sperrys experiment,Sperry took advantage of the fact that in amphibians,the optic nerve will regrow after it has been interrupted Sperry cut the optic nerve and simultaneously rotated the eye 180 degrees in the eye so
21、cket.In learning movements to catch prey,the part of the retina now looking forward(backward)should connect to the part of the brain which causes forward(backward)movement.,The conclusion from this is that the pattern of connections between retina and tectum,and the movement information represented
22、is not based on experience.It is innate based on the initial distribution of chemical markers in the brain.,一个出生不久男婴的一只眼睛因为感染被绷带缠了两个星期，而导致该眼睛失明。原因在于，在婴儿视神经与脑皮层的目标区域建立联系的关键时刻，被绷带缠住的那个眼的神经元不能发出正常工作信号，因此它们的目标区域被其它神经元所占据。,The role of the environment,6.死亡（Death）,Summary of possible cell death mechanisms
23、for cells in the proliferative zone,About 40-75%of all neurons born in embryonic and fetal development do not survive during migration and differentiation,Neuron Death Leads to Synapse Rearrangement,Release and uptake of neurotrophic factors,Neurons receiving insufficient neurotropic factor die,Axon
24、al processes complete for limited neurotrophic factor,7.突触重排（Synapse Rearrangement）,Active synapses likely take up neurotrophic factor that maintains the synapseInactive synapses get too little trophic factor to remain stable,The two input neurons in one eye(top)fire at the same time,this is suffici
25、ent to cause the top LGN target neuron to fire but not the bottom one.This is the same situation as in part a,except that now the two input neurons in the other eye(bottom)are active simultaneously,causing the bottom target neuron to fire.Over time,neurons that fire together wire together.Notice als
26、o that input cells that fire out of sync with the target lose their link.,LGN,Segregation of ocular dominance columns in cat striate contex,Initially the inputs from the LGN serving the eyes(different colour)are intermingled in layer IV.Over the course of fetal and early postnatal development,the in
27、puts from the eyes segregate into ocular dominance columns in layer IV.,Changes in synaptic capacity,神经元胞体、树突和别的神经元之间形成一定数目突触的能力叫“synaptic capacity”突触数目形成能力最高阶段在发育早期，随后逐渐减少。在恒河猴的视觉皮层减少约50%，减少速度5000个/秒。,8.髓鞘化（Myelination）,Myelination lasts for up to 30 Years,Brain Weight During Development and Aging,
28、Critical Periods,Part II 成年脑内神经发生Neurogenesis in Adult Brain,The rise and fall of thecentral dogma of neurobiology,The belief that,in the adult life,neurons can only die and no new neurons are generated can be regarded as the central dogma of neurobiology,which has strongly influenced basic and appl
29、ied neuroscience research as well as clinical practice.The adult nervous system was considered a perennial tissue,The establishment of the dogma,1.Clinical2.Related to neural functions3.Related to the theory of learning and memory4.Technical and experimental(1)Specific diffusible glycoproteins：NGF、b
30、FGF or FGF2、PDGF(2)Specific cellular markers:NSE,GFAP(3)5-bromo-2-deoxyuridine(BrdU)(4)New techniques:fluorescent and confocal microscopy(5)Gene transfer,Bioessays.2008 Feb;30(2):135-45.,Colucci-DAmato L,di Porzio U.Bioessays.2008 Feb;30(2):135-45,Songbirds,HVC,Higher Vocal Center Doubles in Size in
31、 the Spring,What causes this increase in size?,New neurons are born!What mediates the neurogenesis?TestosteroneTestosterone levels increase with environmental cues of springTestosterone leads to increases in neurotrophic factors and more survival of new neurons,一、History of adult neurogenesis,Landma
32、rks in neurogenesis and NSC discoveries,Colucci-DAmato L,di Porzio U.Bioessays.2008;30(2):135-45,Paton JA,Nottebohm FN.Neurons generated in the adult brain are recruited into functional circuits.Science 1984;225:10461048.Eriksson PS,Perfilieva E,Bjork-Eriksson T,Alborn AM,Nordborg C,et al.Neurogenes
33、is in the adult human hippocampus.Nat Med 1998;4:13131317.,二、Neurogenesis in the Adult Rodent Brain,室管下区（subventricular zone，SVZ）颗粒下层（subgranular zone，SGZ）,1.Neurogenesis in adult SGZ layer,2.Neurogenesis in the SVZ,E,ependymal cell;RMS,rostralmigratory stream,G,glomeruli of the olfactory bulb;LV,la
34、teral ventricle.,Theo Hagg,TRENDS in Neurosciences28,589.2005,3.Molecular regulation of adult CNS neurogenesis:,Overlapping neurotransmitter systems could contribute to the creation of neurogenic niches.Dense dopaminergic and noradrenergic projections overlap(yellow)with dense 5-HT-releasing(seroton
35、ergic)projections predominantly in the neurogenic locations(blue)of the SVZ(a)and dentate gyrus(b).This suggests that cooperation of these neurotransmitter systems contributes to establishment of conditions for neurogenesis in these niches.,Molecular regulators of adult CNS neurogenesis,4.Glial influences on neural stem cell development:cellular niches for adult neurogenesis,5.Genetic and Environmental Regulation of Subgranular Zone Neurogenesis and Their Correlation with Cognition,神经发生的经历哪些阶段?简述成年脑内具有神经发生能力的脑区,
