神经系统发育与可塑性Slides 中的部分图和文字引自教材“ Principles of Neurobiology ” ，“ Neuroscience Exploring the Brain ” 以及网络人脑有 1011个神经元 和 1012个神经胶质细胞神经组织由 神经元（ Neuron） 和 神经胶质细胞（ Glia） 构成 。Two contrasting views of brain wiringResonance hypothesisInitial pathways are chosen because of mechanical forces; final connections are selected based on function.Paul A Weiss (1898-1989)Nurture (experience dependent)Roger Sperry (1913-1994)Specific pathways hypothesisAxons are endowed with the ability to choose specific pathwaysNature (genetic specification)Retinal ganglion cells (RGC) in the eye project their axons to optic tectum in an orderly fashion, thus reconstructing the visual image.Sperrys idea (1940s)Facts:Sperrys idea:Will vision be restored, if Sperry severed the RGC axons, rotated the eye by 180 degree and allowed RGC axons to regenerate? In lower vertebrates (e.g. frogs) RGC axons can be severed, allowed for regeneration, and vision can be restored.Sperrys experiments and resultsStriking specificity in retinotectal mapThe combinational code of Eph signalingLemke and Reber. Annu Rev Cell Dev Biol 2005.Eph signal appears working in a short range.Hubel and wiesel, Sci Am 1979.Main visual pathway:RGCLGNVisual cortex(retinal ganglion cells)(lateral geniculate nucleus)Wiesel T, Nature 1982.Visual experience has profound effect on development of binocular visionExpansion of cortical innervation from non-deprived eye at the expense of shrinkage of innervation from deprived eye.Competition from input between both eyesConstantine-Paton and Law, Science 1978.Axons from the third eye would connect to one of the tectum, thus artificially creating competition.Frogs: no binocular vision; all RGCs cross optic chiasm, so left to right tectum and right to left tectum.Create a third eye by transplanting an eye primordium in the right place early in development.Insights from the three-eye frogsYoung Mature Open eye Deprived eyeEarly in development, cortical neurons receive input from both eyesDuring critical period, extensive reorganization occurs that segregates input to eye specific layerDevelopment of ocular dominance columnProblem: ocular dominance columns are already present before eye opening (visual experience) Brain wiring: Nature vs. NurtureInitial axonal pathways are hard-wired (Nature)Final selection of synaptic partners is influenced by activity (Nurture) 可塑性 ：神经连接结构和功能在基因与环境因素的共同作用下调整完善Cellular mechanisms of plasticity可塑性的细胞机制海 蜗 牛 （ Aplysia californica） 海 蜗牛 受刺激 时 ， 会产生 一 个简单 的保 护性反射 动 作 将鳃缩 起來 优点 神经纤维粗 神经细胞少（ 2万） 鳃缩反应明显鳃缩反应虹吸管触觉刺激套膜头 部呼吸器官 (鳃 )强反应 弱反应反应前Gill Withdraw Reflex习惯 化 (habituation)当反复使用一个无害刺激刺激动物，动物对刺激的反应逐渐下降。突触前递质释放减少，突触后受体敏感性没有变化入鲍鱼之肆，久闻而不知其臭；入幽兰之室，久而不闻其香 孔子家语 六本 卷四习惯 化 的电生理记录敏感 化 (sensitization)当动物被给予一个有害刺激，动物不仅对以后的有害刺激反应增强，对其他无害刺激反应也增强。一朝被蛇咬，十年怕井绳敏感 化 电生理记录Classical conditioning 经典条件反射Hebbs ruleEarTongueNoseAB“When an axon in cell A is near enough to excite cell B and repeatedly and persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that As efficacy in firing B is increased”D. O. Hebb (1949)突触可塑性三条突触回路 :内嗅区穿通纤维与齿状回颗粒细胞的轴突（ PP-DG)颗粒细胞发出的苔状纤维的轴突与 CA3区的锥体细胞的树突（ MF-CA3)CA3区的锥体细胞发出薛氏侧枝与 CA1区锥体细胞的树突（ Sch-CA1)SYNAPTIC PLASTICITY MAY INCLUDE: formation or loss of synaptic contacts (developmental) physiological changes in the strength of existing synaptic contacts, over both short and long time frames may involve structural modifications to synapses (structural plasticity)likely critical for refining synaptic connectivity and information storage in neural circuitsLong-Term Potentiation (Depression) LTP is elicited by strong, tetanizing stimulation in specific patterns (i.e. 10 trains of 100Hz);LTD is elicited by low-frequency stimulation over a more prolonged time (i.e. 1Hz for 15 minutes). It is persistent and selective for the stimulated inputs. Broken down into induction and expression/maintenance phases. In vivo evidence for relationship between LTP/LTD and learning/memory.Mechanisms that are important forlong-term plasticity Many forms of LTP/LTD are NMDAreceptor-dependent but some areindependent involve modifications to AMPA receptor trafficking and/or channel function many scaffolding/signaling proteinsknown to be involved may also involve retrograde messengers from the postsynaptic site to modify the presynaptic terminal (i.e. nitric oxide) structural changes to synapses could also be involved (i.e. modifications to dendritic spine shape)Induction of long-term plasticityNMDA receptor acts as a coincident detectorTo activate: need depolarizationMaintenance of long-term plasticity 1. Modulation of AMPA receptor function by phosphorylation and dephosphorylationKinases- S831- conductance; S845 open-channel probabilityMaintenance of long-term plasticity 2. AMPA receptor traffickingMainten