[目的与要求]：熟悉神经元和神经胶质细胞的功能，掌握反射活动的一般规律以及神经系统在调节机体功能活动（如对感觉的分析、躯体运动和内脏活动等）中的作用，理解和掌握本章的基本概念，从而真正理解神经系统在维持稳态、调节机体各器官系统之间的功能平衡中所起的作用。
[重点]：1.突触的基本结构
2.反射的概念，反射弧中枢部分兴奋的传布和中枢抑制医学教育网
3.丘脑及感觉投射系统（特异性怀非特异性投射系统）
视、听和味觉的代表区，内脏痛的特征与牵涉痛
4.脊休克、屈肌反射与对侧伸肌反射、牵张反射
5.脑干对肌紧张的调节，小脑的功能
6.锥体系与锥体外系
7.交感与副交感神经的结构和功能医学教育网
8.脑电的活动与睡眠机制
[难点]：1.中枢抑制（特别是突触前抑制）
2.牵张反射
3.α与r－僵直 医学教 育网收集整理
4.基底神经节对躯体运动的调节
5.诱发电位产生的机制
[课时]：12学时。
[教材]：理学(5版),姚泰主编,人民卫生出版社,2000,北京
[教具]：多媒体投影仪
案例：某患者，女性，30岁，因有机磷农药中毒入院。请列出患者可能出现的症状、体征，发病机理及治疗原则 资料来源 :医 学 教 育网 。
概 述
一、神经系统的作用与地位
神经系统（Nervous System, NS）是进化的产物；
NS分外周神经系统(Peripheral Nervous System, P和中枢神经系统(Central Nervous System, CNS)。
NS是机体最重要的调节系统（起主导地位）；
脑的工作原理是人类面临的最大挑战。
神经系统的基本功能
1. 协调人体内各系统器官的功能活动， 保证人体内部的完整统一；
2．使人体活动能随时适应外界环境的变化，保 证人体与不断变化的外界环境之间的相对平衡；
3．认识客观世界，改造客观世界。
图10-1：大脑沟回结构
二、NS的组成
由神经元（neuron）与神经胶质细胞(neuroglia)组成
（一）神经元
1．NS结构（见图10-2）
图10-2：神经元
胞体（Soma）（物质合成部位，代谢中心）
突起（Cytoplasic process），分为：
树突（ Dendrite)
轴突(Axon)
轴丘（Axon hillock）
突触小体(synaptic knob)：末梢膨大的部分
始段(initial segment)：轴突起始的部位。
2．基本功能：
① 接受信息 整合信息 传递信息； ②神经-内分泌功能。
3．分类
1）按突起数目：假单极、双极、多极
2）按功能：感觉、运动、联络
3）按所含递质：DA、Ach、NE、5-HT等
4）按对下一级神经元所产生的效应：兴奋性、抑制性
（二）神经胶质细胞
数量为神经元的10~50倍（见图10-3）。
1．类型
1）周围神经：
①施万细胞(Schwann’s cell)，又称神经膜细胞，形成轴突髓鞘
②卫星细胞(Satellite cell)，又称被囊细胞，存在于脊神经节中
2）中枢神经系统：
①星形胶质细胞(Astroglia)
②少突胶质细胞(Oligodendrocyte)
③小胶质细胞(Microglia)
胶质细胞无树突、轴突之分，相邻细胞以缝隙连接相连；胞内外具有膜电位差，且随细胞外K+浓度改变，但不能产生AP。
图10-3：胶质细胞
2．功能
1）支持作用
2）修复和再生作用
3）物质代谢和营养性作用
4）绝缘和屏障作用
5）维持合适的离子浓度
6）摄取和分泌神经递质
7）吞噬作用
Astrocytes are now known to be involved in the most integrated functions of the central nervous system. These functions are not only necessary for the normally working brain but are also critically involved in many pathological conditions, including stroke. Astrocytes may contribute to damage by propagating spreading depression or by sending proapoptotic signals to otherwise healthy tissue via gap junction channels. Astrocytes may also inhibit regeneration by participating in formation of the glial scar. On the other hand, astrocytes are important in neuronal antioxidant defense and secrete growth factors, which probably provide neuroprotection in the acute phase, as well as promoting neurogenesis and regeneration in the chronic phase after injury. A detailed understanding of the astrocytic response, as well as the timing and location of the changes, is necessary to develop effective treatment strategies for stroke patients (Anderson MF, Blomstrand F, Blomstrand C, et al. Astrocytes and stroke: networking for survival? Neurochem Res. 2003 , 28(2):293-305.
三、NS涉及的问题
1．感受器的换能作用（见感官章）
2．神经纤维如何传递信息？（见神经纤维的功能等）
3．中枢神经系统如何分析、整合信息？（见突触的传递，兴奋与抑制）
4．NS如何产生感觉？
5．NS如何调节内脏活动和骨骼肌运动？
6．人类NS活动的特点－即高级神经活动
包括条件反射、心理活动、睡眠与觉醒、语言、思维和记忆等。
第一节 神经纤维
一、概述
（一）组成：神经纤维（nerve fiber，Nf）由神经元胞体上的突起（一般是轴突）延伸而来。
图10-4：神经纤维
（二）神经元的轴浆运输(Axoplasm trasport)
1．特点：
1）双向性：
顺向运输(orthoaxoplasmic transport)：多数神经递质、酶、蛋白质等的运输
逆向运输(antiaxoplasmic transport)：外源性物质、神经营养因子等的运输
可用多种方法来证明为双向运输，如用同位素标记的氨基酸注入蛛网膜下腔（可见氨基酸被胞体摄取胜 胞体 轴突近端 轴突远端），或微电极注入辣根过氧化酶（辣根过氧化酶被轴突末梢摄取 胞体）
2）经常性、普遍性
C、快、慢两种速度:
快者达1-4 μm/s；慢速者仅0.01-0.04 μm/s( 1-2 mm/d)
2． 轴浆运输的功能：
1）运输作用：
提供营养物质；输送神经递质和酶
2）反馈作用：保持功能联系
二、神经纤维的分类
（一）按有无髓鞘分为
1．有髓鞘纤维，如躯体传出纤维
2．无髓鞘纤维，如植物神经节后纤维
（二）根据电生理特性分为
1． A类：包括有髓鞘的躯体传入与躯体传出纤维。
根据其传导速度还可分为Aα、Aβ、Aγ和Aδ。
2． B类(有髓)：植物神经的节前纤维
3． C类(无髓)：植物神经的节后纤维和后根中的痛觉传入纤维
（三）根据纤维直径的大小和来源分为
1．Ⅰ类：又分为Ⅰa和Ⅰb类。相当于Aα
2．Ⅱ类：相当于Aβ、Aγ
3．Ⅲ类：相当于Aδ、B类
4．Ⅳ类：相当于C类
三、功能
（一）传递信息
1． 信息的本质：动作电位（action potential），或称神经冲动（Nerve Impulse）
2． 传导机制
在无髓鞘纤维中以局部电流的形式传导；在有髓鞘纤维中以跳跃式传导。
3． 传导速度与影响因素
1）影响传导的因素
①纤维直径：与直径成正比，横切面越大，纵向阻抗越小，传导越快。
传导速度V(m/s)=6×直径（μm）， 也与轴索和总直径的比值有关，其比值= 0.6时为最适比例
②有髓纤维 > 无髓纤维；
③温度：恒温动物 > 变温动物；
在一定范围内，温度↑时传导速度↑；温度↓时传导速度↓。
⑵ 检测传导速度的临床意义：
①评定周围运动和感觉神经传导功能；
②评定纤维病变的程度：传导速度减慢主要反映髓鞘损害；波幅降低反映轴索损害，严重的髓鞘脱失也可继发轴索损害
③鉴别神经与肌肉的病变：如仅为肌肉病变，则神经纤维传导速度不会发生改变。
4．传导特征：
⑴ 完整性：要求结构和生理功能的完整
⑵ 绝缘性：保证了传导的特异性
⑶ 双向性
⑷ 相对不疲劳性
（二）营养作用
通过轴浆流动→末梢释放某些调节性物质→改变组织内在代谢活动，影响其支配组织的结构和功能，与神经冲动无关。
此外，被支配的组织和胶质细胞也能产生支持神经元的神经营养因子( neurotrophin, NT )，其本质为蛋白质，已分离出的NT有：神经生长因子（NGF）、神经营养因子-3 （NT-3）、神经营养因子4/5 (NT-4/5)和脑源性神经营养因子(BDNF)等。
神经营养因子的运输：
NT作用于神经末梢的特异受体→被末梢摄取→逆向轴浆运输 →胞体。
在神经末梢发现有用种NT的受体：Trk A、Trk B和Trk C。
Nerve growth factor was the first identified protein with anti-apoptotic activity on neurons. This prototypic neurotrophic factor, together with the three structurally and functionally related growth factors brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3) and neurotrophin-4/5 (NT4/5), forms the neurotrophin protein family. Target T cells for neurotrophins include many neurons affected by neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and peripheral polyneuropathies. In addition, the neurotrophins act on neurons affected by other neurological and psychiatric pathologies including ischemia, epilepsy, depression and eating disorders. Work with cell cultures and animal models provided solid support for the hypothesis that neurotrophins prevent neuronal death. While no evidence exists that a lack of neurotrophins underlies the etiology of any neurodegenerative disease, these studies have spurred on hopes that neurotrophins might be useful symptomatic-therapeutic agents. However first clinical trials led to variable results and severe side effects were observed. For future therapeutic use of the neurotrophins it is therefore crucial to expand our knowledge about their physiological functions as well as their pharmacokinetic properties. A major challenge is to develop methods for their application in effective doses and in a precisely timed and localized fashion.
第二节 神经元间的功能联系
——突触传递(synapse transmission)
一、突触的结构与分类
（一）经典的突触概念
突触(synapse)最初是指细胞与细胞之间相互接触并传递信息的部位。因此，广义的突触也包括了神经-肌接头。
1． 涵义：具体到神经系统，突触是指神经元之间相互接触并传递信息的部位。
2． 组成：由一个神经元的轴突然袭击与其它神经元的胞体或突起形成。
3． 结构：电镜下可见突触接触处各有膜分开。轴突末梢的分支膨大构成突触小体，突触小体膜称为突触前膜，与前膜相对应的胞体或突起膜称为突触后膜，两膜之间的间隙称为突触间隙。
图10-5：突触的结构
结构特点：①突触前、后膜比一般的神经元膜增厚约7nm
②间隙较宽，约20~30 nm，其间有粘多糖和糖蛋白
③突触小体内有许多的线粒体和囊泡（囊泡内含递质）
④突触后膜上有相应的受体
注意：①一个神经元的轴突末梢分支形成许多突触小体，与其后的神经元形成突触，所以一个神经元可以通过突触与许多其它神经元构 成联系；
②一个神经元的胞体可接触许多神经元的突触，故一个神经又可接受许多不同种类和不同性质神经元的影响。
4．分类
1）按传递信息物质（性质）：分为化学性突触（经典的突触）、电突触（又称缝隙连接，见图10-5）和混合性突触
2）按突触排列方式：分为交互突触；并联突触；串联突触（见图10-6）
3）按对下一级神经元活动的影响：分为兴奋性突触和抑制性突触
4）按接触的部位：分为轴-树突触；轴-体突触；轴-轴突触；体-体突触等（见图10-7）
图10-6：突触的排列方式 图10-7：突触接触的部位
（二）缝隙连接（gap junction）
除了经典的化学性突触传递外，还存在缝隙连接（见图5）。它与经典的突触相比较，神经元膜紧密接触的部位两层膜间的间隙只有2~3nm，连接部位的神经元膜没有增厚，其它轴浆内无突触小泡聚聚，连接部位的膜阻抗较低，容易发生电紧张性扩布。
这种神经元之间的电传导速度快，几乎不存在潜伏期，可能有助于不同神经元产生同步性放电。
（三）非突触性化学传递（nonsynaptic chemical transmission）
在交感神经节肾上腺素能神经元、5-HT能神经纤维和多巴胺能神经纤维等神经元中，发现其轴突末梢有许多分支，在分支上有大量的结节状曲张体（varicosity），曲张体内含有大量的小泡，是递质释放的部位。曲张小体类似于突触小体，但它不与效应器细胞形成经典的突触，而是处于效应器附近（见图10-8）。
图10-8：交感神经肾上腺素能神经元曲张体
它与经典的突触相比，具有以下特点：
①不存在突触前、后膜的特化结构；
②不存在1：1支配关系，一个曲张体能支配多个效应器细胞；
③曲张体与效应器细胞间隔>20nm；
④递质弥散的距离大，传递耽误时间长，常超过1秒；
⑤递质弥散至效应器细胞，能否产生传递效应决定于效应器细胞上有无相应的受体；
⑥除轴突末梢外，树突和轴突膜均可释放递质。
二、突触传递的机制
（一）突触传递的基本过程
AP抵达轴突末梢→突触前膜去极化→电压门控性Ca2+通道开放→Ca2+内流入突触前膜→突触小泡前移与前膜融合、破裂→递质释放入间隙 弥散与突触后膜特异性受体结合→化学门控性通道开放→突触后膜对某些离子通透性增加→突触后膜电位变化（突触后电位）（去极化或超极化）→总和效应→突触后神经元兴奋或抑制
Ca2+在突触传递中的作用：
①降低轴浆的粘度，有利于突触小泡的位移（降低囊泡上肌动蛋白结合蛋白与肌动蛋白的结合）；
②消除突触前膜内侧的负电位，促进突触小泡和前膜接触、融合和胞裂，促进神经递质的释放
（二）突触后电位（Postsynaptic Potential，PSP）
1．兴奋性突触后电位（excitatory Postsynaptic Potential, EPSP）
1）概念：
兴奋性递质引起突触后膜去极化，下一级神经元容易发生兴奋（AP）,这种电位变化称为EPSP。EPSP具有局部电位的特点：①电紧张性扩布；②等级性电位，即其大小与刺激强度呈正比；③可进行时间和空间上的总和。
2）产生的机制：
兴奋性递质（如Ach）→ 突触后膜受体→ Na+、K+和Cl- 等通道开放→ Na+离子内流>K+和Cl-外流→ 膜内正电荷↑→后膜局部去极化（EPSP）（见图10-8）。
由于神经轴突始段比较细小，形成电流的密度较大，当EPSP总和使膜电位改变达阈电位时，轴突始段的电压门控Na+通道打开→ Na+迅速内流→ 爆发AP
3）传递过程：
AP传至轴突末梢 →前膜PCa2+↑→ Ca2+内流→ 释放兴奋性递质→ 通过间隙 →与后膜受体结合 →后膜PNa+↑ 、PK+↑ 、PCl-↑ (特别是PNa+↑↑)→ 后膜去极化 →EPSP →总和→ AP
2．抑制性突触后电位(inhibitory postsynaptic potential, IPSP)
1）概念：
抑制性递质引起突触后膜超极化，下一级神经元难以发生兴奋（AP），这种电位变化称为IPSP。IPSP也具有局部电位的特点：①电紧张性扩布；②等级性电位，即其大小与刺激强度呈正比；③可进行时间和空间上的总和（总和的结果是使突触后神经元不易兴奋-即抑制）。
2）机制：
抑制性递质→突触后膜Cl-和/或K+通道开放→ K+外流和或Cl-内流→ 膜内正电荷 ↓→膜内外电位差↓→ 后膜局部超极化（IPSP）（见图10-9）。
因为后膜电位远离产生AP的阈电位，不易产生AP→ 抑制。
3）传递过程：
AP传至轴突末梢 →前膜PCa2+↑ →Ca2+内流→ 释放抑制性递质→ 通过间隙→ 与后膜受体结合→ 后膜PK+↑ 和PCl- ↑→后膜超极化 →IPSP。
图10-9：兴奋性突触后电位与抑制性突触后电位
表10-1： EPSP与IPSP主要异同点的比较
（三）突触传递的特征
1． 单向传递（因为只有前膜能释放递质）；
2． 突触延搁；
3． 总和，包括时间性总和和空间性总和；
4． 对内环境变化敏感和易疲劳；
5． 兴奋节律性改变（同一反射活动中传入神经与传出神经发放的频率不一致）；
6． 后放（刺激停止后，传出神经在一定时间内仍发放冲动）。
三、神经递质与受体(neurotransmitter and receptor)
（一）递质（neurotransmitter）
突触前膜释放的化学物质称为递质。
1．神经神经递质的确定条件
1）突触前神经元中合成，有合成递质的 前体和酶系统。
2）递质存在于突触小泡内，受到适宜刺激时，能从突触前神经元释放出来。
3）与突触后膜上的受体结合并产生一定的生理效应。
4）存在使其失活的机制。
5）有特异的受体激动剂和拮抗剂。
2．递质的分类
1）按分泌部位分为：中枢神经递质和外周神经递质
2）按化学性质分为胆碱类、胺类、氨基酸类、肽类、嘌呤类、 脂类和气体类等
3．外周神经递质
1）乙酰胆碱（acetylcholine，Ach）
凡以ACh作为递质的神经元和神经纤维，称为胆碱能神经元和胆碱能纤维。
外周胆碱能纤维包括：①交感神经和副交感神经的神经节前纤维；②大多数副交感神经节后纤维③副交感神经的节后纤维；④少数交感神经节后纤维（汗腺和骨骼肌舒血管）；⑤躯体运动神经纤维（神经-肌接头处）。
2）去甲肾上腺素（noradrenaline，NE）
凡以NE作为递质的神经元和神经纤维，称为肾上腺素能神经元和肾上腺素能纤维。
大部分交感节后纤维均为肾上腺素能纤维。
3）嘌呤类/肽类
目前认为，植物神经系统除胆碱能纤维和肾上腺素能纤维外，可能还有第三类纤维，即嘌呤或肽类递质。
理由：利用阿托品阻断胆碱能纤维和胍乙啶阻断肾上腺素能纤维后，用电刺激肠壁仍可引起其舒张。目前研究得较多的有血管活 性肠肽、胃泌素、生长抑素等。
Receptive and adaptive relaxations of the proximal third of the stomach are reflex responses that enable the stomach to accommodate large volumes with minimal increases in intraluminal pressure. The smooth muscle relaxations are termed non-adrenergic non-cholinergic (NANC). Nitric oxide (NO) and vasoactive intestinal polypeptide (VIP) are considered to be the principal neurotransmitters of NANC relaxation of the rat stomach. NO appears to be mainly responsible for the speed of the relaxation and VIP appears to be responsible for the duration. Studies indicate that inhibitory neurons may also release other neurotransmitters, such as adenosine triphosphate (ATP) and peptide histidine isoleucine (PHI). NANC relaxation of the rat stomach is a complex phenomenon that appears to involve many neurotransmitters, each with a specific role(Curro D, Preziosi P. Non-adrenergic non-cholinergic relaxation of the rat stomach. Gen Pharmacol. 1998;31(5):697-703).
4．中枢递质
因为血-脑屏障的存在，以及中枢神经元种类多、功能复杂等原因，对中枢递质的研究相对缓慢。目前的研究认为主要有4类。
1） Ach
中枢Ach常为兴奋性递质，亦可为抑制性递质，主要存在于：①脊髓前角运动神经元；②丘脑后腹侧特异感觉投射纤维；③脑干网状结构上行激动系统；④尾核、壳核、苍白球；⑤边缘系统（梨状区、杏仁核、海马）等。
2）单胺类
包括多巴胺（Dopamine ，DA）, NE和5-羟色胺（ 5-HT）。
NE主要见于低位脑干（延髓、脑桥等），与维持觉醒状态、情绪和内分泌以及躯体运动等有关；DA主要存在于黑质-纹状体、中脑边缘系统和结节漏斗部分，与躯体运动有关；5-HT集中于中缝核内，与维持觉醒和睡眠状态、情绪和内分泌等有关。
3）氨基酸类
具有兴奋作用的氨基酸，如谷氨酸和门冬氨酸等；
具有抑制作用的氨基酸，如GABA和甘氨酸等。
4）肽类
为发现的最多一类递质，包括：神经降压素，血管活性肠肽，脑肠肽，P物质，胆囊收缩素等。
总之，神经系统发挥作用基本上是通过递质来完成的。长期以来，以为一个神经元的全部神经末梢均释放同一种神经递质（戴尔原则）。近年来发现一个神经元内可以存在两种或两种以上的神经递质，末梢可同时释放两种或两种以上的递质（递质共存）。如：支配唾液腺的副交感（ACh/VIP）和支配输精管的交感（NA/NPY）。
根据神经递质对效应器细胞作用的机制不同，有人提出应区分为递质与调质两类。①神经递质（neurotransmitter）：一般是指通过经典的突触联系作用于效应器细胞的递质物质，它的作用时间快速而短暂，作用于受体后，主要引起离子通道开放，从而产生兴奋或抑制效应（如神经-肌接头处的Ach；②神经调质（neuromodulator）：一般是指通过非经典突触联系的方式作用于效应器细胞的调节性物质，它的作用时间缓慢而较持久（常超过1秒），通过第二信使转而改变膜的兴奋性或其它递质的释放，产生调制传递的效应。此类物质多属肽类物质。
5．递质的代谢
1）合成
主要在胞体合成。如胆碱和乙酰辅酶A在胆碱乙酰移位酶的作用下合成Ach；酷氨酸经羟化酶加上一个羟基后生成多巴，后者经脱羧酶作用脱羧成DA，DA经β-羟化酶作用合成NE；谷氨酸经脱羧酶作用脱羧成GABA等。
2）释放
当神经纤维末梢有AP传来 →PCa2+↑→ Ca2+内流→ 使一定量的小囊泡与突触前膜紧贴融合起来→ 然后出现破裂口→ 递质释放。
3） 失活
递质发挥作用后，随后通过酶解（如Ach被胆碱脂酶水解为胆碱和乙酸）、被血液带走、重新利用等失活。
（二）受体(receptor)
1．概念：
细胞膜或细胞内能与某些化学物质（递质、调质、激素等）特异性结合并诱发生物效应的特殊生物分子，其体质为蛋白质。每一种受体均有其相应的激动剂 （agonist）和拮抗剂（antagonist）。神经递质必须通过与受体结合后才能发挥作用。
图10-10：NMDA受体示意
2．特性：
⑴特异性；⑵饱和性；⑶可逆结合性；⑷活性可变化性，包括反应性↑（致敏现象）或受体数目↑（上调）和反应性↓（脱敏现象）或数目↓（下调）。
3．重要的受体系统
1）胆碱能受体（Ach-R）：
胆碱能受体分为毒蕈碱受体（muscarinic receptor，M-R）和烟碱受体（nicotinic receptor，N-R）两型。①M-R分M1~M5五个亚型。M-R兴奋表现为平滑肌收缩，心脏抑制，消化腺分泌，汗腺分泌和骨骼肌血管舒张等。它可被阿托品阻断。N-R分神经原型烟碱受体（N1）和肌肉型烟碱受体（N2）2个亚型。N1被筒箭毒碱和六烃季铵阻断，N2被筒箭毒碱和十烃季铵阻断。
2）肾上腺素能受体(adrenergic receptor) ：
能与肾上腺素（adrenaline，Adr）和NA结合的受体称为肾上腺素能受体。分a （a1、a2和b（b1、b2 和b3）受体2型。
肾上腺素能受体特征：①肾上腺素能受体与M受体具有高度同源性，结构十分相似，作用机制也通过G蛋白介导；②α受体（主要是α1受体）产生的效应主要是兴奋性的，β受体（主要是β2受体）产生的效应主要是抑制性的；③NA对α受体的作用较β受体强； Adr对α和β受体的作用都强；异丙肾上腺素主要对β受体有强烈作用。
肾上腺素能受体阻断剂：①α受体，酚妥拉明（主要是α1受体）和育亨宾（α2受体 ）；②β受体，普萘洛尔（ β1 、 β2受体）、阿提洛尔（β1受体）和丁氧胺（β2受体）。
3)氨基酸受体
①谷氨酸受体：有促代谢型（metabotropic）glu受体（L-AP4-glu-R、ACPD-glu-R）和促离子型（ionotropic）glu受体（NMDA-glu-R促Na+ 、Ca2+ 内流、K+外流， KA-glu-R,AMPA-glu-R促Na+内流、K +外流）两类受体；②GABA受体： GABA受体分为GABAA（Cl- 通道）和GABAB（促代谢型受体，激活后可增加K+通道的电导）两型。
图10-11：谷氮酸受体结构图 图10-12：GABAA受体
4）阿片样肽受体：有μ（β-内啡肽）、κ 和 δ（强啡肽）三种受体。
5）其它受体系统
嘌呤受体： A受体（A1 A2A A2B A3）- 介导咖啡因和茶碱受体
P受体（P2U、P2X、P2Y、P2Z）。
组胺受体：CNS有H1、 H2 、H3（突触前）
NO、CO等气体分子直接进入细胞，激活鸟苷酸环化酶。
第三节 反射活动的一般规律
一、反射的概念
反射（reflex）是指在中枢神经系统参与下，机体对内外环境变化所产生的规律性的应答反应。分条件反射和非条件反射两种。
要完成反射活动，必须有一个完整的反射弧（reflex arc），反射弧是反射的结构基础。反射弧由感受器、传入神经、中枢、传出神经和效应器5部分组成。
二、中枢内神经元的联络方式
中枢由亿万个神经元组成，根据其在反射弧中所处的部位分为：传入神经元、中间神经元（数目最多）和传出神经元（数目最少）。
（一）神经元之间的联络方式
1．辐散（射）(divergence)
辐射（散）：（多见于感觉传入通路）
1）结构形式：一个神经元的轴突分支与多个神经元发生突触联系（图10-13）。
2）意义：一个神经元的兴奋可引起许多神经元同时兴奋或抑制。
2．聚合（convergence）
（多见于运动传出通路）
1）结构形式：多个神经元与少数或一个神经元发生联系（图10-13）。
2）意义：①使CNS内神经元活动能够集中；②使兴奋或抑制能在后一个神经元上发生总和而及时加强或减弱。
3．链状（Chain）
中间神经元多以此联系。
1）结构形式：一个神经元的轴突分支与多个神经元联系（图10-13）。
2）意义：扩大兴奋；贮存信息。
4．环状（Circuit）
中间神经元多以此联系。
1）结构形式：神经元间构成环路（图10-13）。
2）意义：由于环路联系中神经元的性质种类不同而表现出不同的效应。①如果环路中神经元的生理效应一致，兴奋通过环路传递将加强和延续，因此它是正反馈和后发放的结构基础；②如果环路中有些神经元是抑制性的，则兴奋通过环路后活动将减弱或终止，因而它也是负反馈的结构基础。
图10-13：中枢神经元间的联络方式
（二）单突触反射和多突触反射
1．多突触反射（Monosynaptic reflex）
传入神经元与传出神经元间只有一个突触的反射（见图10-14）。
2．多突触反射（Polysynaptic reflex）
传入神经元与传出神经元间存在一个以上中间神经元参与的反射（见图10-15）。
图10-14：腱反射（单突触反射） 图10-15：疼痛反射（双突触反射）
（三）局部回路神经元和局部神经元回路（Local Circuit Neurons and Local Neuronal Circuit）CNS内短轴突或无轴突的神经元间通过轴突和树突构成联系，而不一定需要整个神经元参与，即可进行整合活动；
与高级神经功能活动密切相关；
可形成传递信号的多种突触方式，如串联性突触、混合性突触等
三、中枢兴奋
中枢兴奋是怎样传递兴奋的呢？已在突触（EPSP）中讲授过（简要复习）。
AP传至轴突末梢→ 前膜PCa2+→ Ca2+内流 →释放兴奋性递质→ 通过间隙→ 与后膜受体结合→ 后膜PNa+↑、PK+↑ 、PCl- ↑(特别是PNa+↑↑ )→ 后膜去极化 EPSP 总和 （后一神经元）AP
附：突触前易化（presynapse facilitation）
突触前易化可以定义为相继的神经冲动触发突触前末梢递质释放量增加，导致突触后电位幅值加大，大体可以分为持续数百毫秒的初级易化和持续数毫秒的强直后电位
可能的机制：
某些因素→突触前AP时程↑→Ca2+内流增多→递质释放↑→去极化↑ →EPSP↑。
四、中枢抑制
（一）概述
如前所述，中枢神经系统内存在着兴奋过程，以及兴奋能从一个神经元传递到另一个神经元。那么，是否也存在着相对应的抑制过程呢？
19世纪中叶，俄罗斯学者谢切诺夫提出了中枢抑制(central inhibition)的概念。他将食盐结晶作用于蛙的间脑部位，观察到食盐刺激间脑能使脊髓支配的下肢屈肌反射明显延长，说明高位中枢的兴奋能抑制低位中枢的反射活动。随后许多实验证明存在着中枢抑制。现在，我们可以这样认为：①在任何反射活动中，中枢内即有兴奋活动，又有抑制活动，且两者都是主动过程；②在某一反射过程中，某些其它反射则受受到抑制，如进行吞咽反射时，反射性地停止呼吸。
因此，由于有抑制的存在，使反射活动能按一定顺序、一定强度地调节机体的活动，从而使反射活动更加协调！所以，抑制和兴奋同等重要。根据中枢抑制产生机制的不同，可分为突触前抑制和突触后抑制。
（一）突触后抑制（postsynaptic inhibition）
1． 概念
神经元信息传递过程中，通过兴奋一个抑制性中间神经元释放抑制性递质，而引起它的下一级神经元突触后膜产生IPSP，致使其活动发生的抑制。
注意：一个兴奋性神经元，不能直接抑制另一个神经元，必须通过先兴奋抑制性中间神经元，从而通过这个抑制性中间神经元来抑制其它神经元。
根据抑制性中间神经元的功能和联系不同，突触后抑制分为传入侧枝性抑制和回返性抑制两类。
2．传入侧枝性抑制（afferent collateral inhibition）
1） 过程
如图10-14乙，传入纤维进入中枢后，一方面兴奋与其直接相连的下一个神经元（假定为伸肌运动神经元），同时发出侧支兴奋抑制性中间神经元，通过抑制性中间神经元来抑制屈肌运动神经元。其反射结果是伸肌收缩，屈肌舒张。
同理，支配屈肌运动的神经元，也可通过其传入侧支兴奋抑制性中间神经元，从而抑制伸肌运动神经元。所以，传入侧枝性抑制又称为交互抑制（reciprocal inhibition）.
图10-16：两类突触后抑制模式图
(2)生理意义
使不同中枢之间的活动相协调
2．回返性抑制(recurrent inhibition)
1)过程
见图10-14甲，某一中枢的神经元（A）兴奋时，其传出冲动沿轴突外传，同时又经轴突侧支兴奋另一抑制性中间神经元（B），后者（B）兴奋时，经其轴突外传到与原来兴奋的运动神经元（A）构成的突触处，释放抑制性递质，使运动神经元（A）超极化。
2） 生理意义：①使神经元活动及时终止；②使同一中枢内各神经元同步活动。
3） 临床意义
脊髓前角支配骨骼肌运动的α神经元与闰绍氏细胞(Renshow cell)之间的关系，就是这种典型例证。当α神经元兴奋时，通过侧支使Renshow cell兴奋，而Renshow cell的侧支又与α神经元构成了突触联系，Renshow cell通过释放甘氨酸使α神经元超极化，从而使反射活动及时终止。Renshow cell释放的甘氨酸可被破伤风毒素破坏→ Renshow cell功能降低→ 降低回返性抑制 →病人出现强烈痉挛。
（二）突触前抑制(presynaptic inhibition)
1.概念：抑制发生在突触前部位，不改变突触后膜兴奋性而使EPSP受到抑制的方式。由于它的发生大多与轴突前末梢的持续去极化发生有关，故又称去极化抑制。
2.过程：
如图10-15所示，三个神经元间形成轴-轴-胞体串联型突触。轴突1与运动神经元3形成兴奋性轴-胞体突触；轴突2（中间性神经元）与轴突1构成轴-轴突触（也是兴奋性突触），轴突2不与运动神经元3直接接触，故不直接影响运动神经元3的活动。
如果轴突2先兴奋，一段时间后轴突1再传来兴奋，此时，轴突1兴奋所引起运动神经元3产生的EPSP比单独轴突1兴奋时所产生的EPSP小。由于产生的EPSP小，不能在运动神经元3的始段爆发AP。
图10-17：突触前抑制
3．原理
因为：⑴突触前膜末梢释放的递质与突触末梢的AP幅度有关，即释放量 ∝ AP的幅度；⑵AP幅度的大小 ∝ 膜电位的高低（AP幅度=RP+超射值）。膜电位高，AP幅度大，递质释放多，EPSP大；膜电位低，AP幅度小，递质释放小，EPSP低。
因此，轴突2兴奋→ 释放递质 →轴突1兴奋→ 轴突1膜电位降低（去极化，EPSP）→ 一段时间后轴突1再传来兴奋→ 轴突1 AP幅度→↓ 递质释放→↓ 兴奋所引起运动神经元3产生的EPSP ↓（不足以产生新的AP）。
4．生理意义
1）调节传入神经的活动（选择性的信息传递）
2）控制传入信息，保证特异性传导。
小结
表10-2： 突触前抑制与突触后抑制的比较
第四节 中枢神经系统的感觉分析功能
Process of Sensory Information in Central Nervous System
感觉是一种心理现象，是客观世界的主观反映，反以它是以生理过程为基础的。
感觉的产生：
图10-18：皮肤的感受器
一、脊髓与脑干感觉传导通路
躯体与内脏的各种感受器冲动（除视、听、嗅和味觉外），均经脊髓上传至大脑皮层（中央后回）。
（一） 传导通路（共有四级神经元参与）
浅感觉：传导痛、温觉和轻触觉
深感觉：深部压觉、肌肉本体觉和辨别觉
1． 浅感觉：一级神经元：脊髓神经节的假单极神经元；
二级神经元：脊髓后角；
三级神经元：丘脑→ 大脑后回。
特点：先交叉再上行；
2． 深感觉：
传入纤维入脊髓（一级）先在同侧后索上行 →延髓薄束核和楔束核（二级）→ 经内侧丘系至对侧丘脑（三级）
特点：先上行（延髓）再交叉。
触压觉、肌肉本体感觉： Aβ类纤维。
温度觉、痛觉和触压觉： Aδ类纤维。
温度觉、痛觉和触压觉： C类纤维。
图10-19：脊髓与脑干传导通
（二）临床意义
1．脊髓半横切（一侧脊髓损伤）后的感觉障碍：
横横切面以下：①对侧浅感觉消失；②同侧深感觉消失；③同侧运动障碍
2．脊髓空洞症
轻度：较易受损的是痛、温觉，而轻触觉不受影响（即痛温觉与触觉分离现象）
重度：双侧痛、温觉与触觉均障碍。
二、丘脑及其投射系统
（一）丘脑的功能
在大脑皮层不发达的动物，丘脑是感觉的高级中枢；在人类，丘脑也起了重要作用。
1． 除嗅觉外，各种感觉神经纤维换元的接替站；
2． 非条件反射的皮层下中枢；
3． 有两大投射系统，与皮层的兴奋有关；
4． 与痛觉有关。
（二）核团
丘脑完成上述功能，靠许多神经细胞完成。根据我国著名的神经生理学家张香桐的意见，丘脑的各种细胞群大致可分为三类。
1．感觉接替核：
作用：接受特异性感觉纤维，换元后投射至大脑皮层的特殊区域。
⑴后外侧腹核：
躯干、四肢感觉→脊髓丘脑束（浅）、内侧丘系（深）→后外 侧腹核 →中央后回
⑵后内侧腹核：
头面部感觉→三叉丘系→后内侧腹核→中央后回
⑶内侧膝状体：
耳蜗→听神经→内侧膝状体→视皮层
⑷外侧膝状体：
视网膜→视神经→外侧膝状体→视皮层
图10-20：丘脑的核团
2． 联络核
作用：起联络作用（协调感觉在丘脑与大脑皮层之间的关系）。
⑴丘脑前核：
下丘脑乳头体→丘脑前核→扣回 （内脏感觉与调节）
⑵丘脑外侧核：
小脑、苍白球、丘脑后腹核→丘脑外侧腹核→皮层运动区（调节肌肉运动）
⑶丘脑枕：
内、外侧膝状体→丘脑枕→顶、枕、颞叶中间联络区（各种感觉联系）
⑷丘脑内侧核：
同上
3．中线核群（髓板内核群）
包括：板内核、中央中核、束旁核、网状核和腹前核等
通过多突触接替，弥漫至大脑皮层广泛区域，提高到层的兴奋性。
（三）丘脑的感觉投射系统
图10-21：感觉投射系统示意图
1．特异性投射系统（specific projection system）
1）特点：①点对点的投射关系；
②与皮层第Ⅳ细胞形成突触；
③倒置分布；
④投射面积与外周感受野有关。
2）功能：①产生特定感觉；
②激发皮层发出冲动，引发相应的反应（骨骼肌活动、内脏反应和情绪反应）。
2．非特异性投射系统（non-specific projection system）
1）特点：①弥漫性投射到大脑皮层的广泛区域，非点对点的投射关系；
②与各皮层细胞形成突触；
③引起锥体细胞去极化作用弱。
2）功能：改变大脑皮层兴奋状态，维持觉醒。
实验依据：①刺激猫脑干网状结构，引起唤醒作用；
②中断中脑头端网状结构，引起昏睡；
③巴比妥类安眠药作用。
通过实验证明，脑干网状结构中存在上行激动系统（脑干结构上行激动系统ascending reticular activating system），通过上行非特异性投射系统来完成对大脑皮层的觉醒作用。
表3： 两大投射系统的比较
三、大脑皮层的感觉代表区
大脑皮层是感觉的最高中枢， 其功能定位即为感觉代表区。
图10-22：不同感觉在大脑皮层的投射
（一）结构特点
1．神经元数量多，联系复杂；
2．皮层分6层；
3．大脑皮层功能单位
—“功能柱”（由6层细胞纵行排列而成）
感觉柱（运动）：主要在中央后（前）回。
特点：①同一柱中神经元功能相同；
②同一柱中联系环路只通过柱中几个神经元接替即可；
③同一柱中是传入、传出整合信息的处理单位；
④一柱兴奋，相邻柱抑制（兴奋-抑制镶嵌模式）。
（二） 皮层分区
1． Brodmann分区：
图10-23：人类大脑皮层分区
52区（1909年），见图10-23。
2．功能法分区：
感觉区、运动区、联络区等
（三）大脑皮层典型功能代表区
方法：诱发电位测定法（图10-24）
图10-24：诱发电位图
1．第一体表感觉区：中央后回（3-1-2区）
特点：①交叉投射，但头部是双侧的；
②倒置投射，但头部是正立的；
③投射范围与外周感受器的灵敏成正比关系（有利进行精确的感觉分析）；
④对感觉有精细的分析功能，能定位。
⑤感觉投射的差异性（轻触觉主要在3区，深感觉主要在1、2区）
2． 第二体表感觉区：
图10-25：各种感觉在中央后的投射
位置：中央前回与岛叶之间
特点：①比较原始，仅对感觉作粗糙分析，主要与痛觉有关；
②双侧投射；
③定位是正立的；
④空间分布较小。
3．本体感觉代表区：
中央前回（4区），刺激该区，引起企图发动肢体运动的主观感觉。
特点：①接受骨骼肌、肌键和关节等处的深部感觉冲动；
②空间分布同第一感觉区（对侧、倒立等）；
③中央前回（本体感觉/运动）与中央后回（感觉）机能上密切联系。
4．内脏感觉区：
分布广泛，与第一、二感觉区有关。
5．听觉代表区：
颞上回、颞横回（41、42区）
特点：双侧性
6、视觉代表区：
枕叶内侧、距状裂上、下缘
枕叶 感受野(视网膜)
左侧 左眼颞侧
右眼鼻侧
右侧 右眼颞侧
左眼鼻侧
距状裂 感受野
上缘 上半视网膜
下缘 下半视网膜
后部 黄斑部
前部 周边部
图10-26：视觉传导通路及在大脑皮层的投射
四、躯体感觉和内脏感觉
图10-27：躯体各种感受器
（一）触压觉
1． 感觉器：感受器点状分布，四肢、尤其是手指较敏感；
2． 传导通路：通过后索与内侧丘系、前外侧系两条通路上行；
触觉与压觉为不同类型感觉，前者为精细感觉。
（二）肌肉本体感觉
1．本体感觉（深部感觉）：包括位置觉和运动觉；
2． 感受器大部分为肌梭，部分为关节及其周围的感受器，
以及触压觉感受器；来自这些感受器的信息传入，在
大脑进行综合，对躯体的空间位置形成一个清晰的图象，从而感知躯体的空间位置、姿势、运动状态和方向。
（三）温度觉
温度觉包括冷、热觉，属浅感觉；
感受器呈点状分布，不均，冷感受器多于温感受器；
（四）痛觉
1．概述
1）疼痛(pain)概念：伤害刺激引起的不愉快的感觉体验，常伴有情绪反应、植物神经反应和防御反应，又称伤害感受（nociception）。
2）意义：保护性反应。
3）痛觉感受器（伤害感受器，nociceptor）：
本质：游离神经末梢
特性：无适宜刺激
4）痛觉分类：
⑴按性质：① 快痛：产生快，消失快，定位精确，感觉鲜明，主由Aδ 传导。②慢痛：
产生和消失慢，定位不明确，感觉不鲜明，常伴有情绪和心血管、呼吸等内脏功能变化，主由C类纤维传导
⑵按部位：①浅表痛（皮肤和粘膜），②深部痛（关节、内脏等）
2．痛觉产生机制
1）致痛物质（图10-28）
2）痛的调节（图29）
3）痛觉上传通路（图10-30）
图10-28：致痛物质 图10-29：闸门学说 图10-30：痛觉的上传通路
3．内脏痛与牵涉痛（visceral pain and referred pain）
1） 内脏痛特点：①属于慢痛（缓慢、持久、定位不精确、对刺激分辩力差）②对切割、烧灼等致皮肤痛不敏感，但对牵拉 、缺血、痉挛等刺激激敏感；③常伴有不安、甚至恐惧感； ④常伴有牵涉痛。
2）牵涉痛（referred pain）：
⑴概念：内脏疾病常引起身体的体表部位发生疼痛或痛觉过敏的现象。
⑵常见的牵涉部位：
表10-4：常见内脏疾病牵涉痛的部位和压痛区
⑶机制
常用会聚学说(convergence theory)和易化学说来解释(facilitation theory)（见图10-31）
图10-31：牵涉痛产生的示意图
A. 会聚易化说示意图
B. 会聚投射说示意图
第五节 脑的电活动与觉醒、睡眠周期
Electric Activity of Brain Waking — leep Cycle
一、皮层诱发电位（evoked cortical potential）
（一） 概念
刺激感觉传入系统→皮层表面记录脑电变化。
（二） 种类
听觉诱发电位
视觉诱发电位
体感诱发电位
（三）主要成分
主反应和后发放
（四） 特性
1． 有一定的潜伏期；
2． 有一定的皮层空间分布；
3． 各种诱发电位的褪讲煌úㄐ筒煌?
二、脑电图electroencephalogram，EEG）
（一）EEG的基本波形
1．α波：8-13Hz，20-100微伏
2．β波：14-30Hz，5-20微伏
3．δ波：0.5-3Hz，20-200微伏
4．θ波：4-7Hz，100-150微伏
（见图10-32）
图10-32：正常ECG的各种波
（二）EEG记录电极分布示意图
图10-33：EEG记录电极分布
（三）EEG形成机制
1．EEG是皮层大量神经元突触后电位总和而形成的场电位；
2．丘脑非特异性的投射系统是脑电活动形成的基础。
三、觉醒与睡眠
（一）觉醒(wake)
1．觉醒反应：
脑电觉醒：
行为觉醒：
2．觉醒维持的机制：
1） 脑干网状结构（Ach）
与中脑蓝斑（NA）与脑电觉醒
2）中脑黑质（DA）与行为觉醒
（二） 睡眠(sleep)
是对环境的认知并起反应能力失的一种复杂的、可逆的、循环的生理和行为过程。
1．睡眠两种时相及其生物学意义：
1）慢波睡眠（slow wave sleep， SWS）
表现 及特征：①感觉功能减退，唤醒阈增高；②骨骼肌反射活动及肌张力减弱，无眼球快速运动，故又称非快眼动睡眠（non-rapid eye movement sleep，NREM）；③内脏活动大都降低，但稳定；④EEG呈示为慢波，故又称为同步化睡眠（synchronize sleep）⑤做梦者少；⑥生长激素分泌增加。
生物学意义：机体生长，体力恢复
2）快波睡眠（fast wave sleep，FWS）
表现及特征：①感觉功能进一步减退，唤醒阈更高；②骨骼肌肌张力进一步减弱，但可出现眼球快速运动，故又称快眼动睡眠（rapid eye movement sleep，REM）；③内脏活动进一步降低，但可出现阵发性呼吸急促，血压增高和四肢抽动；（恶梦，心绞痛，哮喘等发病） ④EEG呈示为快波，又称去同步化睡眠（desynchronize sleep），或异相睡眠；⑤做梦多在此时相；⑥动物研究表明，蛋白质合成增加，新突触形成。
生物学意义：NS发育，学习记忆精力恢复
不利作用：与疾病的发作有关（因为阵发性发现心率加快与心绞痛的发生、阵发性呼吸加快与哮喘的发作有关）。
生理状态下：①慢波睡眠 快波睡眠 慢波睡眠 快波睡眠交替出现，每晚转换4-5次；
②慢波睡眠与快波睡眠均可觉醒，但在生理状态下，觉醒只能由慢波睡眠而来。
2．睡眠发生机制：
1）主动过程：CNS某些脑区发动，上行抑制系统发动
2）参与的神经递质：5-HT（SWS，FWS）、NA（FWS）
剥夺睡眠后将出现：免疫力↓； 情绪变化，易激惹； 注意力↓ ，运动技巧能力↓等。
图10-34：维持觉醒的联络通路
第六节 NS对姿势和运动的调节
The Control of Posture and Locomotion
概 述
躯体运动是人类生活的基本形式，受控于中枢神经系统。运动是动物界最普遍的、并可作为其特征的一种功能。人在生活和劳动中所进行的各种形式的躯体运动，都是以骨骼肌作为基础的。
1．运动和姿势是怎样引起的？
CNS→运动神经元→骨骼肌收缩活动→运动和姿势形成
2．运动是怎样协调的？
运动是骨骼肌舒缩的结果，而肌群的协调性收缩，依赖于CNS、外周感受器（特别是骨骼肌本体感受器）信息传入
3．运动的种类
1） 反射性运动：最简单和基本的运动，由特异性的感觉刺激引起。
2） 随意性运动：达到某一目的而进行的运动，可由感觉刺激，也可因主观愿意而引起。
3）节律性运动（如呼吸、咀嚼、行走）
4．骨骼肌肌纤维种类和本体感受器（右图）
快肌纤维和慢肌纤维：运动和肌张力（姿势）本体感受器：肌梭（并行排列）和腱器官（串行排列）
图10-35：本体感受器示意图
一、 脊髓对躯体运动的调节
（一）脊髓的运动神经元及运动单位
脊髓是躯体体运动最基本的反射中枢。脊髓前角中有α、β、γ三类运动神经元，它们的轴突经前根离开脊髓直达所支配的肌肉。α-神经元大小不等，可有几千个突触。α-神经元即可接受来自皮肤、肌肉和关节等外周传入信息，也可接受从脑干到大脑皮层各高级中枢下传的信息，产生一定的反射活动。故α-神经元是脊髓反射的最后公路（final common path）。α-神经元和其所支配的全部肌纤维所组成的功能单位，称为运动单位（motor unit）。γ-运动神经元胞体较小，数量仅为α-神经元的1/3。γ-运动神经元兴奋性较高，常以高频率持续放电。在安静和麻醉时α-神经元无放电，一些γ-运动神经元也持续放电，γ-运动神经元发出纤维支配梭内肌纤维，从而调节肌梭对牵拉刺激的敏感性（见下表）。
β运动神经元支配梭内肌，也支配梭外肌。
表10-5： 两 类 运 动 神 经 元 比 较
（二）脊休克（spinal shock）
为了研究脊髓在调节躯体运动中的作用，需要消除脊髓以外的高级中枢对脊髓功能的影响。
方法：脊髓与高位中枢之间切断。
但脊髓与延髓间切断，动物将出现呼吸停止、动物死亡。
改进：颈脊髓第5节段以下横断，保留膈神经，以维持呼吸。这种脊髓与高位中枢离断的动物，称为脊动物。
1．脊休克的概念
与高位中枢离断后的脊髓，在手术后（暂时）丧失一切反射活动的能力，进入无反应的状态，称为脊休克。
2．表现（横断面以下）
1） 肌张力下降或消失；
2） 血压下降，外周血管扩张；
3） 粪尿潴留；
4） 发汗反射不出现（不出汗）
说明动物躯体与骨脏反射活动均减弱或消失（能持续多久？）。
3．恢复
脊休克发生后，脊髓反射活动可逐渐恢复（说明是暂时失去反应能力）。
恢复的快慢与动物种类有关（进化程度越高，恢复越慢）。
4．产生原因（机制）
突然失去高位中枢的易化作用。
高位中枢的调节包括易化和抑制。
脊休克的产生与恢复说明了什么问题？
（三）脊髓反射(spinal reflex)
牵张反射、屈（伸）肌反射和节间反射
1．屈肌反射和对侧伸肌反射：
屈肌反射(flexor reflex)：伤害性刺激刺激脊动物的皮肤时，可引起受刺激侧肢体的屈肌反射性收缩。
屈肌反射的强度与刺激的强度呈正相关。
如果刺激强度足够大，则出现
对侧伸肌反射(crossed extensor reflex)：在刺激同侧肢体发生屈肌反射的基础上，出现对侧肢体伸直的反射性活动。
生理意义：屈肌反射可使肢体脱离伤害，具有保护意义；
对侧伸肌反射具有维持姿势的作用。
临床上：锥体束或大脑皮层运动区障碍→ 巴彬斯基征（Babinski’ Sign）阳性。
节间反射（intersegmental reflex）：脊髓某节段神经元发出的轴突与邻近上下节段的神经元发生联系，通过上下节段之间的神经元的协同活动所进行的一种反射活动。
2．牵张反射（stretch reflex）
1）概念：有神经支配的骨骼肌，在受到外力牵张刺激时，引起受牵拉的同一块肌肉收缩。
2）类型：(1)腱反射（位相性牵张反射）（tendon reflex）- 快速叩击肌腱引起肌肉收缩。
(2)肌紧张（紧张性牵张反射）（muscle tonus）- 重力牵拉引起肌肉抵抗性持续性收缩。
3)牵张反射的结构基础：
感受器：肌梭与腱器官
图10-36：肌梭结构示意图
肌梭是一种感受牵拉刺激的特殊梭形感受装置，长约几毫米，外层为一层结缔组织囊，肌梭囊内一般含有2~12根肌纤维，称为梭内肌纤维，而梭外的一般肌纤维就称为梭外肌（见图10-36）。
整个肌梭与梭外肌平行，肌梭内的收缩成分位于两端，感受器装置位于中央，当肌肉受到被动牵拉时，感受器装置也受到牵拉而使传入冲动增加；当梭内肌收缩时，感受装置对牵拉刺激的敏感性增加，传入冲动增加。
肌梭（muscle spindle）：感受肌肉长度、位置和收缩速度变化
腱器官(tendon organ)：感受强肌肉收缩或肌肉被过度拉长
●传入神经：Ⅰa （袋、链）、Ⅱ（链）
●反射中枢：
腱反射：脊髓相应节段前角α神经元（单突触）
肌紧张：中间神经元与前角α 神经元（多突触）
如：膝反射：L2-4
二（三）头肌反射：C5-6 （C7-8）
●传出神经：α传出纤维（ α1时相型、 α2紧张型）
●效应器：梭外肌（快肌和慢肌）
（腱器官传入神经为Ⅰb；抑制前角α运动神经元）
图10-37：牵张反射弧
表：10-6 肌梭与腱器官的比较
二、 脑干对肌紧张和姿势的调节
（一） 脑干网状结构对肌紧张的调节
脑干网状结构对肌紧张的调节具有完全相反的两种方式。
1．易化区
电刺激该区域增强肌紧张和肌运动。
机制：通过兴奋网状脊髓束，兴奋脊髓的α-和γ-运动神经元。
2．抑制区
电刺激该区域肌紧张和肌运动
机制：无内源性活动，依赖高级中枢的活动。
（二）去大脑僵直
1．实验：在动物中脑四叠体（上、下丘间）间横断脑干→ 去大脑僵直(decerebrate rigidity)
表现：全身抗重力肌群发生过强收缩
2．发生原因（机制）：
正常时：上位中枢(大脑皮层、基底神经节、小脑、前庭核等)通过脑干网状结构（易化区和抑制区）对前角运动神经元施加影响，使屈肌与伸肌的肌紧张度保持平衡。
损伤后：∵易化区作用＞抑制区的作用；∴牵张反射增强
伸肌是抗重力肌，正常情况下反射活动强于屈肌
伸肌 ＞屈肌 （牵张反射）
3．本质：伸肌的牵张反射增强（同时存在α-和γ僵直）
α-僵直（α-rigidity）：高位中枢的下行作用，直接或间接通过脊髓中间神经元提高α运动神经元的活动而出现的僵直。
γ僵直（γ-rigidity）：高位中枢的下行作用，首先提高γ运动神经元的活动，使肌梭的传入冲动增加，转而增强α运动神经元的活动而出现的僵直（见图10-38）。
图10-38：γ环路示意图
（二） 脑干对姿势的调节
CNS通过引起骨骼肌的运动和调节其紧张度，形成特定的姿势。
正常的姿势是人体直立和平衡的基础，也为随意运动的产生提供稳定的背景
姿势反射包括：状态反射、翻正反射、直线和旋转变速反射。
状态反射：包括迷路紧张反射和颈紧张反射（见图10-39）
图39：颈紧张反射示意图
三、小脑对躯体运动的调节
（一） 结构
见图10-40。
图10-40：小脑的功能分区示意
（二） 功能
1．前庭小脑(vestibulocerebellum)
1）主要的联系
2）功能：
维持身体姿势平衡
损伤后主要表现：平衡失调
2．脊髓小脑(spinocerebellum)
1）包括：前叶、后叶中间带区
2）功能：调节肌张力
抑制区：前叶蚓部（对侧，倒置关系）
易化区：前叶两侧部（对侧，倒置关系）
后叶中间带（双侧）
人类以易化为主
3）受损后表现
（1）肌张力变化（人类为降低）；
（2）小脑性共济失调（方向、力量、范围）；
（3）意向性震颤(intention tremor)：受害动物或患者不能完成精巧动作，肌肉在完成动作时抖动而把握不住动作的方向。
3．皮层小脑(cerebrocerebellum)
1） 结构：后叶的外侧部
2）主要参与精细运动（技巧性运动）的编程及协调（见图10-41）
图10-41：产生协调随意运动的示意图
四、基底神经节对躯体运动的调节
㈠结构及其纤维联系
主要包括新纹状体（尾状核和壳核）、旧纹状体（苍白球）、丘脑底核黑质和红核。
纤维联系见图10-42。
图10-42：基底神经节的主要神经联系
㈡功能
1． 参与随意运动的产生和稳定；
2． 参与肌紧张的调节；参与本体感受器传入信息的处理。
㈢与基底神经节有关的疾病
1． 运动过少而肌紧张过强（震颤麻痹）；
震颤麻痹（Paralysis agitons），也称帕金森氏病（Parkinson’s disease）
1）症状：肌肉强直、随意运动减少、动作缓慢、面部表情呆板、静止性震颤
2）病变部位：中脑黑质
3）可能机理：黑质的DA递质系统功能不足，纹状体的Ach递质系统功能亢进；丘脑外侧腹核功能异常。
4）治疗机制 左旋多巴，M-R拮抗剂，5-羟色胺酸及手术切除苍白球。
Anticholinergics were the first drugs available for the symptomatic treatment of Parkinson's disease and they are still widely used today, both as monotherapy and as part of combination regimes. They are commonly believed to be associated with a less favourable side effect profile than other antiparkinsonian drugs, in particular with respect to neuropsychiatric and cognitive adverse events. They have been claimed to exert a better effect on tremor than on other parkinsonian features. To determine the efficacy and tolerability of anticholinergics in the symptomatic treatment of Parkinson's disease compared to placebo or no treatment. The literature search included electronic searches of the Cochrane Controlled Trials Register,。Randomised controlled trials of anticholinergic drugs versus placebo or no treatment in de-novo or advanced Parkinson's disease, either as monotherapy or as an add-on to other antiparkinsonian drugs were included. Trials of anticholinergic drugs that were never in general clinical use were excluded. Differences were settled by discussion among all authors. Data collected included patient characteristics, disease duration and severity, concomitant medication, interventions including duration and dose of anticholinergic treatment, outcome measures, rates of and reasons for withdrawals, and neuropsychiatric and cognitive adverse events. The initial search yielded 14 potentially eligible studies, five of which were subsequently excluded. In three cases this was because they dealt with substances that had never been marketed or had not been licensed for as far as could be traced back. One trial had been published twice in different languages. One study was excluded based on the assessment of its methodological quality. The remaining nine studies were all of double-blind cross-over design and included 221 patients. Trial duration was between five and 20 weeks and drugs investigated were benzhexol (mean doses: 8 to 20 mg/d), orphenadrine (mean dose not reported), benztropine (mean dose not reported), bornaprine (8 to 8.25 mg/d), benapryzine (200 mg/d), and methixine (45 mg/d). Only one study involved two anticholinergic drugs. Outcome measures varied widely across studies and in many cases, the scales applied were the authors' own and were not defined in detail. Incomplete reporting of methodology and results was frequent. The heterogeneous study designs as well as incomplete reporting precluded combined statistical analysis. Five studies used both tremor and other parkinsonian features as outcome measures. Outcome measures in these five studies were too different for a combined analysis and results varied widely, from a significant improvement in tremor only to significant improvement in other features but not in tremor. All studies except one (dealing with methixine) found a significant improvement from baseline on the anticholinergic drug in at least one outcome measure. The difference between placebo and active drug was reported in four studies and was found to be significant in all cases. No study failed to show superiority of the anticholinergic over placebo. The occurrence of neuropsychiatric and cognitive adverse events was reported in all but three studies (in 35 patients on active drug versus 13 on placebo). The most frequently reported reason for drop-outs from studies was in patients on placebo due to withdrawal from pre-trial anticholinergic treatment. As monotherapy or as an adjunct to other antiparkinsonian drugs, anticholinergics are more effective than placebo in improving motor function in Parkinson's disease. Neuropsychiatric and cognitive adverse events occur more frequently on anticholinergics than on placebo and are a more common reason for withdrawal than lack of efficacy. Results regarding a potentially better effect of the anticholinergic drug on tremor than on other outcome measures are conflicting and data do not strongly support a differential clinical effect on individual parkinsonian features. Data is insufficient to allow comparisons in efficacy or tolerability between individual anticholinergic drugs（Katzenschlager R, Sampaio C, Costa J, Lees A. Anticholinergics for symptomatic management of Parkinson's disease. Cochrane Database Syst Rev. 2003;(2):CD003735）.
2．运动过多而肌紧张不全
舞蹈病 (Chorea)，也称亨延顿病。
病变部位：新、旧纹状体病变（神经元变性）症状：不自主的上肢和头部的舞蹈样动作，肌张力降低。
3） 治疗机制：利血平可缓解症状（为什么？）
Chorea (Greek for "dance") refers to irregular, rapid, flowing, non-stereotyped and random involuntary movements that often possess a writhing quality, referred to as choreoathetosis. When mild, it may be difficult to differentiate from restlessness. The movements can be strikingly asymmetric, as in hemichorea, or generalized. When chorea（Huntington's disease ，HD） is proximal and of large amplitude, it is called ballism. Chorea is worsened by stress and anxiety and subsides during sleep. Movements can interfere with the completion of many daily activities, making fastening a button a substantial effort. Chorea often is incorporated into a purposeful activity in an attempt to disguise it. Motor impersistence is a common associated feature, demonstrated by varying intensity of grip strength (milkmaid's grasp) or by an inability to sustain eye closure or tongue protrusion.
HD is an autosomal, dominantly inherited neurodegenerative disorder that is characterized by abnormal involuntary movements (chorea), intellectual impairment and selective neuronal loss. The expansion of a polymorphic trinucleotide repeat (the sequence CAG that codes for glutamine) to a length that exceeds 40 repeat units in exon 1 of the gene, HD, correlates with the onset and progression of the disease. The protein encoded by HD, huntingtin, is normally localized in the cytoplasm, whereas the mutant protein is also found in the nucleus, suggesting that its translocation to this site is important for the pathogenesis of HD. Although several proteins that interact with huntingtin have been identified in vitro, the significance of these interactions with the mutant protein in the pathogenesis of HD has yet to be determined. Recent progress in the development of cellular and animal models for the disease have provided invaluable insights and resources for studying the disease mechanisms underlying HD, and will be useful for screening and evaluating possible therapeutic strategies.
Rheumatic fever is a multisystem inflammatory disease that occurs as a delayed sequelae to group A streptococcal pharyngitis . The important clinical manifestations are migratory polyarthritis, carditis, chorea, subcutaneous nodules and erythema marginatum occurring in varying combinations. The pathogenesis of this disorder remains elusive: an antigenic mimicry hypothesis best explains the affliction of various organ systems after a lag period following pharyngeal infection. In its classic milder form, the disorder is largely self-limited and resolves without sequelae, but carditis may be fatal in severe forms of the disease. Chronic and progressive damage to the heart valves leads to the most important public health manifestations of the disease. Anti-inflammatory agents provide dramatic clinical improvement, but do not prevent the subsequent development of rheumatic heart disease. The role of corticosteroids in treatment of carditis is uncertain and controlled studies have failed to demonstrate improved long term prognosis. Chorea, once considered a benign self-limited disease, is now felt to require more aggressive treatment, in particular with sedatives. Prevention of first and subsequent attacks of rheumatic fever is the mainstay in the limited arsenal available to alter the natural history of this disease.
四、 大脑皮层对躯体运动的调节
大脑皮层是感觉、运动和植物神经的最高级中枢。
作用：调节肌紧张、发动和调节各种随意运动。
（一）大脑皮层的主要运动区
1． 主要运动区：中央前回和运动前区（4区、6区）
（图10-43）
图10-43：中央前回运动皮层对身体各部分运动控制的分布规律示意图
特征：①基本交叉，但头面部大多为双侧支配（面、舌肌除外）；
②基本倒置，但头面部是正立的；
③机能定位相当精确；
④投射范围与运动的灵敏性成正比。
2．其它运动区：
运动辅助区：双侧、粗糙
体表感觉区：
其它感觉区：视皮层
（二）运动传导通路
1．主要的传导路（锥体系）：
作用：发动随意运动，多为交叉性支配，主要控制α-运动神经元，控制精细、技巧运动
⑴皮层脊髓束：
皮层脊髓侧束（80%）：延髓锥体交叉，支配四肢远端肌肉，主要参与精细的、技巧性运动，进化新。
皮层脊髓前束（20%）：不交叉，支配四肢近端肌肉及躯干肌肉，主要参与姿势维持和粗大运动。
⑵皮层脑干束：
2．经（源自）皮层下性传导路（锥体外系）：
作用：主要协调肌群间运动，调节肌张力(姿势)；配合锥体系完成各种精细运动；完成某些节律性和习惯性动作。
特点：多为双侧控制，主要作用于γ-运动神经元
包括：（1）顶盖（网状、前庭、）脊髓束，（2）红核脊髓束可调节精细运动
（三） 功能
1．参与随意运动的产生和稳定；
2． 参与肌紧张的调节；
3． 参与本体感受器传入信息的处理。
（四）运动神经元和运动传导通路受损后表现
1．瘫痪（麻痹）-随意运动丧失；
2．软痪-肌张力↓，腱反射消失或减弱，肌肉萎缩等。
3．硬痪- 肌张力↑，腱反射亢进，出现病理征（如巴彬氏征）等。（主要皮层脊髓侧束损伤）。
表10-7 上运动神经元与下运动神经元损伤后的区别
第七节 神经系统对内脏活动的调节
一、 植物NS概述
（一） 概念
指支配内脏器官的传出神经，不包括传入神经。
因内脏活动不受意志控制，故又称为自主NS。
图10-44：植物神经分布示意图
（二）结构特征
⒈中枢→神经节（节前纤维）→效应器（节后纤维）；
⒉节前纤维：B类（直径较大，传速较快，多有髓鞘）节后纤维：C类（直径较小，传速较慢，无髓鞘）
⒊主要支配平滑肌、心肌和腺体；
⒋到达效应器前形成神经丛，攀附内脏
（三） 植物NS与运动NS比较
表10-8：植物NS与运动NS比较
（四）交感与副交感的区别
表10-9：交感与副交感的区别
（五）植物NS的功能
1．主要功能：调节心肌、平滑肌和腺体（消化腺、汗腺、部分内分泌腺）的活动。
2．功能特点：
1）对同一效应器的双重支配：
除汗腺、竖毛肌、肾上腺髓质仅受交感神经支配外，其余脏器均受双重支配。
大多情况下为拮抗作用，但作用也有一致性（如唾液分泌）
2）紧张性支配：
外周感受器传入信息→CNS紧张性活动→紧张性支配
3）中枢间的交互抑制：
如心交感与心迷走。
4）效应器所处的功能状态的影响：
交感神经对子宫的影响（有孕收缩，无孕舒张）
5）对整体生理功能调节的意义：
交感神经自稳定性作用：环境急剧变化时活动增加，动员体内许多脏器的潜在能力，维持内环境稳定。如应急反应和应激反应。
副交感神经贮能作用：安静时活动增加，以促进消化、加强排泄、聚集能量，利于生殖、机体休整恢复等。如迷走—胰岛素系统
二、CNS各级水平对内脏活动的调节
㈠脊髓（初级中枢）
有一定的调节作用，但调节能力差。
为所有交感、部分副交感神经的发源地
可完成下列反射：
①血管张力反射；
②勃起反射；
③排尿、排便反射；
④发汗反射。
㈡脑干
1．延髓（生命基本中枢）：
心血管反射中枢；
呼吸节律中枢；
吞咽、呕吐、唾液分泌反射中枢
肾上腺髓质反射性分泌中心
2．脑桥
呼吸调整中枢
3．中脑
瞳孔对光反射中枢
另外膀胱收缩、皮肤电反应的调节
㈢下丘脑
分为视前区、视上区、漏斗区和乳头体区
1．体温调节：
体温调定点：视前区-下丘脑前区（冷、热敏神经元）（见能量代谢与体温章）。
2．水、电解质平衡管理
视上核、室旁核 ，存在渗透压感受器(brain osmoreceptor)，调节ADH的分泌。
尿崩症：尿量可多达20L/D，口渴和饮水多，低比重尿（见尿的生成和排出章）
3．对摄食行为的影响：饱中枢（satiety center）与摄食中枢(feeding center).
4．对腺垂体激素分泌的调节
下丘脑促垂体区：分泌多肽类激素-下丘脑调节肽（hypothalamus regulatory peptide）（见内分泌与生殖章）。
5．对情绪反应的影响
下丘脑参与发动和整合伴随情绪而出现的自主性活动和躯体性活动
“愤怒区”：穹窿周围区、下丘脑腹内侧核及周围区
假怒(sham rage)：刺激猫上述区域（在去大脑动物更易出现），出现张牙舞爪、吼叫咆哮、瞳孔扩大、毛发竖立、挣扎、呼吸增快、血压增高，甚至寻找“敌手”，扑咬人。
“逃避区”：
6．对生殖和性行为的影响：
乳头体核：发情与性行为
其它区域：
7．对生物节律的控制
生物节律(biorhythm)：机体内的各种活动按一定的时间顺序发生变化，这种变化的节律称为生物节律。
高频：周期低于一天，如心动周期与呼吸周期；
中频（日周期）：如睡眠与觉醒、体温周期等；
低频：周期长于一天，如月经周期。
部位：视交叉上核
（四）大脑皮层
1．新皮层：4区、6区、8区与此19区
2．边缘叶与边缘系统：
功能：参与情绪反应、摄食行为、学习与记忆、觉醒与睡眠、植物神经性功能的调节。
边缘系统的活动大致有两方面：
维持个体生存的反应：摄食与防御
维持种系生存的反应：生殖与性行为
三、本能行为和情绪反应的神经基础（自学）
本能行为：摄食、防御及种族延伸
情绪反应：心理活动伴有的生理反应
㈠本能行为的调节：
1．摄食行为的调节
2．性行为的调节
㈡情绪反应的调节：
1．恐惧和发怒：
2．动机：奖赏与惩罚
四、 NS对内分泌和免疫的调节（自学）
第八节 脑的高级功能
一、学习和记忆
学习（learning）：人和动物不断地接受环境变化而获得新的行为习惯（或经验）的过程。（获得外界信息的神经过程）
记忆(memory)：将获得的行为习惯或经验贮存一定时期的能力，也可以说是经验的保存与再现。（信息的贮存和读出的神经过程）。
㈠学习的形式
1．非联合型学习(nonassociative learing)：
习惯化（habituation）
敏感化（Sensitization）：通过习惯化，可以学会去除许多无意义的信息应答；敏感化有利于人和动物注意伤害性刺激。
2．联合型学习(associative learing)：
⑴经典条件反射（被动式条件反射）：
非条件刺激：如食物、伤害电刺激
无关刺激：如铃声、灯光
强化（reinforcement）：无关刺激与非条件刺激在时间上的结合过程。
⑵操作式条件反射（operant conditioning）（主动式条件反射）：
奖赏性
惩罚性
㈡条件反射活动的基本规律
⒈形成的基本条件：
机体状态：健康、反应状态良好
强化
⒉条件反射的泛化、分化及消退：
⒊人类的条件反射：（语词可建立）
⒋两种信号系统：
第一信号与第一信号系统(first signal system)：具体的信号及相关的神经结构
第二信号与第二信号系统(second signal system)：抽象的信号及相关的神经结构
两种信号系统的意义：
（三）记忆的过程
1．记忆的分类：
1）依形成机制及保持时间长短分为：短时记忆和长时记忆
（1）短时记忆(short term memory)：贮存的信息保持可读出的时间范围为几秒至数分钟。
分类：感觉性记忆和第一级记忆
特点：①信息贮存量有限（7±2个项目）；②容易受损害：昏迷、脑缺氧、深度麻醉、电休克；③可通过巩固转为长时记忆。
（2）长时记忆(long short term memory)：信息贮存的时间可达数小时、数天、数年甚至终身
分类：第二级记忆、第三级记忆
特点：①容量无限；②不易受影响：如麻醉、休克等；③一旦形成，不易遗忘。
2）根据信息贮存和回忆的方式分为：⑴陈述性记忆；⑵程序性记忆
2．记忆的过程
包括：获得、贮存与巩固、再现和读出三个过程
图10-45：记忆分级模式
（四）遗忘（amnesia）（记忆障碍）
部分或完全失去回忆和再认的能力
1．顺行性遗忘
多见于慢性酒精中毒；
不能保留新近获得的信息；
机制：第一级记忆向第二级记忆转化障碍。
2．逆行性遗忘
多见于脑震荡，麻醉，电休克等；
事件发生前的一段记忆丧失；
机制：第二级记忆发生障碍
（五）学习和记忆的机制
1．脑功能定位 专一区域？或多个区域联合？
有关区域：大脑皮层联络区、海马及其周围区、丘脑及脑干网状结构。
海马环路（hippocampal circuit）与近期记忆：
海马→穹窿→下丘脑乳头体→丘脑前核→扣带回→海马
2．学习和记忆的机制
感觉性记忆：神经元活动后放电
第一级记忆：神经环路（海马环路）活动
第二级记忆：脑内神经元蛋白合成
第三级记忆：脑内神经元间新的突触形成㈠两侧大脑皮层功能的相关
二、大脑皮层的语言中枢
㈠两侧大脑皮层功能的相关
胼胝体作用
㈡大脑皮层功能的一侧优势
左右半球的不对称性：
一侧优势：左：语言功能
右：空间辨认、深度知觉、触觉、音乐欣赏
优势半球(domain cerebral hemisphere)：在语言活动功能上占优势的半球。
（三） 大脑皮层的语言中枢
表10-10：大脑皮层的语言中枢及损伤后的表现
附：LTP产生的分子机制
The molecular mechanisms for long-term potentiation (LTP) may seem hopelessly complex, and no doubt the lack of clarity and concision of the immense LTP literature is a source of frustration for many. However, being inherently optimistic it seems to me that certain generalizations are beginning to emerge that allow an initial formulation of a molecular explanation for LTP. At this point in time we do not have in hand all the puzzle pieces concerning the molecular basis for LTP, so any explanation is by necessity incomplete and likely to contain some errors. Nevertheless, I feel it is constructive to present a working draft of a molecular model for one specific type of LTP, in the hope that it will present a useful framework for further discussion and experimentation.
What LTP Are We Talking About? There are many different types of LTP in the mammalian CNS- hippocampal, cortical, cerebellar, NMDA receptor-dependent and independent-just to name a few prominent categories. Therefore, we need to specify, to the best extent possible, exactly which LTP we are discussing. In this commentary I will be discussing NMDA receptor-dependent LTP at Schaffer Collateral/ commissural synapses in area CA1 of rat or mouse hippocampus, in most cases induced using multiple, spaced trains of 1 sec/100 Hz stimuli. I choose this subtype of LTP because it has the widest variety of direct biochemical data available.
What Aspect of LTP Are We Talking About? LTP, as originally defined by Bliss and Lomo, is manifest as two physiologic components. The first component, which has received by far the most attention, is an increase in synaptic strength. This is typically measured as an increase in the initial slope of the EPSP (or EPSP magnitude). This effect is subserved by an increase in neurotransmitter release, an increase in postsynaptic receptor number or efficacy, or both. Although the locus of LTP expression (pre- vs. postsynaptic) has been widely debated and is a source of continuing controversy, my reading of the literature leads me to conclude that there is a convincing case that postsynaptic changes in AMPA receptor function contribute to the expression of LTP. My model will incorporate mechanisms to achieve this effect. The physiologic evidence for changes in neurotransmitter release is less convincing to me, but there is convincing biochemical evidence that presynaptic changes do occur in LTP. Thus my model will contain a mechanism to account for lasting changes in both the pre- and postsynaptic compartments.
A second component of LTP discovered by Bliss and Lomo is referred to as EPSP-slope (E-S) potentiation, which is a term used to refer to the postsynaptic cell having an increased probability of firing an action potential at a constant strength of synaptic input. While E-S potentiation was originally explained based on alterations in recurrent inhibitory connections in area CA1, more recent work has suggested that E-S potentiation is a manifestation of increased excitability in the postsynaptic neuron. My model will incorporate a molecular mechanism to account for this aspect of LTP.
Finally, I should note in passing that emerging evidence suggests that morphological changes are likely to occur in LTP. I will not try to explicitly address a molecular basis for this effect as the mechanisms underlying these types of morphological changes are ill-defined at present. However, many of the molecules already implicated in LTP, such as cytoskeletal proteins, cell-adhesion molecules, and postsynaptic scaffolding proteins, are likely to be involved in subserving these types of changes. I similarly will duck the important issue of the basis of control of local protein synthesis at synapses, based on a dearth of information concerning the signal transduction mechanisms operating to control this process in LTP. In the future it will likely be necessary that any model for LTP will have to incorporate mechanisms for both local protein synthesis and morphological changes.
What Types of Mechanisms Are Involved in LTP Biochemistry? I would like to point out three terms widely used and abused in the LTP literature, so that we can use a common nomenclature in discussing the molecular mechanisms of LTP. Induction refers to the transient events serving to trigger the formation of LTP. A maintenance mechanism refers to the persisting biochemical signal that lasts in the cell. This persisting biochemical signal acts upon an effector, for example a glutamate receptor, resulting in the expression of LTP. It is important to keep in mind that these processes can be differentially inhibited, as was beautifully illustrated in an early experiment by Malinow, Madison, and Tsien. Imagine that you apply an enzyme inhibitor before, during, and after the period of LTP-inducing, high-frequency stimulation and find that the inhibitor blocks LTP. You could not distinguish whether the inhibited enzyme is required for the induction, the expression, or the maintenance of LTP. To distinguish among these possibilities, imagine instead applying the inhibitor selectively at different time points in the experiment. If you apply the inhibitor only during the tetanus and it blocks LTP you can conclude that the enzyme is necessary for LTP induction. If you apply the inhibitor after the tetanus and it reverses the potentiation it may be blocking either the maintenance or expression of LTP. To illustrate this, imagine that the mechanism of LTP maintenance and expression is an autonomously active protein kinase phosphorylating an AMPA receptor. In this case transient application of a kinase inhibitor would reversibly block LTP by blocking the capacity of the kinase to phosphorylate the receptor, but the potentiation will recover after removal of the inhibitor because the kinase is still autonomously active. This is a blockade of LTP expression. However, if the kinase inhibitor causes the kinase to return to its basal state the potentiation will not recover, and the inhibitor has blocked the maintenance of LTP.
What Phase of LTP Are We Talking About? Contemporary models divide long-lasting LTP into three phases. LTP comprising all three phases is induced with repeated trains of high-frequency stimulation in area CA1, and the phases are expressed sequentially over time to constitute what we call LTP. Late LTP (L-LTP) is dependent for its induction on changes in gene expression and lasts many hours. Early LTP (E-LTP) is subserved by persistently activated protein kinases and starts at around 30 min or less and is over by ~2-3 hr. The first stage of LTP, generally referred to as short-term potentiation, is independent of protein kinase activity for its induction or expression and lasts ~30-45 min. I prefer to refer to the first stage of LTP as initial LTP to emphasize that it is a persistent form of NMDA receptor-dependent synaptic plasticity that is induced by LTP-inducing tetanic stimulation and is a prelude to E-LTP and L-LTP. The biochemical mechanisms for initial-LTP induction, maintenance, and expression are completely mysterious at this time. The mechanisms for E-LTP and L-LTP are the subject of the remainder of this commentary.
It is important for the reader to synthesize the two preceding paragraphs. Simply stated, three phases of LTP (Initial-, E-, and L-LTP) times three distinct underlying mechanisms for each phase (induction, maintenance, and expression) gives nine separate categories into which any particular molecular mechanism contributing to LTP may fit.
What Are the Core Mechanisms for LTP? Before proposing a specific set of core mechanisms for LTP, I would like to review some fundamental principles; while the specifics are likely to change, the fundamentals can serve as a lasting guide in evaluating new information. I will review several experimental criteria that I think serve as useful guidelines in deciding if a particular molecular mechanism should be promoted to "core" status. All the criteria are general principles of hypothesis testing and will be quite remedial for most readers; thus, one might argue that there is no need to present them. On the other hand, one need only pick up any randomly selected LTP paper to see why their reiteration is useful they emphasize that hypothesis testing is a process wherein multiple, independent lines of evidence are needed to support any one hypothesis. Experimental manipulations of any single sort, which can of necessity test only a single prediction of a hypothesis, are insufficient to consider a hypothesis well supported.
CRITERION 1 REPRODUCIBILITY This criterion is so obvious that I will not belabor it. I list it only for the sake of completeness, and as a contrived means of being able to inject some editorial comments into my commentary. As has been emphasized the Nature of modern Science is such that publication of any single finding in a high-profile journal does not necessarily imply any assurance of reproducibility. In fact, the more cynical would likely assert that journal impact factor has tended to correlate negatively with reproducibility, at least as far as the LTP literature goes. The LTP literature is replete with nonreproducible and quasireproducible (i.e., reproducible within a single lab) results. What is the take-home message? Review writers and commentators should make a good-faith effort to assess the reproducibility of the data implicating any single molecule in LTP before promulgating it as a candidate component of LTP biochemistry. Newcomers to the field should scour the literature to assess the reproducibility of any particular finding before attempting to follow it up experimentally, keeping in mind that the data refuting any high-profile finding is likely buried in a more obscure journal.
Returning to the main line of our discussion, the following three criteria are specific types of experimental manipulations that are used to test the predictions of hypotheses. No single one or combination of any two can stand on their own. However, if all three criteria are met a very compelling case has been made and the hypothesis can be considered rigorously tested. I propose that the following three criteria, in conjunction with the reproducibility criterion above, be met before any molecule (or molecular cascade) is included as part of the "core" mechanism for LTP.
CRITERION 2 BLOCKING THE ACTIVITY OF THE MOLECULE BLOCKS LTP INDUCTION This typically is accomplished using pharmacologic inhibition or genetic manipulation and, by far, is the predominant category of experiments implicating molecules in LTP. Assuming perfect specificity of the experimental manipulation it is still important to keep in mind that an inhibitor can act by affecting any of the mechanisms highlighted in Table 1, that is, the manipulation may block induction, maintenance, or expression. In addition, it is possible for a molecule or its activity to be necessary for LTP because it subserves some obligatory baseline function, but yet the molecule may have no direct involvement in any signal transduction cascade necessary for LTP. For example, assume that NMDA receptors are constitutively phosphorylated by some protein kinase and that this phosphorylation event is necessary for the NMDA receptor to be functional. Removing the kinase would by definition block any form of NMDA receptor-dependent LTP, but the kinase itself would play no role as a downstream effector involved in LTP induction, maintenance, or expression.
CRITERION 3 DIRECTLY ACTIVATING THE MOLECULE SHOULD PRODUCE EITHER LTP OR SYNAPTIC POTENTIATION This experiment is most straightforward in the context of mechanisms for LTP maintenance, where application of the activated form of the molecule should be capable of producing synaptic potentiation. Similarly, if a molecule is involved in LTP induction and that pathway is sufficient to elicit LTP (or a phase thereof), application of the molecule should produce LTP. This experiment is more problematic in a situation where the molecule may be necessary, but not sufficient, for LTP induction; in this case application of the molecule will not produce LTP. However, even in this case concomitant application of the molecule along with the additional necessary factors should be capable of producing LTP. The mirror image of this caveat is not often considered; what if a molecule is sufficient but not necessary for LTP induction? Or if the molecule plays a necessary role in LTP induction but by an entirely different mechanism is capable of producing LTP when strongly or aberrantly activated? The more we learn about the multitude of sites and mechanisms for plasticity at hippocampal synapses, the greater our realization of the potential for this situation to occur.
CRITERION 4 THE MOLECULE SHOULD BE ACTIVATED (OR ELEVATED) WITH LTP-INDUCING STIMULATION This is one of the classic criteria among biochemistry types for implicating a molecule in a signal transduction cascade, arising from the experimental traditions of Earl Sutherland and his coworkers in discovering the cAMP cascade. However, this type of experiment has not been as popular in the electrophysiologist-dominated LTP field. This is partly due, in my opinion, to technical considerations and partly due to the correlative nature of the data obtained using this approach. Nevertheless, data of this sort in combination with pharmacologic/genetic data addressing the necessity and sufficiency of a molecule for LTP (criteria 2 and 3) allow a compelling case to be made for a role for a given molecule in LTP.
Ideally for any molecule or signal transduction cascade to be promoted to core status for LTP induction, maintenance, or expression, each of the four criteria above must be fulfilled. This is a stringent vetting procedure and I hope that the criteria will be useful in the future as a checklist in evaluating candidate molecules. However, are there candidate signal transduction pathways than can pass this test right now? In my opinion, a convincing case can be made for four pathways at present; the PKA cascade, the MAPK (ERK) cascade, CaMKII, and PKC. As space constraints do not allow a review of the extensive literature relevant to the roles of these pathways in LTP. A Core Signal Transduction Cascade for LTP The proposed core signal transduction cascade for LTP is presented graphically in Figure 1. Though a static diagram is presented, it should be kept in mind that the effects described can be divided into three broad temporal categories: 1. Transient effects due to second messenger-dependent protein kinase activation, and so forth, that are involved in the induction of both E-LTP and L-LTP. Concerning transient signals a wide variety of interacting downstream effectors of the kinases are likely involved in the induction of both E-LTP and L-LTP (see below). One prominent effector involved in the induction of L-LTP is the transcription factor CREB.2. Longer-term effects due to generations of persistently activated second messenger-independent forms of PKC and CaMKII that maintain the increase in synaptic strength in E-LTP through phosphorylation of AMPA receptors and (putatively) maintain increased excitability in E-LTP through phosphorylation of voltage-dependent potassium channels.3. Long-lasting effects downstream of altered protein synthesis or gene expression that subserve L-LTP. Although the ultimate effectors of the various pathways for altered mRNA and protein synthesis have not been identified definitively.An interesting issue in this context is how the mechanisms of L-LTP (and potential later phases of synaptic potentiation) overcome the constraint of molecular turnover. As a recent treatment of this topic has been published, I will not discuss it here. Another issue that is not dealt with explicitly in the model is how the decrement in the mechanism for one phase of LTP is compensated for by an increase in synaptic strength by the molecular mechanisms for the next phase of LTP, such that the strength of the synapse remains constant. This issue was also dealt with in a previously published paper
Modulators of LTP Induction What place do these other molecules have in a scheme for LTP? I categorize many of these molecules as modulators of LTP induction . Many molecules implicated in LTP are extrinsic factors, such as modulatory neurotransmitters, that likely alter the magnitude or probability of induction of LTP by impinging on the signal transduction pathways of the core pathway. In my estimation dopamine receptors, -adrenergic receptors, and acetylcholine receptors fit into this category. Another category is intrinsic factors that are activated concomitantly with the core signal transduction pathway and that tend to promote LTP induction, but that are not required for LTP induction in all circumstances. The prototype for this category is nitric oxide (NO) synthase; I also place postsynaptic metabotropic glutamate receptors in this category. It is important to note that the effects of all the modulators of LTP induction are likely to be more or less pronounced depending on induction parameters such a stimulus strength, temperature, and physiologic stimulation protocol.
Components of the Synaptic Infrastructure Another category of molecule necessary for LTP induction is molecules whose presence or function are necessary for normal operation of the synapse. Presynaptic calcium channels, the molecules intrinsic to mediating calcium-induced vesicle fusion, AMPA and NMDA receptors, and postsynaptic scaffolding proteins all can be included in this category. It is important to bear in mind that these same molecules are likely to be effectors of the processes that maintain LTP or modulate LTP induction.
Finally an additional subcategory of molecules are those that are normally basally active and help maintain the synaptic infrastructure. A nice example of this category is BDNF, its receptor and effectors, which have been proposed to be constitutively active at the synapse and are necessary for a normal presynaptic response to high frequency tetanic stimulation.
The Molecular Complexity of LTP Induction: A Refutation of Occam's RazorThe law of parsimony, commonly known as Occam's Razor, states that when choosing among competing hypotheses to explain a phenomenon, choose the simplest that is compatible with the existing data. This principle was formulated by William of Occam in ~1300 AD and has served science well in the 700 years since. In 1988 John Lisman formulated a parsimonious model for LTP that was consistent with available data and was completely adequate to explain LTP; generation of an autonomously active, self-regenerating CaMKII that increased synaptic strength. In light of data obtained since 1988 the model has, to borrow one of Lisman's phrases, "turned to mush." It is now clear that no single process is likely to explain LTP or even a single phase of it. Even the relatively complicated core model presented in Figure 1 is an oversimplification, as it covers only a fraction of the processes reliably implicated in LTP induction.
How can one bring some sense of order to the immense complexity of interacting signal transduction cascades that are involved in LTP induction? Unfortunately a complete review of all the interacting molecular cascades involved in LTP induction is beyond the scope of this commentary, so I leave that to a future effort. Nevertheless, I believe that it is constructive at this point to present a brief overview of several themes that have emerged from analyzing the molecular cascades that are involved in LTP. These themes serve to provide a set of categories in which to place molecular events that have already been implicated in LTP induction, maintenance, and expression, and a context in which to place future discoveries. These broad themes are also of use because they allow one to infer certain functional consequences of the ways in which the biochemistry of LTP operates.
Theme One Signal AmplificationPronounced signal amplification is perhaps the most striking attribute of LTP biochemistry that has emerged. Many of the individual component processes that have been implicated in LTP induction serve to produce a highly amplified final outcome from the core LTP induction processes shown in Figure 1. Three subcategories of signal amplification mechanisms have emerged thus far: I refer to them as serial amplification, feedback amplification, and cross-talk amplification. I will provide a few specific examples for illustrative purposes.
SERIAL AMPLIFICATION The MAP kinase cascade, with its serially linked chain of one kinase catalytically activating a downstream kinase that catalytically activates yet another kinase, is the prototype of a highly amplified signal transduction cascade. A catalytic chain reaction of this sort is capable of tremendous signal amplification .
FEEDBACK AMPLIFICATION I use feedback amplification as a term to describe biochemical mechanisms that allow postsynaptic Ca2+ influx or membrane depolarization to augment themselves in a positive-feedback fashion. In Figure 1 a few specific examples of feedback signal amplification mechanisms in LTP induction are indicated with dashed arrows. These arrows describe the capacity of PKA to enhance voltage-gated Ca2+ channel function, attenuate voltage-dependent K channel function, and enhance AMPA receptor function. By these mechanisms an initial NMDA receptor-dependent influx of Ca2+ can amplify itself (via activation of the PKA cascade) through secondarily augmenting AMPA receptor-dependent membrane depolarization and through promoting influx of additional Ca2+ through voltage-dependent Ca2+ channels.
CROSSTALK AMPLIFICATION I use this term to describe the capacity of one signal transduction cascade to amplify another signal transduction cascade. This is exemplified in Figure 1 by PKA activating through phosphorylation the protein phosphatase inhibitor Inhibitor-1. By this mechanism of phosphatase inhibition PKA can amplify not only phosphorylation of its own substrates but also the level of phosphorylation of the substrates of other kinases such as CaMKII and PKC.
FUNCTIONAL CONSEQUENCES OF SIGNAL AMPLIFICATION The hallmark of highly amplified biochemical systems is that they tend to create a step function for triggering an effect, in this case LTP. An additional implication of the extensive serial, feedback, and cross-talk effects of one signal transduction mechanism on another in LTP is that it is essentially impossible to selectively inhibit any one enzyme involved in LTP induction. Even an absolutely selective inhibitor (or genetic manipulation) is likely to have pronounced secondary consequences on the other signal transduction molecules involved in LTP induction. This is one reason why multiple lines of experimental evidence, such as those presented as criteria 3 and 4, are so important as adjuncts to inhibitor studies.
Theme Two Signal IntegrationTEMPORAL INTEGRATION It is important to keep in mind that all of the processes diagramed in Figure 1 are not terminated instantaneously, but typically decay with a half-life on the order of minutes. Thus, delivery of one tetanic stimulus may serve to amplify subsequent temporally spaced stimuli, allowing for temporal integration of signals. This is likely to be the means by which multiple, spaced tetanic stimuli are able to selectively produce late-phase LTP.
FUNCTIONAL INTEGRATION An additional consideration is that many of the protein kinases outlined in Figure 1 converge on the same substrates. Probably the best example of this is CaMKII and PKC phosphorylation of AMPA receptors. Strikingly, CaMKII and PKC phosphorylate the identical amino acid on GluR1 AMPA receptors, a post-translational event that increases current through the receptor. Thus, the AMPA receptor serves as a functional integrator of inputs from the PKC and CaMKII pathways. This is likely to explain the experimental observation that simultaneous inhibition of both PKC and CaMKII is necessary to reverse the expression of E-LTP .
CONSEQUENCES OF SIGNAL INTEGRATION The net effect of signal integration mechanisms such as those described above is to allow disparate stimuli to achieve additive, synergistic, or redundant effects in the induction or expression of LTP.
Theme Three Signal Divergence Protein kinases are pluripotent molecules. Activation of a single subtype of protein kinase typically elicits changes in a wide variety of downstream cellular targets. To pick just one example in the context of LTP, PKA can regulate AMPA receptors, voltage-dependent K+ channels, voltage-dependent Ca2+ channels, and gene transcription (through CREB phosphorylation). Thus, through the pluripotence of protein kinases, a single molecular signal can produce broadly divergent responses in the cell. The functional consequence is that activation of a single signaling cascade can produce a multicomponent but coordinated molecular response that is geared toward a unified cellular outcome.
Epiphenomena and a New Biology of Cellular Communication in the CNS Before concluding, I would like to briefly discuss one additional topic. A reasonably large number of LTP experiments have been performed looking at biochemical changes resulting from LTP-inducing stimulation. Measuring correlative changes in this fashion is subject to the criticism that the observed changes may simply be epiphenomena. I assume that what is meant by this criticism is that the observed change may not be causally related to increasing synaptic strength, at least by any mechanism we can conceive of at the present time. My bias is that true biochemical epiphenomena, that is, stimulus-evoked events causally related to nothing, are rare. Nevertheless, the epiphenomenon criticism misses the point of these types of biochemical experiments on two counts. One is that, as described above, they test specific predictions of various models for how LTP works and indeed are a very powerful test in the context of additional data using inhibitors and activators of the pathway under study. A second goal of these types of experiments, which is often overlooked, is that they can give insights into the cellular locus of plastic changes. As has been emphasized by one of the pioneers in this area, Aryeh Routtenberg, this second aspect is nicely illustrated by biochemical studies of the presynaptic protein GAP-43, also known as B50, F1, and neuromodulin,. There is very good biochemical evidence that PKC-mediated GAP-43 phosphorylation increases in LTP. Taking these GAP-43 data together with other biochemical evidence from studies of other presynaptic proteins, a strong case can be made that NMDA receptor-dependent, postsynaptically induced presynaptic changes occur in LTP. Are these changes causally related to increasing neurotransmitter release? In the case of GAP-43, probably not. But to dismiss the data on this basis is to miss the much more profound conclusion that can be drawn from the observation; neurons in the CNS are capable of retrograde signaling. This conclusion stands independent of whether or not increased neurotransmitter release contributes to the expression of LTP.
Concluding Comments It is impossible to formulate a comprehensive molecular model of LTP at this time. This commentary serves as a first attempt at reducing the enormously complicated molecular picture of LTP to a manageable level by emphasizing a common vocabulary, outlining a set of criteria for categorizing molecular studies of LTP, and presenting an initial model for the core signal transduction mechanisms of LTP. My overriding goal has been to present an optimistic outlook on the state of our understanding of LTP through these devices.
As studies of synaptic function have proceeded from the peripheral to the central nervous system, one common characteristic of CNS synapses is their astounding plasticity. It is likely that many synapses in the CNS have no static, default level, but from the moment of formation are subject to regulation by plastic processes. In this light, an understanding of synaptic function in the CNS cannot be derived independently of an understanding of the mechanisms of synaptic plasticity. In many respects studies of LTP are the driving force in advancing our understanding of basic synaptic biology in the CNS.
Should we have a moratorium on molecular studies of LTP , or should molecular studies proceed apace? I liken our assembling a complete molecular model for LTP to assembling a jigsaw puzzle. When putting together a puzzle you typically first find the edge pieces, which are readily recognizable by a single characteristic. When progressing to the interior of the puzzle one looks for patterns and colors to identify pieces to be able to group together and assemble known components of the overall picture. In the final stages one can many times identify the place for an individual puzzle piece simply on the basis of its shape being appropriate to fill an empty spot in the puzzle. At each stage different algorithms are used that lead to identification of the correct placement of pieces. At no stage in the process is one well-served by not having all the puzzle pieces available.
复习思考题
1. 神经胶质细胞有什么生理功能？如何理解它们在对神经细胞保护中所起的作用？
2. 如何理解中枢抑制的生理作用与临床意义？
3. 根据你已掌握的神经递质与受体的知识，怎样来制定治疗运动障碍性疾病（如帕金森氏病）的计划？
4. 根据LTP产生的分子机制，你认为人的记忆容量是否为有限的？
5. 在中枢神经系统内，神经元之间的联络方式有哪些，有何生理意义？
6. 何谓内脏痛，它有什么特征？牵涉痛发生的机制是什么？了解它有什么临床意义？
7. 何谓脊休克？它的主要表现和发生机理是什么？
8. 学习神经系统后，对你最大的帮助或启迪是什么？
参考文献
1. 姚泰 主编. 生理学，第五版，北京：人民卫生出版社，2002 P47~74
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