Part I 脑发育 Brain Development第1页/共79页一、外胚层（ectoderm） 神经管（neural tube）(a)在受精后第在受精后第18天，天，胚胎植入子宫壁，胚胎植入子宫壁，这时胚胎由外胚这时胚胎由外胚层、中胚层和内层、中胚层和内胚层组成外胚胚层组成外胚层增厚形成神经层增厚形成神经盘盘(b) 在第在第 20 天神经天神经槽形成槽形成第2页/共79页(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）第3页/共79页- The neural plate is induced by signals from adjacent mesoderm- The 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 plateneural grooveneural foldneural tubeneural tube神经管形成的扫描电镜图第4页/共79页 脑起源于神经管的头段脑起源于神经管的头段1.脑泡的形成和外形的演变脑泡的形成和外形的演变 第第4周末，神经管头段周末，神经管头段形成三个膨大的脑泡形成三个膨大的脑泡(brain vesicle)，分别为前脑泡、中脑泡和菱脑泡。
分别为前脑泡、中脑泡和菱脑泡 二、脑的发生 第4 4周 前脑 中脑 菱脑 脊髓 头曲颈曲第5页/共79页 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 6周 端脑 间脑 中脑 后脑 末脑 第6页/共79页神经管管腔的演变：前脑泡腔 两侧的侧脑室和间脑的第3 3脑室中脑泡腔 中脑导水管菱脑泡腔 第4 4脑室侧脑室第3 3脑室导水管第4 4脑室第7页/共79页注意沟 （sulci和回（gyri）的出现时间脑发育动态过程第8页/共79页三、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第9页/共79页Part II 胚胎和胎儿阶段脑内神经发生Neural Development in Embryo and Fetus第10页/共79页1. 增殖（增殖（Proliferation）2. 迁移（迁移（Migration）3. 分化（分化（Differentiation）4. 聚集（聚集（Aggregation）5. 突触形成（突触形成（Synaptogenesis）6. 神经元死亡（神经元死亡（Neuron Death）7. 突触重排（突触重排（Synapse Rearrangement）8. 髓鞘化（髓鞘化（Myelination）神经发生的八个阶段第11页/共79页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第12页/共79页2. 迁移（Migration） 当细胞在室管带增殖后，迁移就开始了； 迁移的细胞是不成熟的，没有轴突和树突之分； 迁移的同时出现细胞分化。
第13页/共79页A:A:神经细胞迁移过程中神经细胞迁移过程中, ,有领先突起领先突起有分枝有领先突起领先突起有分枝, ,动态竞争动态竞争, ,其中一其中一枝成为主干枝成为主干, ,带领细胞体的移动带领细胞体的移动, ,其后其后, ,又不断重复分枝竞争又不断重复分枝竞争, ,决定细胞移决定细胞移动方向B:B:迁移的神经细胞也可以原来领先突起的生长锥消失迁移的神经细胞也可以原来领先突起的生长锥消失, ,在细胞体完全相反在细胞体完全相反的一边长出新的突起的一边长出新的突起, ,导致细胞导致细胞180180度转向迁移的神经细胞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A AB B第14页/共79页 神经管内迁移的两种类型： (1) 放射状迁移 (2) 水平迁移第15页/共79页迁移的两种方法： (1)胞体迁移（Somal migration） (2)胶质细胞介导的迁移（Glial-mediated migration）第16页/共79页Migration-放射胶质细胞（Radial Glia）Radial glial cells act as guide wires for the migration of neurons第17页/共79页Radial Glial Cells: Are They Really Glia?第18页/共79页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）第19页/共79页以小鼠为例。
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第20页/共79页3. 分化（Differentiation）第21页/共79页- 细胞分化：细胞表现出神经元特征的过程细胞分化：细胞表现出神经元特征的过程 神经前体细胞（神经前体细胞（neuroblast）首先发出突起（）首先发出突起（ neurites），在），在它到达最终固定位置时已经分化完成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树突数目在后期具有可变性，这有赖于环境的变化可变性，这有赖于环境的变化 第22页/共79页Cortical progenitor cells follow an intrinsic developmental sequence both in vivo and in vitro. A, astrocyte; N, neuron; O, oligodendrocyte; P, progenitor cell 第23页/共79页神经元命运的确定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第24页/共79页4. 聚集（Aggregation）Like neurons move together and form layers第25页/共79页5. 突触形成（Synaptogenesis）1 neuron makes up to 1000 synapses with other neurons第26页/共79页Synapse Formation第27页/共79页Synapse junction between axon and another neuron (where neurotransmission takes place) composed of presynaptic terminal, synaptic gap and postsynaptic site(Prokop et al., 1996)第28页/共79页Yoshimura, T. et al. J. Neurosci. 2006;26:10626-106301. 伪足形成（伪足形成（Lamellipodia）2. 短小突起形成短小突起形成3. 轴突（轴突（ axon）形成）形成4. 树突（树突（ dendrites）形成）形成5. 突触形成突触形成神经突起 (Neurite)第29页/共79页生长锥（Growth Cones）Growth cones crawl forward as they elaborate the axons training behind them. Their extension is controlled by cues in their outside environment that ultimately direct them toward their appropriate targets第30页/共79页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）介导第31页/共79页Major elements of the cytoskeleton： microtubules tubulin polymers provide structure support and act as conveyers microfilaments actin polymers predominantly in growth cone neurofilaments support radial growthMAPs (MAP2, tau) promote assembly and stabilize microtubules(Sanes, Reh, and Harris, 2006)第32页/共79页Cytoskeletal components of axons and dendrites differDuring development in primary neuronal cultures: Tau gradually segregates into axons MAP2 segregates into dendrites a combination of protein stability, differential protein sorting, and dendrite-specific transport of MAP2 mRNA are responsible for spatial segregationcourtesy of P. Lein第33页/共79页调节突起生长的外界因子ECM-associatedlamininfibronectinheparin sulfatesCAMsN-cadherinNCAML1Neurotrophic factors NGFBDNFGDNFNT-3,4BMPInhibitoryCSPGsNG2MAGNogoGuidingsemaphorinsephrinsnetrinsslitsPermissive第34页/共79页(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第35页/共79页Factors regulating synapse formation(Goda and Davis, 2003)A. during neurite outgrowth genes encoding pre and postsynaptic proteins expressed, priming factors released by neurons and glia (e.g. FGF, Wnts, NTs, cholesterol)B. cell adhesion molecules (e.g. N-CAM, SynCAM) stabilize contact sitesC. differentiation into pre and postsynaptic elements promoted by signaling of neurolignin and Wnt-7 via neurixin and frizzled. Active zone elements (vesicles, receptors) accumulate.D. synaptic vesicles docked and receptors embedded in PSD scaffold.第36页/共79页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 Harris, 2006)01234567020406080100Days in CultureNumber of Synapses/Cell(Fletcher et al., J. Neurosci., 1994)synapse formation in primary hippocampal cellssynapse formation in cat visual cortex第37页/共79页Synapse Formation Characterization and AssessmentMicroscopic assessment of synapses(Use of pre and postsynaptic proteins as markers)(Abcam 2007)SYNAPSINpresynaptic vesicle proteinpostsynaptic density protein, PSD第38页/共79页Genesis of connection: for example第39页/共79页The three phases of pathway formation Pathway selection pathTarget selection structureAddress selection cellThe three phases depends on :1.Direct cell-to-cell contract2.Contract between cells and extracellular secretions of other cell3.Communication via action potentials and synaptic transmission About 100 billion neurons in brain - remarkably precise interconnection among them - to perform the functions of the brain.第40页/共79页Axons locate their target tissues by using chemical attractants (blue) and repellants (orange) located around or 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 molecules (orange). Right: A day later, the axon has grown around only guide cells 1 and 3. 第41页/共79页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 socket. 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.第42页/共79页nThe conclusion from this is that the pattern of connections between retina and tectum, and the movement information represented is not based on experience.nIt is innate based on the initial distribution of chemical markers in the brain.第43页/共79页 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第44页/共79页6. 死亡（Death）第45页/共79页Summary of possible cell death mechanisms for cells in the proliferative zoneAbout 40-75% of all neurons born in embryonic and fetal development do not survive during migration and differentiation第46页/共79页Neuron Death Leads to Synapse RearrangementRelease and uptake of neurotrophic factorsNeurons receiving insufficient neurotropic factor dieAxonal processes complete for limited neurotrophic factor第47页/共79页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第48页/共79页a. The two input neurons in one eye (top) fire at the same time, this is sufficient to cause the top LGN target neuron to fire but not the bottom one. b. 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.c. Over time, neurons that fire together wire together. Notice also that input cells that fire out of sync with the target lose their link.LGN第49页/共79页Segregation of ocular dominance columns in cat striate contexa. Initially the inputs from the LGN serving the eyes (different colour) are intermingled in layer IV.b. Over the course of fetal and early postnatal development, the inputs from the eyes segregate into ocular dominance columns in layer IV.第50页/共79页Changes in synaptic capacity 神经元胞体、树突和别的神经神经元胞体、树突和别的神经元之间形成一定数目突触的能元之间形成一定数目突触的能力叫力叫“ synaptic capacity” 突触数目形成能力最高阶段在突触数目形成能力最高阶段在发育早期，随后逐渐减少。
在发育早期，随后逐渐减少在恒河猴的视觉皮层减少约恒河猴的视觉皮层减少约50%，减少速度减少速度5000个个/秒第51页/共79页8. 髓鞘化（Myelination）第52页/共79页Myelination lasts for up to 30 Years第53页/共79页Brain Weight During Development and Aging第54页/共79页Critical Periods第55页/共79页Part II 成年脑内神经发生成年脑内神经发生Neurogenesis in Adult Brain第56页/共79页The rise and fall of thecentral dogma of neurobiology第57页/共79页 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 applied neuroscience research as well as clinical practice. The adult nervous system was considered a perennial tissueThe establishment of the dogma第58页/共79页1. Clinical2. Related to neural functions3. Related to the theory of learning and memory4. Technical and experimental (1) Specific diffusible glycoproteins：NGF、bFGF or FGF2、PDGF (2) Specific cellular markers: NSE, GFAP (3) 5-bromo-2-deoxyuridine (BrdU) (4) New techniques: fluorescent and confocal microscopy (5) Gene transferBioessays. 2008 Feb;30(2):135-45.Colucci-DAmato L, di Porzio U. Bioessays. 2008 Feb;30(2):135-45 第59页/共79页SongbirdsHVCHigher Vocal Center Doubles in Size in the Spring第60页/共79页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第61页/共79页一、History of adult neurogenesis第62页/共79页Landmarks in neurogenesis and NSC discoveriesColucci-DAmato L, di Porzio U. Bioessays. 2008;30(2):135-45 第63页/共79页 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. Neurogenesis in the adult human hippocampus. Nat Med 1998;4:13131317.第64页/共79页二、Neurogenesis in the Adult Rodent Brain室管下区（subventricular zone，SVZ）颗粒下层（subgranular zone，SGZ）第65页/共79页1. Neurogenesis in adult SGZ layer第66页/共79页第67页/共79页第68页/共79页2.Neurogenesis in the SVZE, ependymal cell ; RMS, rostralmigratory stream 第69页/共79页第70页/共79页第71页/共79页G, glomeruli of the olfactory bulb; LV, lateral ventricle.Theo Hagg,TRENDS in Neurosciences28, 589.20053.Molecular regulation of adult CNS neurogenesis:第72页/共79页Overlapping neurotransmitter systems could contribute to the creation of neurogenic niches. Dense dopaminergic and noradrenergic projections overlap (yellow) with dense 5-HT-releasing (serotonergic) 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.第73页/共79页Molecular regulators of adult CNS neurogenesis第74页/共79页4.Glial influences on neural stem cell development: cellular niches for adult neurogenesis第75页/共79页5.Genetic and Environmental Regulation of Subgranular Zone Neurogenesis and Their Correlation with Cognition第76页/共79页第77页/共79页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第78页/共79页感谢您的观看！第79页/共79页。