2024年12月3日 (二) 15:27的版本

神经系统的突触传递

本页英文内容取自：经典教材医学生理学（第三版） (Medical Physiology, 3rd Edtion, Walter F Boron, published in 2016)

中文内容由 BH1RBH (Jack Tan) 粗糙翻译

蓝色 【注】 后内容为 BH1RBH (Jack Tan) 所加之注释

After meticulous study of spinal reflexes, Charles Sherrington N10-2 deduced that neurons somehow communicate information, one to the next, by a mechanism that is fundamentally different from the way that they conduct signals along their axons. Sherrington had merged his physiological conclusions with the anatomical observations (Fig. 13-1) of his contemporary, the preeminent neuroanatomist Santiago Ramón y Cajal. N10-1 Ramón y Cajal had proposed that neurons are distinct entities, fundamental units of the nervous system that are discontinuous with each other. Discontinuous neurons must nevertheless communicate, and Sherrington in 1897 proposed that the synapse, a specialized apposition between cells, mediates the signals. The word synapse implies “contiguity, not continuity” between neurons, as Ramón y Cajal himself explained it. When the fine structure of synapses was finally revealed with the electron microscope in the 1950s, the vision of Ramón y Cajal and Sherrington was amply sustained. Neurons come very close together at chemical synapses (see p. 206), but their membranes and cytoplasm remain distinct. At electrical synapses (see p. 205), which are less common than chemical synapses, the membranes remain distinct, but ions and other small solutes can diffuse through the gap junctions, a form of continuity.

在对脊髓反射进行细致的研究后，Charles Sherrington [N10-2] 推断出神经元以某种方式将信息从一个传递到另一个，这种机制与它们沿轴突传导信号的方式根本不同。Sherrington 将他的生理学结论与他同时代杰出的神经解剖学家 Santiago Ramón y Cajal 的解剖观察（图 13-1）相结合[N10-1]Ramón y Cajal 提出神经元是不同的实体，是神经系统的基本单位，彼此不连续。然而，不连续的神经元必须进行交流，Sherrington 在 1897 年提出突触，即细胞之间的特殊并置，介导信号。突触这个词意味着神经元之间的“毗连性，而不是连续性”，正如 Ramón y Cajal 本人所解释的那样。当电子显微镜最终在 1950 年代揭示突触的精细结构时，Ramón y Cajal 和 Sherrington 的愿景得到了充分的支持。神经元在化学突触处非常靠近（见第 206 页），但它们的膜和细胞质仍然不同。在电突触（见第 205 页）处，比化学突触更不常见，膜保持清晰，但离子和其他小溶质可以通过间隙连接扩散，这是一种连续性形式。

1 Neuronal Synapses（神经元突触）

1.1 神经元突触的分子机制与神经肌肉接头的分子机制相似但不相同

The molecular mechanisms of neuronal synapses are similar but not identical to those of the neuromuscular junction

Chemical synapses use diffusible transmitter molecules to communicate messages between two cells. The first chemical synapse to be understood in detail was the neuromuscular junction (the nerve-muscle synapse) in vertebrate skeletal muscle, which is described in Chapter 8. In this chapter, we are concerned with the properties of the synapses that occur between neurons. We now know that all synapses share certain basic biochemical and physiological mechanisms, and thus many basic insights gained from the neuromuscular junction are also applicable to synapses in the brain. However, neuronal synapses differ from neuromuscular junctions in many important ways; they also differ widely among themselves, and it is the diverse properties of synapses that help make each part of the brain unique.

化学突触使用可扩散的递质分子在两个细胞之间传递信息。第一个需要详细理解的化学突触是脊椎动物骨骼肌中的神经肌肉接头（神经肌肉突触），这在第 8 章中进行了描述。在本章中，我们关注神经元之间发生的突触的特性。我们现在知道所有突触都有某些基本的生化和生理机制，因此从神经肌肉接头获得的许多基本见解也适用于大脑中的突触。然而，神经元突触在许多重要方面与神经肌肉接头不同；它们之间也有很大差异，正是突触的不同特性有助于使大脑的每个部分都独一无二。

It is useful to begin by reviewing some of the mechanisms that are common to all chemical synapses (see Figs. 8-2 and 8-3). N13-1 Synaptic transmission at chemical synapses occurs in seven steps:

首先回顾所有化学突触共有的一些机制是有用的（见图 8-2 和 8-3）。N13-1 化学突触的突触传递分为七个步骤：

Step 1: Neurotransmitter molecules are packaged into membranous vesicles, and the vesicles are concentrated and docked at the presynaptic terminal.

第 1 步：神经递质分子被包装成膜囊泡，囊泡浓缩并停靠在突触前末梢。

Step 2: The presynaptic membrane depolarizes, usually as the result of an action potential, although some synapses respond to graded variations of membrane potential (Vm).

第 2 步：突触前膜去极化，通常是动作电位的结果，尽管一些突触对膜电位 (Vm) 的分级变化做出反应。

Step 3: The depolarization causes voltage-gated Ca2+ channels to open and allows Ca2+ ions to flow into the terminal.

第 3 步：去极化导致电压门控 Ca2+ 通道打开，并允许 Ca2+ 离子流入端子。

Step 4: The resulting increase in intracellular [Ca2+] triggers fusion of vesicles with the presynaptic membrane (see pp. 219–221), and the rate of transmitter release increases ~100,000-fold above baseline. The Ca2+ dependence of fusion is conferred by neuron-specific protein components of the fusion apparatus called synaptotagmins. The actual fusion events are incredibly fast; each individual exocytosis requires only a fraction of a millisecond to be completed.

第 4 步：细胞内 [Ca2+] 的增加触发囊泡与突触前膜的融合（参见第 219-221 页），递质释放速率比基线增加 ~100,000 倍。融合的 Ca2+ 依赖性是由融合装置的神经元特异性蛋白质成分（称为突触结合蛋白）赋予的。实际的融合事件非常快;每个单独的胞吐作用只需要几分之一毫秒即可完成。

Step 5: The transmitter is released into the extracellular space in quantized amounts and diffuses passively across the synaptic cleft.

第 5 步：递质以量化量释放到细胞外间隙中，并被动地扩散穿过突触间隙。

Step 6: Some of the transmitter molecules bind to receptors in the postsynaptic membrane, and the activated receptors trigger some postsynaptic event, usually the opening of an ion channel or the activation of a G protein–coupled signal cascade.

第 6 步：一些递质分子与突触后膜中的受体结合，激活的受体触发一些突触后事件，通常是离子通道的打开或 G 蛋白偶联信号级联的激活。

Step 7: Transmitter molecules diffuse away from postsynaptic receptors and are eventually cleared away by continued diffusion, enzymatic degradation, or active uptake into cells. In addition, the presynaptic machinery retrieves the membrane of the exocytosed synaptic vesicle, perhaps by endocytosis from the cell surface.

第 7 步：递质分子从突触后受体扩散出去，最终通过持续扩散、酶降解或主动摄取到细胞中清除。此外，突触前机制可能通过细胞表面的内吞作用取回胞吐作用突触囊泡的膜。

The molecular machinery of synapses is closely related to components that are universal in eukaryotic cells (see p. 37). A large set of proteins is involved in the docking and fusion of vesicles, and the proteins present in nerve terminals are remarkably similar to the ones mediating fusion and secretion in yeast. Docking and fusion of synaptic vesicles are discussed on page 219. Ligand-gated ion channels and G protein–coupled receptors (GPCRs), the receptors on the postsynaptic membrane, are also present in all eukaryotic cells and mediate processes as disparate as the recognition of nutrients and poisons, and the identification of other members of the species. Even most of the neurotransmitters themselves are simple molecules, identical or very similar to those used in general cellular metabolism. Clearly, the evolutionary roots of synaptic transmission are much older than nervous systems themselves.

突触的分子机制与真核细胞中普遍存在的成分密切相关（见第 37 页）。大量蛋白质参与囊泡的对接和融合，存在于神经末梢的蛋白质与酵母中介导融合和分泌的蛋白质非常相似。突触小泡的对接和融合在第 219 页讨论。配体门控离子通道和 G 蛋白偶联受体 （GPCR） 是突触后膜上的受体，也存在于所有真核细胞中，并介导与识别营养物质和毒物以及识别该物种的其他成员一样不同的过程。甚至大多数神经递质本身也是简单的分子，与一般细胞代谢中使用的分子相同或非常相似。显然，突触传递的进化根源比神经系统本身要古老得多。

Within nervous systems, however, myriad variations on the basic molecular building blocks yield synapses with wide-ranging properties. Neuronal synapses vary widely in the size of the synaptic contact, the identity of the neurotransmitter, the nature of the postsynaptic receptors, the efficiency of synaptic transmission, the mechanism used for terminating transmitter action, and the degree and modes of synaptic plasticity. Thus, the properties of neuronal synapses can be tuned to achieve the diverse functions of the brain.

然而，在神经系统中，基本分子构建单元的无数变化会产生具有广泛特性的突触。神经元突触在突触接触的大小、神经递质的身份、突触后受体的性质、突触传递的效率、用于终止递质作用的机制以及突触可塑性的程度和模式方面差异很大。因此，可以调整神经元突触的特性以实现大脑的各种功能。

A major difference between the neuromuscular junction and most neuronal synapses is the type of neurotransmitter used. All skeletal neuromuscular junctions use acetylcholine (ACh). In contrast, neuronal synapses use many transmitters. The most ubiquitous are amino acids: glutamate and aspartate excite, whereas gamma-aminobutyric acid (GABA) and glycine inhibit. Other transmitters include simple amines, such as ACh, norepinephrine, serotonin, and histamine, ubiquitous molecules such as ATP and adenosine, and a wide array of peptides.

神经肌肉接头和大多数神经元突触之间的一个主要区别是所使用的神经递质类型。所有骨骼神经肌肉接头都使用乙酰胆碱 （ACh）。相比之下，神经元突触使用许多递质。最普遍的是氨基酸：谷氨酸和天冬氨酸兴奋，而 γ-氨基丁酸 （GABA） 和甘氨酸则具有抑制作用。其他递质包括简单的胺，如 ACh、去甲肾上腺素、血清素和组胺，普遍存在的分子，如 ATP 和腺苷，以及多种肽。

Even more varied than the neuronal transmitters are their receptors. Whereas skeletal muscle manufactures a few modest variants of its ACh receptors, the nervous system typically has several major receptor variants for each neurotransmitter. Knowledge about the wide range of transmitters and receptors is essential to understand the chemical activity of the brain as well as the drugs that influence brain activity. For one thing, the many transmitter systems in the brain generate responses with widely varying durations that range from a few milliseconds to days (Fig. 13-2).

比神经元递质更多样化的是它们的受体。骨骼肌产生一些适度的 ACh 受体变体，而神经系统通常为每种神经递质提供几种主要的受体变体。了解各种递质和受体对于了解大脑的化学活动以及影响大脑活动的药物至关重要。首先，大脑中的许多发射器系统产生的反应持续时间差异很大，从几毫秒到几天不等（图 13-2）。

1.2 突触前末梢可能接触树突、体细胞或轴突处的神经元，并且可能包含透明囊泡和致密核心颗粒

Presynaptic terminals may contact neurons at the dendrite, soma, or axon and may contain both clear vesicles and dense-core granules

Chemical synapses between neurons are generally small, often <1 μm in diameter, which means that their detailed structure can be seen only with an electron microscope (Fig. 13-3); under the light microscope, brain synapses are usually visible only as swellings along or at the termination of the axons (see Fig. 13-1). These swellings are actually the silhouettes of the bouton terminals—the presynaptic terminals. Most presynaptic terminals arise from axons, and they can form synapses on virtually any part of a neuron. The contact site and direction of communication determine the way in which a synapse is named: axodendritic, axosomatic, and axoaxonic synapses (Fig. 13-4). These synapses are the most common types in the nervous system. In many cases, synapses occur on small outpockets of the dendritic membrane called spines and are termed axospinous synapses. However, not all synapses arise from axons, and dendrodendritic, somatosomatic, and even somatodendritic synapses may be found in the mammalian brain.

神经元之间的化学突触通常很小，直径通常为 <1 μm，这意味着它们的详细结构只能用电子显微镜看到（图 13-3）；在光学显微镜下，脑突触通常只能看到沿轴突或轴突末端的肿胀（见图 13-1）。这些肿胀实际上是钮扣末梢的轮廓——突触前末梢。大多数突触前末梢起源于轴突，它们几乎可以在神经元的任何部分形成突触。接触部位和通信方向决定了突触的命名方式：轴突突触、轴突突触和轴突突触（图 13-4）。这些突触是神经系统中最常见的类型。在许多情况下，突触发生在树突状膜的小外袋上，称为轴棘突触。然而，并非所有突触都起源于轴突，树突突、体体甚至体突突可能在哺乳动物的大脑中发现。

Despite their differences in size, site, and shape, all synapses share one basic function: they deliver a small amount of chemical transmitter onto a circumscribed patch of postsynaptic membrane. To accomplish this task, they use certain common anatomical features, most of them familiar from discussions of the neuromuscular junction (see Chapter 8).

尽管它们的大小、位置和形状不同，但所有突触都有一个基本功能：它们将少量化学递质输送到突触后膜的限定斑块上。为了完成这项任务，他们使用了某些常见的解剖特征，其中大多数在神经肌肉接头的讨论中很熟悉（见第 8 章）。

Synapses are polarized, which means that their two apposed sides have different structures. This polarity reflects the fact that most synapses transmit information primarily in one direction, although retrograde transmission also occurs in many synapses in one direction but not in the other (we will see that some rare exceptions do exist). The presynaptic side contains numerous clear vesicles, 40 to 50 nm in diameter, that appear empty when viewed by transmission electron microscopy. Synaptic termini may also contain large (100 to 200 nm in diameter) dense-core secretory granules that are morphologically quite similar to the secretory granules of endocrine cells. These granules contain neuropeptides; that is, peptides or small proteins that act as neurotransmitters and for which receptors exist in the postsynaptic membranes. Many of these neuropeptides are identical to substances secreted by “traditional” endocrine cells. Endocrine hormones such as adrenocorticotropic hormone, vasoactive intestinal peptide, and cholecystokinin are found in dense-core secretory granules present in the terminals of certain central and peripheral neurons.

突触是极化的，这意味着它们的两个并置侧具有不同的结构。这种极性反映了大多数突触主要在一个方向上传递信息的事实，尽管逆行传递也发生在一个方向的许多突触中，但不发生在另一个方向上（我们将看到确实存在一些罕见的例外）。突触前侧包含许多直径为 40 至 50 nm 的透明囊泡，通过透射电子显微镜观察时看起来是空的。突触末端也可能包含大的（直径为 100 至 200 nm）致密核心分泌颗粒，其形态与内分泌细胞的分泌颗粒非常相似。这些颗粒含有神经肽;也就是说，充当神经递质的肽或小蛋白，其受体存在于突触后膜中。这些神经肽中的许多与 “传统” 内分泌细胞分泌的物质相同。内分泌激素，如促肾上腺皮质激素、血管活性肠肽和胆囊收缩素，存在于某些中枢和外周神经元末端的致密核心分泌颗粒中。

The clear synaptic vesicles (i.e., not the dense-core granules) are anchored and shifted about by a dense network of cytoskeletal proteins. Some vesicles are clustered close to the part of the presynaptic membrane that apposes the synaptic contact; these vesicle attachment sites are called active zones. Synaptic vesicles are lined up several deep along the active zones, which are the regions of actual exocytosis. The number of active zones per synapse varies greatly (active zones are marked with arrows in the synapses in Fig. 13-3). Most synapses in the central nervous system (CNS) have relatively few active zones, often only 1 but occasionally as many as 10 or 20 (versus the hundreds in the neuromuscular junction). If we could view the presynaptic face of an active zone from the perspective of a synaptic vesicle, we would see filaments and particles projecting from the presynaptic membrane, often forming a regular hexagonal arrangement called a presynaptic grid. Specific points along the grid are thought to be the vesicle release sites.

透明的突触囊泡（即不是致密的核心颗粒）被致密的细胞骨架蛋白网络锚定和移动。一些囊泡聚集在突触前膜与突触接触的部分附近;这些囊泡附着位点称为活动区。突触囊泡沿着活动区排列了几个深处，这些活动区是实际胞吐作用的区域。每个突触的活性区数量差异很大（图 13-3 中活性区在突触中用箭头标记）。中枢神经系统 （CNS） 中的大多数突触的活动区相对较少，通常只有 1 个，但偶尔多达 10 或 20 个（而神经肌肉接头有数百个）。如果我们能从突触小泡的角度观察活动区的突触前面，我们会看到从突触前膜伸出的细丝和颗粒，通常形成一个规则的六边形排列，称为突触前网格。沿网格的特定点被认为是囊泡释放部位。

Unlike the clear synaptic vesicles containing nonpeptide transmitters, dense-core secretory granules are distributed randomly throughout the cytoplasm of the synaptic terminus. They are not concentrated at the presynaptic density, and they do not appear to release their contents at the active zone. Although the molecular pathways that control exocytosis of the neuronal dense-core granules are still being elucidated, it appears that a rise in [Ca2+]i is a primary stimulus.

与含有非肽递质的透明突触囊泡不同，致密核心分泌颗粒随机分布在整个突触末端的细胞质中。它们不集中在突触前密度，并且它们似乎不会在活性区释放其内容物。尽管控制神经元致密核心颗粒胞吐作用的分子途径仍在阐明中，但 [Ca2+]i 的增加似乎是主要刺激因素。

1.3 突触后膜包含递质受体和许多聚集在突触后致密区的蛋白质

The postsynaptic membrane contains transmitter receptors and numerous proteins clustered in the postsynaptic density

The postsynaptic membrane lies parallel to the presynaptic membrane, and they are separated by a narrow synaptic cleft (~30 nm wide) that is filled with extracellular fluid. Transmitter molecules released from the presynaptic terminal must diffuse across the cleft to reach postsynaptic receptors. The most characteristic anatomical feature of the postsynaptic side is the postsynaptic density, a strip of granular material visible under the electron microscope on the cytoplasmic face of the membrane (see Fig. 13-3). The most important molecular feature of the postsynaptic side is the cluster of transmitter receptors embedded within the postsynaptic membrane. Staining methods that use specific antibodies, toxins, or ligands coupled to some visible tag molecule can reveal the positions of the receptors.

突触后膜与突触前膜平行，它们被一个充满细胞外液的狭窄突触裂隙（~30 nm 宽）隔开。从突触前末梢释放的递质分子必须穿过裂隙扩散才能到达突触后受体。突触后侧最具特征的解剖学特征是突触后致密，即在电子显微镜下在膜的细胞质表面可见的一条颗粒状物质（见图 13-3）。突触后侧最重要的分子特征是嵌入突触后膜内的递质受体簇。使用特异性抗体、毒素或配体与一些可见标签分子偶联的染色方法可以揭示受体的位置。

In >90% of all excitatory synapses in the CNS, the postsynaptic site is a dendritic spine. The ubiquity of spines implies that they serve prominent functions, but their small size (usually <1 μm long) makes their function extremely difficult to study. Spines come in a variety of shapes, and their density varies from one dendrite to another (Fig. 13-5); indeed, some central neurons have no spines. The postsynaptic density of spines (as for all central synapses) contains >30 proteins in high concentration, including transmitter receptors, protein kinases, a host of structural proteins, and proteins that are involved in endocytosis and glycolysis.

在 CNS 中 >90% 的兴奋性突触中，突触后部位是树突状棘。棘的普遍性意味着它们发挥着突出的功能，但它们的小尺寸（通常<1微米长）使得它们的功能极难研究。棘的形状多种多样，它们的密度因树突而异（图 13-5）;事实上，一些中枢神经元没有棘。棘的突触后密度（与所有中枢突触一样）包含 >30 种高浓度的蛋白质，包括递质受体、蛋白激酶、宿主结构蛋白，以及参与内吞作用和糖酵解的蛋白质。

Numerous functions for spines have been proposed. It may be that spines increase the opportunity for a dendrite to form synapses with nearby axons. Many hypotheses have focused on the possibility that spines isolate individual synapses from the rest of a cell. This isolation may be electrical or chemical; the narrow spine neck may reduce current flow or the diffusion of chemicals from the spine head into the dendritic shaft. Evidence suggests that the high electrical resistance of the spine neck can amplify the size of an excitatory postsynaptic potential within the spine while reducing its amplitude along the shaft of the dendrite; this mechanism may allow neurons to integrate larger numbers of synaptic inputs. Activation of some excitatory synapses allows substantial amounts of Ca2+ to enter the postsynaptic cell. Spines may compartmentalize this Ca2+, thus allowing it to rise to higher levels or preventing it from influencing other synapses on the cell. Because increases in postsynaptic [Ca2+]i are an essential trigger for many forms of long-term synaptic plasticity, an attractive but unproven possibility is that dendritic spines play an important role in the mechanisms of learning and memory.

已经提出了许多用于脊柱的功能。可能是棘增加了树突与附近轴突形成突触的机会。许多假说都集中在脊柱将单个突触与细胞其余部分隔离开来的可能性上。这种隔离可以是电气的或化学的;狭窄的棘颈可能会减少电流或化学物质从脊柱头扩散到树突轴。有证据表明，脊柱颈部的高电阻可以放大脊柱内兴奋性突触后电位的大小，同时减小其沿树突干的振幅;这种机制可能允许神经元整合更多的突触输入。一些兴奋性突触的激活允许大量 Ca2+ 进入突触后细胞。棘可以将这种 Ca2+ 区区，从而使其上升到更高的水平或防止它影响细胞上的其他突触。因为突触后 [Ca2+]i 的增加是许多形式的长期突触可塑性的重要触发因素，所以一个有吸引力但未经证实的可能性是树突棘在学习和记忆机制中起着重要作用。

1.4 弥散分布的神经元系统使用一些递质来调节大脑的一般兴奋性

Some transmitters are used by diffusely distributed systems of neurons to modulate the general excitability of the brain

The brain carries out many sensory, motor, and cognitive functions that require fast, specific, spatially organized neural connections and operations. Consider the detailed neural mapping that allows you to read this sentence or the precise timing required to play the piano. These functions require spatially focused networks (Fig. 13-6A).

大脑执行许多感觉、运动和认知功能，这些功能需要快速、特定、空间组织的神经连接和操作。考虑一下允许您阅读这句话的详细神经映射或弹奏钢琴所需的精确时间。这些功能需要空间聚焦的网络（图 13-6A）。

Other functions, such as falling asleep, waking up, becoming attentive, or changing mood, involve more general alterations of the brain. Several systems of neurons regulate the general excitability of the CNS. Each of these modulatory systems uses a different neurotransmitter, and the axons of each make widely dispersed, diffuse, almost meandering synaptic connections to carry a simple message to vast regions of the brain. This arrangement can be achieved by a widely divergent network (see Fig. 13-6B). The functions of the different systems are not well understood, but each appears to be essential for certain aspects of arousal, motor control, memory, mood, motivation, and metabolic state. The modulatory systems are of central importance to clinical medicine. Both the activity of psychoactive drugs and the pathological processes of most psychiatric disorders seem to involve alterations in one or more of the modulatory systems.

其他功能，例如入睡、醒来、变得专注或改变情绪，涉及大脑的更普遍改变。几个神经元系统调节 CNS 的一般兴奋性。这些调节系统中的每一个都使用不同的神经递质，每个系统的轴突建立广泛分散、弥散、几乎蜿蜒的突触连接，将简单的信息传递到大脑的广大区域。这种安排可以通过一个发散广泛的网络来实现（见图 13-6B）。不同系统的功能尚不清楚，但每个系统似乎对于唤醒、运动控制、记忆、情绪、动机和代谢状态的某些方面都是必不可少的。调节系统对临床医学至关重要。精神活性药物的活性和大多数精神疾病的病理过程似乎都涉及一个或多个调节系统的改变。

The brain has several modulatory systems with diffuse central connections. Although they differ in structure and function, they have certain similarities:

大脑有几个具有弥散性中央连接的调节系统。尽管它们在结构和功能上有所不同，但它们具有某些相似之处：

1. Typically, a small set of neurons (several thousand) forms the center of the system.

1. 通常，一小群神经元（数千个）构成系统的中心。

2. Neurons of the diffuse systems arise from the central core of the brain, most of them from the brainstem.

2. 弥散系统的神经元来自大脑的中央核心，其中大部分来自脑干。

3. Each neuron can influence many others because each one has an axon that may contact tens of thousands of postsynaptic neurons spread widely across the brain.

3. 每个神经元都可以影响许多其他神经元，因为每个神经元都有一个轴突，可以接触广泛分布在大脑中的数以万计的突触后神经元。

4. The synapses made by some of these systems seem designed to release transmitter molecules into the extracellular fluid so that they can diffuse to many neurons rather than be confined to the vicinity of a single synaptic cleft.

4. 其中一些系统产生的突触似乎旨在将递质分子释放到细胞外液中，以便它们可以扩散到许多神经元，而不是局限于单个突触间隙附近。

The main modulatory systems of the brain are distinct anatomically and biochemically. Separate systems use norepinephrine, serotonin (5-hydroxytryptamine [5-HT]), dopamine, ACh, or histamine as their neurotransmitter. They all tend to involve numerous metabotropic transmitter receptors (see p. 206). Unlike ionotropic receptors, which are themselves ion channels, metabotropic receptors are coupled to enzymes such as adenylyl cyclase or phospholipase C through G proteins. For example, the brain has 10 to 100 times more metabotropic (i.e., muscarinic) ACh receptors than ionotropic (i.e., nicotinic) ACh receptors. We briefly describe the anatomy and possible functions of each major system (Fig. 13-7).

大脑的主要调节系统在解剖学和生化学上是不同的。单独的系统使用去甲肾上腺素、血清素（5-羟色胺 [5-HT]）、多巴胺、ACh 或组胺作为其神经递质。它们都倾向于涉及许多代谢性递质受体（见第 206 页）。与本身是离子通道的离子型受体不同，代谢型受体通过 G 蛋白与腺苷酸环化酶或磷脂酶 C 等酶偶联。例如，大脑的代谢型（即毒蕈碱型）ACh 受体是离子型（即烟碱型）ACh 受体的 10 到 100 倍。我们简要描述了每个主要系统的解剖结构和可能的功能（图 13-7）。

Norepinephrine-containing neurons are in the tiny locus coeruleus (from the Latin for “blue spot” because of the pigment in its cells), located bilaterally in the brainstem (see Fig. 13-7A). Each human locus coeruleus has ~12,000 neurons. Axons from the locus coeruleus innervate just about every part of the brain: the entire cerebral cortex, the thalamus and hypothalamus, the olfactory bulb, the cerebellum, the midbrain, and the spinal cord. Just one of its neurons can make >250,000 synapses, and that cell can have one axon branch in the cerebral cortex and another in the cerebellar cortex! Locus coeruleus cells seem to be involved in the regulation of attention, arousal, and sleep-wake cycles as well as in learning and memory, anxiety and pain, mood, and brain metabolism. Recordings from awake rats and monkeys in behavioral studies show that locus coeruleus neurons are best activated by new, unexpected, nonpainful sensory stimuli in the animal’s environment. They are least active when the animals are not vigilant, just sitting around quietly digesting a meal. The locus coeruleus may participate in general arousal of the brain during interesting events in the outside world.

含去甲肾上腺素的神经元位于脑干双侧的微小蓝斑（来自拉丁语中的“蓝点”，因为它的细胞中有色素），（见图 13-7A）。每个人类蓝斑位点都有 ~12,000 个神经元。来自蓝斑的轴突几乎支配大脑的每个部分：整个大脑皮层、丘脑和下丘脑、嗅球、小脑、中脑和脊髓。只要它的一个神经元可以产生>250,000个突触，而这个细胞可以在大脑皮层中有一个轴突分支，在小脑皮层中可以有一个轴突分支！蓝斑细胞似乎参与注意力、唤醒和睡眠-觉醒周期的调节，以及学习和记忆、焦虑和疼痛、情绪和大脑新陈代谢。行为研究中清醒的大鼠和猴子的记录表明，蓝斑神经元最好被动物环境中新的、意想不到的、无痛的感觉刺激激活。当动物不警惕时，它们最不活跃，只是静静地坐在那里消化一顿饭。蓝斑可能在外界的有趣事件中参与大脑的一般唤醒。

Serotonin-containing neurons are mostly clustered within the nine raphé nuclei (see Fig. 13-7B). Raphé means “ridge” or “seam” in Greek, and indeed the raphé nuclei lie to either side of the midline of the brainstem. Each nucleus projects to different regions of the brain, and together they innervate most of the CNS in the same diffuse way as the locus coeruleus neurons. Similar to neurons of the locus coeruleus, cells of the raphé nuclei fire most rapidly during wakefulness, when an animal is aroused and active. Raphé neurons are quietest during certain stages of sleep. The locus coeruleus and the raphé nuclei are part of a venerable concept called the ascending reticular activating system, which implicates the reticular “core” of the brainstem in processes that arouse and awaken the forebrain. Raphé neurons seem to be intimately involved in the control of sleep-wake cycles as well as the different stages of sleep. Serotonergic raphé neurons have also been implicated in the control of mood and certain types of emotional behavior. Many hallucinogenic drugs, such as lysergic acid diethylamide (LSD), apparently exert their effects through interaction with serotonin receptors. Serotonin may also be involved in clinical depression; some of the most effective drugs now used to treat depression (e.g., fluoxetine [Prozac]) are potent blockers of serotonin re-uptake and thus prolong its action in the brain.

含血清素的神经元大多聚集在 9 个 raphé 核内（见图 13-7B）。Raphé 在希腊语中的意思是“脊”或“接缝”，事实上，raphé 核位于脑干中线的两侧。每个细胞核都投射到大脑的不同区域，它们一起以与蓝斑神经元相同的弥散方式支配大部分 CNS。与蓝斑的神经元类似，raphé 核的细胞在清醒时最迅速地放电，此时动物被唤醒并活跃。Raphé 神经元在睡眠的某些阶段是最安静的。蓝斑和 raphé 核是一个古老的概念的一部分，称为升位网状激活系统，它涉及脑干的网状“核心”参与唤醒和唤醒前脑的过程。Raphé 神经元似乎与睡眠-觉醒周期的控制以及睡眠的不同阶段密切相关。血清素能 raphé 神经元也与情绪和某些类型的情绪行为的控制有关。许多致幻药物，如麦角酸二乙胺 （LSD），显然通过与血清素受体的相互作用来发挥作用。血清素也可能与临床抑郁症有关;现在用于治疗抑郁症的一些最有效的药物（例如氟西汀 [百忧解]）是血清素再摄取的有效阻断剂，从而延长其在大脑中的作用。

Although dopamine-containing neurons are scattered throughout the CNS, two closely related groups of dopaminergic cells have characteristics of the diffuse modulatory systems (see Fig. 13-7C). One of these groups is the substantia nigra in the midbrain. Its cells project axons to the striatum, a part of the basal ganglia, and they somehow facilitate the initiation of voluntary movement. Degeneration of the dopamine-containing cells in the substantia nigra produces the progressively worsening motor dysfunction of Parkinson disease. Another set of dopaminergic neurons lies in the ventral tegmental area of the midbrain; these neurons innervate the part of the forebrain that includes the prefrontal cortex and parts of the limbic system. They have been implicated in neural systems that mediate reinforcement or reward as well as in aspects of drug addiction and psychiatric disorders, most notably schizophrenia. Members of the class of antipsychotic drugs called neuroleptics are antagonists of certain dopamine receptors.

尽管含多巴胺的神经元分散在整个 CNS 中，但两组密切相关的多巴胺能细胞具有弥漫性调节系统的特征（见图 13-7C）。其中一组是中脑中的黑质。它的细胞将轴突投射到纹状体（基底神经节的一部分），它们以某种方式促进了自主运动的启动。黑质中含多巴胺的细胞变性导致帕金森病的运动功能障碍进行性恶化。另一组多巴胺能神经元位于中脑的腹侧被盖区;这些神经元支配前脑的一部分，包括前额叶皮层和边缘系统的一部分。它们与介导强化或奖励的神经系统以及药物成瘾和精神疾病（最著名的是精神分裂症）方面有关。称为抗精神病药的一类抗精神病药物的成员是某些多巴胺受体的拮抗剂。

Acetylcholine is the familiar transmitter of the neuromuscular junction and the autonomic nervous system. Within the brain are two major diffuse modulatory cholinergic systems: the basal forebrain complex (which innervates the hippocampus and all of the neocortex) and the pontomesencephalotegmental cholinergic complex (which innervates the dorsal thalamus and parts of the forebrain) (see Fig. 13-7D). The functions of these systems are poorly understood, but interest has been fueled by evidence that they are involved in the regulation of general brain excitability during arousal and sleep-wake cycles as well as perhaps in learning and memory formation.

乙酰胆碱是神经肌肉接头和自主神经系统的常见递质。大脑内有两个主要的弥漫性调节胆碱能系统：基底前脑复合体（支配海马体和所有新皮层）和脑桥脑胆碱能复合体（支配背丘脑和前脑部分）（见图 13-7D）。这些系统的功能知之甚少，但有证据表明它们参与唤醒和睡眠-觉醒周期期间一般大脑兴奋性的调节，并且可能参与学习和记忆形成，这激发了人们的兴趣。

Collectively, the diffuse modulatory systems may be viewed as providing general regulation of brain function, much like the autonomic nervous system (see Chapter 14) regulates the organ systems of the body. Because their axons spread so widely within the CNS, the few modulatory neurons can have an inordinately strong influence on behavior.

总的来说，弥散调节系统可以被视为提供大脑功能的一般调节，就像自主神经系统（见第 14 章）调节身体的器官系统一样。因为它们的轴突在 CNS 内传播得如此广泛，所以少数调节神经元可以对行为产生非常强大的影响。

1.5 电突触在哺乳动物神经系统中发挥着特殊功能

Electrical synapses serve specialized functions in the mammalian nervous system

Many cells are coupled to one another through gap junctions. The large and relatively nonselective gap junction channels (see p. 165) allow ion currents to flow in both directions (in most types of gap junctions) or unidirectionally (in rare types). It follows from Ohm’s law that if two cells are coupled by gap junctions and they have different membrane voltages, current will flow from one cell into the other (see Fig. 6-18C). If the first cell generates an action potential, current will flow through the gap junction channels and depolarize the second cell; this type of current flow, for example, is the basis for conduction of excitation across cardiac muscle. Such an arrangement has all the earmarks of a synapse, and indeed, when gap junctions interconnect neurons, we describe them as electrical synapses.

许多细胞通过间隙连接相互耦合。大且相对非选择性的间隙结通道（见第 165 页）允许离子电流双向流动（在大多数类型的间隙结中）或单向流动（在罕见类型中）。根据欧姆定律，如果两个电池通过间隙结耦合并且它们具有不同的膜电压，则电流将从一个电池流向另一个电池（见图 6-18C）。如果第一个电池产生动作电位，电流将流过间隙结通道并使第二个电池去极化;例如，这种类型的电流是磁激通过心肌传导的基础。这样的排列具有突触的所有特征，事实上，当间隙连接互连神经元时，我们将它们描述为电突触。

Electrical synapses would seem to have many advantages over chemical synapses: they are extremely fast and limited only by the time constants of the systems involved, they use relatively little metabolic energy or molecular machinery, they are highly reliable, and they can be bidirectional. Indeed, electrical synapses have now been observed in nearly every part of the mammalian CNS. They interconnect inhibitory neurons of the cerebral cortex and thalamus, excitatory neurons of the brainstem and retina, and a variety of other neurons in the hypothalamus, basal ganglia, and spinal cord. At nearly all of these sites, the gap junction protein connexin-36 (Cx36)—which is expressed exclusively in CNS neurons and β cells of the pancreas—is an essential component of the electrical synapse (see Fig. 6-18C). Glial cells in the brain express several other types of connexins. However, in all of the aforementioned sites, electrical synapses tend to be outnumbered by chemical synapses. Gap junctions universally interconnect the photoreceptors of the retina, astrocytes and other types of glia (see p. 289) throughout the CNS, and most types of cells early in development.

与化学突触相比，电突触似乎具有许多优势：它们速度极快，并且仅受所涉及系统的时间常数的限制，它们使用相对较少的代谢能或分子机制，它们高度可靠，并且可以是双向的。事实上，现在几乎在哺乳动物 CNS 的每个部分都观察到电突触。它们将大脑皮层和丘脑的抑制性神经元、脑干和视网膜的兴奋性神经元以及下丘脑、基底神经节和脊髓中的各种其他神经元相互连接。在几乎所有这些位点，间隙连接蛋白连接蛋白 36 （Cx36） — 仅在胰腺的 CNS 神经元和 β 细胞中表达 — 是电突触的重要组成部分（见图 6-18C）。大脑中的神经胶质细胞表达几种其他类型的连接蛋白。然而，在上述所有位点中，电突触的数量往往超过化学突触。间隙连接普遍互连整个 CNS 中视网膜、星形胶质细胞和其他类型的神经胶质细胞（见第 289 页）的光感受器，以及发育早期的大多数类型的细胞。

Why are chemical synapses, as complex and relatively slow as they are, more prevalent than electrical synapses in the mature brain? Comparative studies suggest several reasons for the predominance of chemical synapses among mammalian neurons. The first is amplification. Electrical synapses do not amplify the signal passed from one cell to the next; they can only diminish it. Therefore, if a presynaptic cell is small relative to its coupled postsynaptic cell, the current that it can generate through an electrical synapse will also be small, and thus “synaptic strength” will be low. By contrast, a small bolus of neurotransmitter from a chemical synapse can trigger an amplifying cascade of molecular events that can cause a relatively large postsynaptic change.

为什么在成熟大脑中，化学突触虽然复杂且相对缓慢，但比电突触更普遍？比较研究表明，化学突触在哺乳动物神经元中占主导地位的几个原因。首先是放大。电突触不会放大从一个细胞传递到另一个细胞的信号;他们只能减少它。因此，如果突触前细胞相对于其耦合的突触后细胞较小，则它可以通过电突触产生的电流也将很小，因此“突触强度”将较低。相比之下，来自化学突触的一小团神经递质可以触发分子事件的放大级联反应，从而导致相对较大的突触后变化。

A second advantage of chemical synapses is their ability to either excite or inhibit postsynaptic neurons selectively. Electrical synapses are not inherently excitatory or inhibitory, although they can mediate either effect under the right circumstances. Chemical synapses can reliably inhibit by simply opening channels that are selective for ions with relatively negative equilibrium potentials; they can excite by opening channels selective for ions with equilibrium potentials positive to resting potential.

化学突触的第二个优点是它们能够选择性地激发或抑制突触后神经元。电突触本身并不是兴奋性的或抑制性的，尽管它们可以在适当的情况下介导这两种作用。化学突触可以通过简单地打开对具有相对负平衡电位的离子具有选择性的通道来可靠地抑制;它们可以通过打开对离子选择性的通道进行激发，这些离子的平衡电位为正静息电位。

A third advantage of chemical synapses is that they can transmit information over a broad time domain. By using different transmitters, receptors, second messengers, and effectors, chemical synapses can produce a wide array of postsynaptic effects with time courses ranging from a few milliseconds to minutes and even hours. The effects of electrical synapses are generally limited to the time course of the presynaptic event.

化学突触的第三个优点是它们可以在很宽的时域上传输信息。通过使用不同的递质、受体、第二信使和效应器，化学突触可以产生广泛的突触后效应，时间过程从几毫秒到几分钟甚至几小时不等。电突触的影响通常仅限于突触前事件的时间进程。

A fourth advantage of chemical synapses is that they are champions of plasticity; their strength can be a strong function of recent neural activity, and they can therefore play a role in learning and memory, which are essential to the success of vertebrate species. Electrical synapses also display forms of long-term plasticity, although this has not been well studied in the mammalian CNS.

化学突触的第四个优点是它们是可塑性的冠军;它们的力量可以是近期神经活动的强大功能，因此它们可以在学习和记忆中发挥作用，这对脊椎动物物种的成功至关重要。电突触也显示出长期可塑性的形式，尽管这尚未在哺乳动物 CNS 中得到充分研究。

It might also be noted that the few perceived advantages of electrical synapses may be more apparent than real. Bidirectionality is clearly not useful in many neural circuits, and the difference in speed of transmission may be too small to matter in most cases. Electrical synapses serve important but specialized functions in the nervous system. They seem to be most prevalent in neural circuits in which speed or a high degree of synchrony is at a premium: quick-escape systems, the fine coordination of rapid eye movements, or the synchronization of neurons generating rhythmic activity. Gap junctions are also effective in diffusely spreading current through large networks of cells, which appears to be their function in photoreceptors and glia.

还可以注意到，电突触的少数感知优势可能比实际更明显。双向性在许多神经回路中显然没有用，而且在大多数情况下，传输速度的差异可能太小而无关紧要。电突触在神经系统中起着重要但特殊的功能。它们似乎在速度或高度同步至关重要的神经回路中最为普遍：快速逃脱系统、快速眼球运动的精细协调或神经元产生节律活动的同步。间隙连接还可有效地通过大型细胞网络扩散电流，这似乎是它们在光感受器和神经胶质细胞中的功能。

2 大脑的神经递质系统

NEUROTRANSMITTER SYSTEMS OF THE BRAIN

3 Reference

• Physiology
• Pharmacology
• Addiction
• BBB 血脑屏障概述

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