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1、学 习 与 记 忆,Learning & Memory,北京大学 神经科学研究所Neuroscience Research Institute, Peking University,主讲教师: 王韵,Neuroscience,概述 Introduction,Behavior,Genes,Environment,Learning and memory,Beneficial,Harmful,Interesting questionsWhat are major forms of learning?What types of information about the environment are
2、 learned most easily?Do different types of learning give rise to different memory processes?How is memory stored and retrieved?,目录 Contents,概念 Concepts学习及记忆的基本过程 Process of Learning and Memory 学习的基本类型 Ways of Learning 记忆的基本类型 Ways of Memory学习及记忆的突触机制 Synaptic Mechanisms of Memory中枢突触可塑性与学习记忆 Central
3、 Synaptic Plasticity and Learning & Memory学习及记忆的分子机制 Molecular Mechanisms of Memory递质的调节 Regulation of Neurotransmitters,Neuroscience,概念 Concepts,学习(Learning)：the process by which we acquire knowledge about the world via the nerve system 人或动物通过神经系统接受外界环境信息而影响自身行为 记忆(Memory)：the process by which that
4、 knowledge is encoded, stored and later retrieved 获取的信息或经验在脑内贮存和提取(再现)的神经活动过程,Return,Neuroscience,学习与记忆的基本过程 (Process of Learning and Memory),Acquired or encoded 获得(识记或登陆)：感知外界事物或接受外界信息(外界刺激)的阶段，也即通过感觉系统向脑内输入讯号学习过程Consolidated 巩固：获取的信息在脑内编码贮存和保持的阶段Retrieved 再现：将贮存于脑内的信息提取出来使之再现于意识中的过程回忆过程,return,Neu
5、roscience,非联合型学习 Nonassociative learning,学习的基本形式 Ways of Learning,习惯化 habituationrepeat non-noxious stimuli-reduced response敏化 Sensitization-harmful stimulivigorously response to all stimuli,联合型学习 Associative learning,经典式条件反射 Classical conditioned reflex操作性条件反射 Operant conditioned reflex或称器具性条件反射 In
6、strumental conditioned reflex,Return,Neuroscience,记忆的基本形式 Ways of Memory,First OrderMemory,Sensory Memory,外界信息输入,遗忘,（信息丢失）,注意,不重复,遗忘,Second OrderMemory,重复,Third OrderMemory,可能 遗忘,再现,终生不忘,Short-term Memory,Long-term Memory,不注意,Neuroscience,按时程进行分类,记忆时程及其特点的比较,Return,按信息储存和回忆的方式分类陈述性记忆 (declarative me
7、mory )或称外显性记忆(explicit memory)进入意识系统，比较具体，可以清楚地描述非陈述性记忆 (nondeclarative memory )，反射性记忆（reflexive memory）或称内隐性记忆(implicit memory) 无意识成分参加，只涉及刺激顺序的相互关系，贮存各事件间相关联的信息，只有通过程序性的操作过程才能体现出来,Neuroscience,陈述式记忆与非陈述式记忆的区别,脑内记忆系统陈述性记忆的神经回路需要边缘系统参与,大脑皮层V1V2, V3, V4,边缘系统,内侧颞叶 内侧丘脑 腹内侧额叶,基底前脑胆碱能系统,Neuroscience,颞下回
8、,嗅皮层、杏仁复合体和海马,Motimer Mishkin,非陈述性记忆的神经回路边缘系统及运动系统共同参与,大脑皮层,尾 核,苍 白球,运 动系统,丘脑,边 缘系统,伏隔核,VIP,GLu,GABA,GABA,DA,Neuroscience,学习记忆的神经基础 短时记忆与长时记忆是整个记忆过程的不同阶段,具有不同的神经机制短时记忆的读出机制易受影响 长时记忆相对稳定短时记忆神经可塑性变化 长时记忆与脑内某些长期性的功能和结构,新蛋白质的合成,Neuroscience,非联合型学习记忆的机制,记忆的突触机制 Synaptic Mechanisms of Memory,联合型学习记忆的机制,习惯
9、化的机制突触效能减弱敏化的机制突触前易化,时间特异的、活动依赖的突触前易化,Fig,Fig,Fig,Return,Neuroscience,突触效能减弱的机制,习惯化的机制 Mechanisms of hibituation,突触前感觉神经元末梢递质释放量减少,递质释放减少的可能机制,可动员的突触囊泡数目减少,Return,Neuroscience,突触前膜N型Ca2+通道失活,敏化的机制 Mechanisms of Short Term Sensitization,突触前易化的机制,突触前易化使突触效能增强,Gs-protein,ATP,cAMP,PKA激 活,K+ channel关闭,AP
10、 时程 ,Return,AC,Neuroscience,5-HT,感觉神经元5- HTR,中间神经元,K+电导 ,Ca2+内流,N-type Ca2+Channel open,L-type Ca2+Channel open,vesicle mobilized to active zone,Transmitter release,Go-protein,PLC,DAG,PKC,联合型学习的突触机制,Return,Neuroscience,特异的、时间依赖的突触前易化,突触前易化的可能的分子机制,Fig,Fig,Neuroscience,LTP in mossy fiber pathway is n
11、on-NMDA mediated, presynaptic induction, nonassociativeCa2+ influx in presynaptic neuron,cAMPPKA activated,b-adrenergic receptors,adenylyl cyclase,CA3,长时程增强（Long-Term Potentiation, LTP）,海马的长时程增强海马的结构,Modulatory input,LTP in CA1,LTP in CA1 is associative，NMDA receptor dependent, presynatic and postsy
12、naptic inductionTwo features differ from that of LTP in CA3Cooperativity(协同性): requires activation of several afferent axons togetherAssociativity (联合性)：requires concomitant activity in both presynaptic and postsynaptic cells to adequately depolarize the postsynaptic cell,LTP产生的必要条件Activation of syn
13、apseStrong depolarization of postsynaptic cell in CA1引起突触后神经元去极化的条件As high as enough frequencyEPSP temporal summationAs many as enough synapseEPSP spatial summation诱导CA1 LTP产生的突触后因素 postsynatic depolarizaion activation of NMDA receptors influx of Ca2+ activation by Ca2+ of several second-messenger s
14、ystems in the postsynaptic cell,Neuroscience,LTP Has a Transient Early and a Consolidated Late Phase,Early LTP- one stimulus train produces an early, short term phase of LTP, lasting 1-3 hours-No new protein synthesisLate LTP- Four or more trains induce a more persistent phase of LTP that lasts at l
15、east 24 hoursrequires new protein and RNA synthesis,Mechanisms of Early LTP,Activity changes of AMPA receptor,Influx of Na+,Retrograde signal generator,Glu is released from presynaptic cell,AMPA receptor,NMDA receptor,Remove the blockage of Mg2+ to NMDA receptor,Ca2+ influx in postsynaptic cell acti
16、vation of protein kinases,Single train of AP depolarization of the membrane of postsynaptic cell,NO?,Mechanisms of Late LTP,Repeated trains depolarization of the membrane of postsynaptic cell,Remove the blockage of Mg2+ to NMDA receptor,Ca2+ influx in postsynaptic cell,Ca2+/calmodulin,Adenylyl cycla
17、se,cAMP kinase activation,MAP kinase,cAMP,PCREB-1,CRE,Effectors(tPA, BDNF),New synapse,Regulators(C/EBPb),长时程抑制 (Long-term Depression, LTD )CA1区的LTD低频刺激诱导Ca2+解除Mg2+对NMDA受体的阻断作用,Fig,突触蛋白磷酸化,高频刺激,Ca2+i5mm 蛋白激酶,低频刺激,Ca2+i1mm蛋白磷酸酶,LTP,突触蛋白去磷酸化,LTD,Neuroscience,小脑内长时程抑制机制谷氨酸,突触后AMPA受体,细胞内Na+PKC激活,浦肯野细胞去极
18、化,细胞内Ca2+,?,突触后AMPA受体通道开放,Fig,return,Neuroscience,学习记忆的分子基础cAMP 海兔缩鳃反射的习惯化和敏感化过程中cAMP的作用 是关键性的cAMP信号通路在LTP的蛋白合成依赖性时相中起关键性作用 蛋白激酶CaMKII的持续活化对LTP的诱导及维持起重要作用PKA在长时敏化中起重要作用CREB影响长时记忆,Neuroscience,Fig,参与长时敏化的分子链,return,Neuroscience,5-HT,感觉神经元5- HTR,中间神经元,cAMP,PKA,Transmitter Release,MAPK,CREB-2,PCREB-1,U
19、biquitinhydrolase,Persistent activity of PKA,CRE Early,C/EBP,CAAT Late,Growth of new synaptic connections,Similar molecular mechanisms betweenshort term and long term sensitization,Involve changes in the strength of connections at several synaptic sites-sensory and motor neuronsThe increase in the s
20、ynaptic strength of connections is due to the enhanced release of neurotransmitterThey triggered by the same neurotranmitterserotoninThey shared the same key molecules -cAMP and PKA,蛋白质合成：蛋白质抑制剂不影响学习过程，但影响记忆过程学习记忆的分子解剖学基础海兔长时敏化伴随有突触结构的变化感觉神经元突触前活化区数目、范围和囊泡数目感觉神经元突触前的曲张体数目增加，轴突的树状突起增加,Neuroscience,神经
21、递质和神经肽对学习记忆的调节中枢胆碱能系统功能减退影响学习记忆去甲肾上腺素 增强记忆GABA减退记忆ADH：增强记忆阿片肽 :破坏记忆保持,return,Neuroscience,Disorders of learning and Memory and its,Eric Kandel,2000年诺贝尔生理学或医学奖获得者之一,Neuroscience,Neuroscience,Neuroscience,Neuroscience,Neuroscience,Siphon,Sensoryneuron,Motorneuron,Gill muscle,L29,Shock,Neuroscience,ATP,cAMP,Neuroscience,Return,PO4,Neuroscience,
