神經(jīng)發(fā)生課件

1、腦發(fā)育與神經(jīng)細胞發(fā)生張家興Email: Part I 腦發(fā)育 Brain Development一、外胚層（ectoderm） 神經(jīng)管（neural tube）在受精后第18天，胚胎植入子宮壁，這時胚胎由外胚層、中胚層和內(nèi)胚層組成。外胚層增厚形成神經(jīng)盤(b) 在第 20 天神經(jīng)槽形成(c) 在第 22 天神經(jīng)槽閉合形成神經(jīng)管 (d) 在第 24 天形成：端腦（ telencephalon）、 間腦（diencephalon）、中腦（mesencephalon）、 菱腦（rhombencephalon）The neural plate is induced by signals from adj

2、acent mesodermThe 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神經(jīng)管形成的掃描電鏡圖 前腦泡 頭端：向兩側(cè)膨大，形成左右兩個端腦 尾端：形成間腦中腦泡 中腦菱腦泡 頭段：形成后腦，演化

3、為腦橋和小腦 末段：形成末腦，演化為延髓 第6周 端腦 間腦 中腦 后腦 末腦 神經(jīng)管管腔的演變：前腦泡腔 兩側(cè)的側(cè)腦室和間腦的第3腦室中腦泡腔 中腦導水管菱腦泡腔 第4腦室側(cè)腦室第3腦室導水管第4腦室三、腦發(fā)育畸形（brain malformation）腦小畸形無腦畸形無腦回畸形腦穿通畸形巨腦回畸形Part II 胚胎和胎兒階段腦內(nèi)神經(jīng)發(fā)生Neural Development in Embryo and Fetus增殖（Proliferation）遷移（Migration）分化（Differentiation）聚集（Aggregation）突觸形成（Synaptogenesis）神經(jīng)元死亡（

4、Neuron Death）突觸重排（Synapse Rearrangement）髓鞘化（Myelination）神經(jīng)發(fā)生的八個階段2. 遷移（Migration） 當細胞在室管帶增殖后，遷移就開始了； 遷移的細胞是不成熟的，沒有軸突和樹突之分； 遷移的同時出現(xiàn)細胞分化。A:神經(jīng)細胞遷移過程中,有領(lǐng)先突起。領(lǐng)先突起有分枝,動態(tài)競爭,其中一枝成為主干,帶領(lǐng)細胞體的移動,其后,又不斷重復(fù)分枝競爭,決定細胞移動方向。B:遷移的神經(jīng)細胞也可以原來領(lǐng)先突起的生長錐消失,在細胞體完全相反的一邊長出新的突起,導致細胞180度轉(zhuǎn)向。遷移的神經(jīng)細胞鼠腦室管膜下帶細胞：肌動蛋白絲染綠色微管紅色AB遷移的兩種方法：

5、(1)胞體遷移（Somal migration） (2)膠質(zhì)細胞介導的遷移（Glial-mediated migration）Migration-放射膠質(zhì)細胞（Radial Glia）Radial glial cells act as guide wires for the migration of neuronsRadial Glial Cells: Are They Really Glia?PS: 軟膜表面; MZ: 邊緣帶; CP: 皮質(zhì)板; SP: 底板; IZ: 中間帶; SVZ: 亞室管膜層; VZ: 室管膜層; RG: 輻射狀神經(jīng)膠質(zhì)細胞細胞遷移與大腦皮層的形成（inside-o

6、utside）以小鼠為例。 皮層發(fā)育時先形成內(nèi)層, 后形成靠近邊緣的外層皮層神經(jīng)細胞遷移模式3. 分化（Differentiation）Cortical progenitor cells follow an intrinsic developmental sequence both in vivo and in vitro. A, astrocyte; N, neuron; O, oligodendrocyte; P, progenitor cell 神經(jīng)元命運的確定lateral inhibition跨膜蛋白Delta和Notch的相互作用在神經(jīng)元命運確定中起關(guān)鍵作用。二者相互作用后，Not

7、ch通過一系列反應(yīng)抑制Neuro D和Neurogenin的表達。Neurogenin是激活Delta表達所必需的。誘導細胞分化的因素5. 突觸形成（Synaptogenesis）1 neuron makes up to 1000 synapses with other neuronsSynapse FormationSynapse junction between axon and another neuron (where neurotransmission takes place) composed of presynaptic terminal, synaptic gap and po

8、stsynaptic site(Prokop et al., 1996)Yoshimura, T. et al. J. Neurosci. 2006;26:10626-10630偽足形成（Lamellipodia）短小突起形成軸突（ axon）形成樹突（ dendrites）形成突觸形成神經(jīng)突起 (Neurite)生長錐（Growth Cones）Growth cones crawl forward as they elaborate the axons training behind them. Their extension is controlled by cues in their o

9、utside environment that ultimately direct them toward their appropriate targets生長錐的形成是由骨架網(wǎng)格所含運動蛋白actin 和 肌球蛋白（myosin）介導Major elements of the cytoskeleton： microtubules tubulin polymers provide structure support and act as conveyers microfilaments actin polymers predominantly in growth cone neurofila

10、ments support radial growthMAPs (MAP2, tau) promote assembly and stabilize microtubules(Sanes, Reh, and Harris, 2006)Cytoskeletal components of axons and dendrites differDuring development in primary neuronal cultures: Tau gradually segregates into axons MAP2 segregates into dendrites a combination

11、of protein stability, differential protein sorting, and dendrite-specific transport of MAP2 mRNA are responsible for spatial segregationcourtesy of P. Lein調(diào)節(jié)突起生長的外界因子ECM-associatedlamininfibronectinheparin sulfatesCAMsN-cadherinNCAML1Neurotrophic factors NGFBDNFGDNFNT-3,4BMPInhibitoryCSPGsNG2MAGNogo

12、GuidingsemaphorinsephrinsnetrinsslitsPermissive(Yoshimura, T. et al. J. Neurosci. 2006;26:10626-10630)細胞外基質(zhì) (ECMs)調(diào)節(jié)突起生長的細胞內(nèi)分子機制Factors regulating synapse formation(Goda and Davis, 2003)during neurite outgrowth genes encoding pre and postsynaptic proteins expressed, priming factors released by neuro

13、ns 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 elements (vesicles, receptors) accumulate.synapti

14、c 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 Harris, 2006)(Fletcher et al., J. Neurosci.,

15、 1994)synapse formation in primary hippocampal cellssynapse formation in cat visual cortexSynapse Formation Characterization and AssessmentMicroscopic assessment of synapses(Use of pre and postsynaptic proteins as markers)(Abcam 2007)SYNAPSINpresynaptic vesicle proteinpostsynaptic density protein, P

16、SDGenesis of connection: for exampleThe 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 other cellCommunication via action potential

17、s 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 on the surface of guide cells. Left:

18、 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 l

19、ater, the axon has grown around only guide cells 1 and 3. Sperrys experimentSperry 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 movement

20、s 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 is not based on expe

21、rience.It is innate based on the initial distribution of chemical markers in the brain.一個出生不久男嬰的一只眼睛因為感染被繃帶纏了兩個星期，而導致該眼睛失明。原因在于，在嬰兒視神經(jīng)與腦皮層的目標區(qū)域建立聯(lián)系的關(guān)鍵時刻，被繃帶纏住的那個眼的神經(jīng)元不能發(fā)出正常工作信號，因此它們的目標區(qū)域被其它神經(jīng)元所占據(jù)。The role of the environment6. 死亡（Death）Summary of possible cell death mechanisms for cells in the prolif

22、erative zoneAbout 40-75% of all neurons born in embryonic and fetal development do not survive during migration and differentiationNeuron Death Leads to Synapse RearrangementRelease and uptake of neurotrophic factorsNeurons receiving insufficient neurotropic factor dieAxonal processes complete for l

23、imited neurotrophic factor7. 突觸重排（Synapse Rearrangement）Active synapses likely take up neurotrophic factor that maintains the synapseInactive synapses get too little trophic factor to remain stableThe two input neurons in one eye (top) fire at the same time, this is sufficient to cause the top LGN t

24、arget 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 also that input cells

25、that fire out of sync with the target lose their link.LGNSegregation of ocular dominance columns in cat striate contexInitially 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 inputs from the eyes

26、 segregate into ocular dominance columns in layer IV.Changes in synaptic capacity神經(jīng)元胞體、樹突和別的神經(jīng)元之間形成一定數(shù)目突觸的能力叫“ synaptic capacity”突觸數(shù)目形成能力最高階段在發(fā)育早期，隨后逐漸減少。在恒河猴的視覺皮層減少約50%，減少速度5000個/秒。8. 髓鞘化（Myelination）Myelination lasts for up to 30 YearsBrain Weight During Development and AgingCritical PeriodsPart I

27、I 成年腦內(nèi)神經(jīng)發(fā)生Neurogenesis in Adult BrainThe rise and fall of thecentral dogma of neurobiologyThe 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 resea

28、rch as well as clinical practice.The adult nervous system was considered a perennial tissueThe establishment of the dogma1. 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 (

29、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 SongbirdsHVCHigher Vocal Center Doubles in Size in the S

30、pringWhat 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 neurogenesisLandmarks in neu

31、rogenesis and NSC discoveriesColucci-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. Neurogenesis in the adult human hippocampus. Nat Med 1998;4:13131317.二、Neurogenesis in the Adu