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== 轴突传导 ==
<b style=color:#f80>AXONAL CONDUCTION</b>

=== 轴突专门用于快速、可靠和高效的电信号传输 ===
<b style=color:#0ae>Axons are specialized for rapid, reliable, and efficient transmission of electrical signals</b>

At first glance, the job of the axon seems mundane compared with the complex computational functions of synapses, dendrites, and somata. After all, the axon has the relatively simple job of carrying the computed signal—a sequence of action potentials—from one place in the brain to another without changing it significantly. Some axons are thin, unmyelinated, and slow; these properties are sufficient to achieve their functions. However, the axon can be exquisitely optimized, with myelin and nodes of Ranvier, for fast and reliable saltatory conduction of action potentials over very long distances (see p. 200). Consider the sensory endings in the skin of your foot, which must send their signals to your lumbar spinal cord 1 m away (see Fig. 10-11B). The axon of such a sensory cell transmits its message in just a few tens of milliseconds! As we see in our discussion of spinal reflexes on pages 392–395, axons of similar length carry signals in the opposite direction, from your spinal cord to the muscles within your feet, and they do it even faster than most of the sensory axons. Axons within the CNS can also be very long; examples include the corticospinal axons that originate in the cerebral cortex and terminate in the lumbar spinal cord. Alternatively, many central axons are quite short, only tens of micrometers in length, and they transmit their messages locally between neurons. The spinal interneuron between a sensory neuron and a motor neuron (see Fig. 10-11B) is an example. Some axons target their signal precisely, from one soma to only a few other cells, whereas others may branch profusely to target thousands of postsynaptic cells.

乍一看，与突触、树突和胞体的复杂计算功能相比，轴突的工作似乎很平凡。毕竟，轴突的工作相对简单，就是将计算出的信号（一系列动作电位）从大脑的一个地方传送到另一个地方，而不会发生显著的变化。一些轴突很薄，无髓且缓慢;这些特性足以实现它们的功能。然而，轴突可以通过髓鞘和 Ranvier 节点进行精细优化，以便在非常长的距离上快速可靠地进行动作电位的盐化传导（见第 200 页）。考虑足部皮肤的感觉末梢，它们必须将其信号发送到 1 m 外的腰椎脊髓（见图 10-11B）。这种感觉细胞的轴突在短短几十毫秒内就传递了它的信息！正如我们在第 392-395 页对脊髓反射的讨论中所看到的，相似长度的轴突将信号从脊髓传递到脚内的肌肉，而且它们比大多数感觉轴突都更快。CNS 内的轴突也可以很长;例子包括起源于大脑皮层并终止于腰脊髓的皮质脊髓轴突。或者，许多中央轴突很短，只有几十微米长，它们在神经元之间局部传递信息。感觉神经元和运动神经元之间的脊髓中间神经元（见图 10-11B）就是一个例子。一些轴突精确地靶向它们的信号，从一个胞体到几个其他细胞，而其他轴突可能会大量分支以靶向数千个突触后细胞。


Different parts of the brain have different signaling needs, and their axons are adapted to the local requirements. Nevertheless, the primary function of all axons is to carry electrical signals, in the form of action potentials, from one place to other places and to do so rapidly, efficiently, and reliably. Without myelinated axons, the large, complex brains necessary to control warm, fast mammalian bodies could not exist. For unmyelinated axons to conduct action potentials sufficiently fast for many purposes, their diameters would have to be so large that the axons alone would take up far too much space and use impossibly large amounts of energy.

大脑的不同部分有不同的信号需求，它们的轴突适应局部需求。然而，所有轴突的主要功能是将电信号以动作电位的形式从一个地方传输到另一个地方，并快速、高效、可靠地完成。没有有髓轴突，控制温暖、快速的哺乳动物身体所需的大型复杂大脑就不可能存在。为了使无髓轴突能够足够快地传导动作电位以达到多种目的，它们的直径必须非常大，以至于仅轴突就会占用太多空间并消耗难以置信的大量能量。

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=== 动作电位通常在初始节段启动 ===
<b style=color:#0ae>Action potentials are usually initiated at the initial segment</b>

The soma, axon hillock, and initial segment of the axon together serve as a kind of focal point in most neurons. The many graded synaptic potentials carried by numerous dendrites converge at the soma and generate one electrical signal. During the 1950s, Sir John Eccles N12-2 and colleagues used glass microelectrodes to probe the details of this process in spinal motor neurons. Because it appeared that the threshold for action potentials in the initial segment was only ~10 mV above the resting potential, whereas the threshold in the soma was closer to 30 mV above resting potential, they concluded that the neuron’s action potentials would be first triggered at the initial segment. Direct recordings from various parts of neurons now indicate that spikes begin at the initial segment, at least for many types of vertebrate neurons. EPSPs evoked in the dendrites propagate down to and through the soma and trigger an action potential in a myelin-free zone of axon ~15 to 50 μm from the soma (Fig. 12-5A). The action potential then propagates in two directions: forward—orthrodromic conduction—into the axon, with no loss of amplitude, and backward—antidromic conduction—into the soma and dendrites, with strong attenuation, as we saw above in Figure 12-3. Orthodromic propagation carries the signal to the next set of neurons. The function of antidromic propagation is not completely understood. It is very likely that backwardly propagating spikes trigger biochemical changes in the neuron’s dendrites and synapses and they may have a role in plasticity of synapses and intrinsic membrane properties.

体细胞、轴突小丘和轴突的初始段共同作为大多数神经元的一种焦点。由众多树突携带的许多分级突触电位在胞体汇聚并产生一个电信号。在 1950 年代，John Eccles N12-2 爵士及其同事使用玻璃微电极来探测脊髓运动神经元中这一过程的细节。因为看起来初始段中的动作电位阈值仅比静息电位高 ~10 mV，而胞体中的阈值接近高于静息电位 30 mV，所以他们得出结论，神经元的动作电位将首先在初始段触发。来自神经元各个部分的直接记录现在表明，尖峰始于初始节段，至少对于许多类型的脊椎动物神经元来说是这样。树突中诱发的 EPSP 向下传播并通过胞体传播，并在距离胞体 ~15 至 50 μm 的轴突无髓鞘区触发动作电位（图 12-5A）。然后动作电位沿两个方向传播：向前 - 正常传导 - 进入轴突，没有幅度损失，以及向后 - 逆向传导 - 进入胞体和树突，具有很强的衰减，如上图 12-3 所示。顺向传播将信号带到下一组神经元。逆向传播的功能尚不完全清楚。向后传播的尖峰很可能会触发神经元树突和突触的生化变化，它们可能在突触的可塑性和内在膜特性中发挥作用。


The axon achieves a uniquely low threshold in its initial segment (see Fig. 12-5B) by two main mechanisms. First, the initial segment has a remarkably high density of voltage-gated Na+ channels (see Fig. 12-5C). The Na+ channel density in the axon initial segment is estimated to be 3-fold to 40-fold higher than in the membrane of the soma and dendrites, depending on neuron type and experimental methodology. The scaffolding protein ankyrin-G is a molecular marker for the initial segment and seems to be critical for organizing its unique distribution of ion channels. Second, initial segments often include Na+ channel types (see Table 7-1) such as Nav1.6 that activate at relatively negative voltages compared to channels such as Nav1.2 that are common in the soma and dendrites. The combination of large numbers of Na+ channels and their opening at relatively negative voltage allows the initial segment to reach action potential threshold before other sites on the dendrites and soma.

轴突通过其两个主要机制在其初始段（见图 12-5B）中达到独特的低阈值。首先，初始段具有非常高密度的电压门控 Na+ 通道（见图 12-5C）。轴突初始段中的 Na + 通道密度估计比胞体和树突膜中的 Na + 通道密度高 3 到 40 倍，具体取决于神经元类型和实验方法。支架蛋白锚蛋白-G 是初始片段的分子标记物，似乎对于组织其独特的离子通道分布至关重要。其次，初始段通常包括 Na + 通道类型（见表 7-1），例如 Nav1.6，与胞体和树突中常见的通道（如 Nav1.2）相比，它们在相对负的电压下激活。大量 Na + 通道的组合及其在相对负电压下的打开允许初始段在树突和体细胞上的其他位点之前达到动作电位阈值。

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=== 有髓轴突的传导速度随直径线性增加 ===
<b style=color:#0ae>Conduction velocity of a myelinated axon increases linearly with diameter</b>

The larger the diameter of an axon, the faster its conduction velocity, other things remaining equal. However, conduction velocity is usually much faster in myelinated axons than it is in unmyelinated axons (see p. 200). Thus, a myelinated axon 10 μm in diameter conducts impulses at about the same velocity as an unmyelinated axon ~500 μm in diameter. Myelination confers not only substantial speed advantages but also advantages in efficiency. Almost 2500 of the 10-μm myelinated axons can pack into the volume occupied by one 500-μm axon!

轴突的直径越大，其传导速度越快，其他条件保持不变。然而，有髓轴突的传导速度通常比无髓轴突快得多（见第 200 页）。因此，直径为 10 μm 的有髓轴突以与直径 ~500 μm 的无髓轴突大致相同的速度传导脉冲。髓鞘形成不仅具有显着的速度优势，而且具有效率优势。近 2500 个 10 μm 有髓轴突可以堆积到一个 500 μm 轴突所占据的体积中！


Unmyelinated axons still have a role in vertebrates. At diameters below ~1 μm, unmyelinated axons in the peripheral nervous system (PNS) conduct more rapidly than myelinated ones do. In a testament to evolutionary frugality, the thinnest axons of the peripheral sensory nerves, called C fibers, are ~1 μm wide or less, and all are unmyelinated. Axons larger than ~1 μm in diameter are all myelinated (Table 12-1). Every axon has its biological price: the largest axons obviously take up the most room and are the most expensive to synthesize and to maintain metabolically. The largest, swiftest axons are therefore used sparingly. They are used only to carry sensory information about the most rapidly changing stimuli over the longest distances (e.g., stretch receptors in muscle, mechanoreceptors in tendons and skin), or they are used to control finely coordinated contractions of muscles. The thinnest, slowest C fibers in the periphery are mainly sensory axons related to chronic pain and temperature sensation, for which the speed of the message is not as critical.

无髓轴突在脊椎动物中仍然发挥作用。在直径低于 ~1 μm 时，周围神经系统 （PNS） 中无髓轴突的传导速度比有髓轴突更快。为了证明进化节俭，周围感觉神经最细的轴突（称为 C 纤维）宽 ~1 μm 或更小，并且都是无髓的。直径大于 ~1 μm 的轴突都是有髓的（表 12-1）。每个轴突都有其生物学价格：最大的轴突显然占据了最多的空间，并且合成和维持代谢的成本最高。因此，最大、最快的轴突被谨慎使用。它们仅用于在最长距离上传递有关最快速变化的刺激的感觉信息（例如，肌肉中的拉伸感受器、肌腱和皮肤中的机械感受器），或者用于控制肌肉的精细协调收缩。外围最细、最慢的 C 纤维主要是与慢性疼痛和温度感觉相关的感觉轴突，对于它们来说，信息的速度并不那么重要。


The relationship between form and function for axons in the CNS is less obvious than it is for those in the PNS, in part because it is more difficult to identify each axon’s function. Interestingly, in the brain and spinal cord, the critical diameter for the myelination transition may be smaller than in the periphery. Many central myelinated axons are as thin as 0.2 μm. At the other extreme, very few myelinated central axons are >4 μm in diameter.

CNS 中轴突的形式和功能之间的关系不如 PNS 中的轴突明显，部分原因是更难识别每个轴突的功能。有趣的是，在大脑和脊髓中，髓鞘形成转变的临界直径可能小于外周。许多中央有髓轴突薄至 0.2 μm。在另一个极端，很少有有髓中央轴突的直径为 >4 μm。


The myelinated axon membrane has a variety of ion channels that may contribute to its normal and pathological function. Of primary importance is the voltage-gated Na+ channel, which provides the rapidly activating and inactivating inward current that yields the action potential. Nine isoforms of the α subunit of the voltage-gated Na+ channel exist (see Table 7-1). In normal central axons, it is specifically Nav1.6 channels that populate mature nodes of Ranvier at a density of 1000 to 2000 channels per square micrometer (see Fig. 12-5). The same axonal membrane in the internodal regions, under the myelin, has <25 channels per square micrometer (versus between 2 and 200 channels per square micrometer in unmyelinated axons). The dramatically different distribution of channels between nodal and internodal membrane has important implications for conduction along pathologically demyelinated axons (see below). K+ channels are relatively less important in myelinated axons than they are in most other excitable membranes. Very few of these channels are present in the nodal membrane, and fast K+ currents contribute little to repolarization of the action potential in mature myelinated axons. This diminished role for K+ channels may be a cost-cutting adaptation because the absence of K+ currents decreases the metabolic expense of a single action potential by ~40%. However, some K+ channels are located in the axonal membrane under the myelin, particularly in the paranodal region. The function of these K+ channels is unclear; they may set the resting Vm of the internodes and help stabilize the firing properties of the axon.

有髓轴突膜具有多种离子通道，可能有助于其正常和病理功能。最重要的是电压门控 Na+ 通道，它提供快速激活和失活的向内电流，从而产生动作电位。电压门控 Na + 通道的 α 亚基存在 9 种亚型（见表 7-1）。在正常的中央轴突中，特别是 Nav1.6 通道以每平方微米 1000 至 2000 个通道的密度填充 Ranvier 的成熟节点（见图 12-5）。在髓鞘下的结间区域，相同的轴突膜每 μm 有 <25 个通道（而无髓轴突每平方微米有 2 到 200 个通道）。淋巴结膜和淋巴结间膜之间通道的显着差异分布对沿病理脱髓鞘轴突的传导具有重要意义（见下文）。K+ 通道在有髓轴突中的重要性相对低于在大多数其他可兴奋膜中的重要性。这些通道很少存在于结膜中，快速的 K+ 电流对成熟有髓轴突动作电位的复极化几乎没有贡献。K+ 通道的这种作用减弱可能是一种降低成本的适应，因为 K+ 电流的缺失将单个动作电位的代谢费用降低了 ~40%。然而，一些 K+ 通道位于髓鞘下方的轴突膜中，特别是在结旁区域。这些 K+ 通道的功能尚不清楚;它们可以设置节间的静止 Vm 并帮助稳定轴突的放电特性。

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=== 脱髓鞘轴突缓慢、不可靠或根本不传导动作电位 ===
<b style=color:#0ae>Demyelinated axons conduct action potentials slowly, unreliably, or not at all</b>

Numerous clinical disorders selectively damage or destroy myelin sheaths and leave the axonal membranes intact but bare. These demyelinating diseases may affect either peripheral or central axons and can lead to severely impaired conduction (Fig. 12-6). The most common demyelinating disease of the CNS is multiple sclerosis (Box 12-1), a progressive disorder characterized by distributed zones of demyelination in the brain and spinal cord. The specific clinical signs of these disorders vary and depend on the particular sets of axons affected.

许多临床疾病选择性地损伤或破坏髓鞘，使轴突膜完好无损但裸露。这些脱髓鞘疾病可能影响外周或中央轴突，并可能导致严重的传导受损（图 12-6）。CNS 最常见的脱髓鞘疾病是多发性硬化症 （Box 12-1），这是一种进行性疾病，其特征是大脑和脊髓中分布的脱髓鞘区。这些疾病的具体临床症状各不相同，取决于受影响的特定轴突集。


In a normal, myelinated axon, the action currents generated at a node can effectively charge the adjacent node and bring it to threshold within ~20 μsec (Fig. 12-7A), because myelin serves to increase the resistance and to reduce the capacitance of the pathways between the axoplasm and the extracellular fluid (see pp. 199–201). The inward membrane current flowing across each node is actually 5-fold to 7-fold higher than necessary to initiate an action potential at the adjacent node. Removal of the insulating myelin, however, means that the same nodal action current is distributed across a much longer, leakier, higher-capacitance stretch of axonal membrane (see Fig. 12-7B). Several consequences are possible. Compared with normal conduction, conduction in a demyelinated axon may continue, but at a lower velocity, if the demyelination is not too severe (see Fig. 12-7B, record 1). In experimental studies, the internodal conduction time through demyelinated fibers can be as slow as 500 μs, 25 times longer than normal. The ability of axons to transmit high-frequency trains of impulses may also be impaired (see Fig. 12-7B, record 2). Extensive demyelination of an axon causes total blockade of conduction (see Fig. 12-7B, record 3). Clinical studies indicate that the blockade of action potentials is more closely related to symptoms than is the simple slowing of conduction. Demyelinated axons can also become the source of spontaneous, ectopically generated action potentials because of changes in their intrinsic excitability (see Fig. 12-7B, record 4) or mechanosensitivity (see Fig. 12-7B, record 5). Moreover, the signal from one demyelinated axon can excite an adjacent demyelinated axon and induce crosstalk (see Fig. 12-7C), which may cause action potentials to be conducted in both directions in the adjacent axon.

在正常的有髓轴突中，节点处产生的动作电流可以有效地为相邻节点充电，并在 ~20 μsec 内使其达到阈值（图 12-7A），因为髓鞘的作用是增加电阻并降低轴质和细胞外液之间通路的电容（见第 199-201 页）。流过每个节点的向内膜电流实际上比在相邻节点启动动作电位所需的电流高 5 到 7 倍。然而，去除绝缘髓鞘意味着相同的节点作用电流分布在更长、泄漏更大、电容更高的轴突膜上（见图 12-7B）。可能有多种后果。与正常传导相比，如果脱髓鞘不太严重，脱髓鞘轴突中的传导可能会继续，但速度会更低（见图 12-7B，记录 1）。在实验研究中，通过脱髓鞘纤维的结间传导时间可慢至 500 μs，比正常时间长 25 倍。轴突传递高频脉冲序列的能力也可能受损（见图 12-7B，记录 2）。轴突的广泛脱髓鞘导致传导完全阻塞（参见图 12-7B，记录 3）。临床研究表明，动作电位的阻断与症状的相关性比简单的传导减慢更密切。脱髓鞘的轴突也可以成为自发的、异位产生的动作电位的来源，因为它们的内在兴奋性（见图 12-7B，记录 4）或机械敏感性（见图 12-7B，记录 5）发生了变化。此外，来自一个脱髓鞘轴突的信号可以激发相邻的脱髓鞘轴突并诱导串扰（见图 12-7C），这可能导致动作电位在相邻轴突中双向传导。

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