2024年12月11日 (三) 18:03的最后版本

神经元微环境

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

[编辑] 1 概述

[编辑] 1.1 大脑细胞外液为中枢神经元提供了高度调节的环境

Extracellular fluid in the brain provides a highly regulated environment for central nervous system neurons

Everything that surrounds individual neurons can be considered part of the neuronal microenvironment. Technically, therefore, the neuronal microenvironment includes the extracellular fluid (ECF), capillaries, glial cells, and adjacent neurons. Although the term often is restricted to just the immediate ECF, the ECF cannot be meaningfully discussed in isolation because of its extensive interaction with brain capillaries, glial cells, and cerebrospinal fluid (CSF). How the microenvironment interacts with neurons and how the brain (used here synonymously with central nervous system, or CNS) stabilizes it to provide constancy for neuronal function are the subjects of this discussion.

围绕单个神经元的一切都可以被认为是神经元微环境的一部分。因此，从技术上讲，神经元微环境包括细胞外液 （ECF）、毛细血管、神经胶质细胞和相邻的神经元。尽管该术语通常仅限于直接的 ECF，但由于 ECF 与脑毛细血管、神经胶质细胞和脑脊液 （CSF） 的广泛相互作用，因此不能单独有意义地讨论 ECF。微环境如何与神经元相互作用以及大脑（此处与中枢神经系统或 CNS 同义）如何稳定它以为神经元功能提供稳定性是本次讨论的主题。

The concentrations of solutes in brain extracellular fluid (BECF) fluctuate with neural activity, and conversely, changes in ECF composition can influence nerve cell behavior. Not surprisingly, therefore, the brain carefully controls the composition of this important compartment. It does so in three major ways: First, the brain uses the blood-brain barrier (BBB) to protect the BECF from fluctuations in blood composition. Second, the CSF, produced by choroid plexus epithelial cells, strongly influences the composition of the BECF. Third, the surrounding glial cells “condition” the BECF.

脑细胞外液 （BECF） 中溶质的浓度随神经活动而波动，相反，细胞外液 (ECF) 组成的变化会影响神经细胞的行为。因此，大脑小心翼翼地控制着这个重要隔室的组成也就不足为奇了。它主要通过三种方式做到这一点：首先，大脑使用血脑屏障 （BBB） 来保护脑细胞外液 (BECF) 免受血液成分波动的影响。其次，由脉络丛上皮细胞产生的脑脊液 (CSF) 强烈影响脑细胞外液 (BECF) 的组成。第三，周围的神经胶质细胞 “调节” 脑细胞外液。

[编辑] 1.2 大脑在物理和代谢上都很脆弱

The brain is physically and metabolically fragile

The ratio of brain weight to body weight in humans is the highest in the animal kingdom. The average adult brain weight is ~1400 g in men and ~1300 g in women— approximately the same weight as the liver (see p. 944). This large and vital structure, which has the consistency of thick pudding, is protected from mechanical injury by a surrounding layer of bone and by the CSF in which it floats.

人类的脑重与体重之比是动物界最高的。男性成人的平均脑重为 ~1400 克，女性为 ~1300 克——与肝脏的重量大致相同（见第 944 页）。这个大而重要的结构具有厚布丁的稠度，周围的骨层和漂浮在其中的脑脊液 (CSF) 可以保护它免受机械损伤。

The brain is also metabolically fragile. This fragility arises from its high rate of energy consumption, absence of significant stored fuel in the form of glycogen (~5% of the amount in the liver), and rapid development of cellular damage when ATP is depleted. However, the brain is not the greediest of the body’s organs; both the heart and kidney cortex have higher metabolic rates. Nevertheless, although it constitutes only 2% of the body by weight, the brain receives ~15% of resting blood flow and accounts for ~20% and 50% of total resting oxygen and glucose utilization, respectively. The brain’s high metabolic demands arise from the need of its neurons to maintain the steep ion gradients on which neuronal excitability depends. In addition, neurons rapidly turn over their actin cytoskeleton. Neuroglial cells, the other major cells in the brain, also maintain steep transmembrane ion gradients. More than half of the energy consumed by the brain is directed to maintain ion gradients, primarily through operation of the Na-K pump (see pp. 115–117). An interruption of the continuous supply of oxygen or glucose to the brain results in rapid depletion of energy stores and disruption of ion gradients. Because of falling ATP levels in the brain, consciousness is lost within 10 seconds of a blockade in cerebral blood flow. Irreversible nerve cell injury can occur after only 5 to 10 minutes of interrupted blood flow.

大脑的新陈代谢也很脆弱。这种脆弱性源于其高能耗、缺乏以糖原形式储存的大量燃料（肝脏中量的 ~5%）以及当 ATP 耗尽时细胞损伤的快速发展。然而，大脑并不是身体器官中最贪婪的；心脏和肾脏皮层的代谢率都较高。然而，尽管它仅占身体重量的 2%，但大脑接收 ~15% 的静息血流量，分别占总静息氧和葡萄糖利用率的 ~20% 和 50%。大脑的高代谢需求源于其神经元需要维持神经元兴奋性所依赖的陡峭离子梯度。此外，神经元会迅速翻转其肌动蛋白细胞骨架。神经胶质细胞是大脑中的其他主要细胞，也保持陡峭的跨膜离子梯度。大脑消耗的能量中有一半以上用于维持离子梯度，主要是通过 Na-K 泵的操作（参见第 115-117 页）。大脑持续供应氧气或葡萄糖的中断会导致能量储存的快速耗尽和离子梯度的破坏。由于大脑中的 ATP 水平下降，意识在脑血流阻塞后的 10 秒内就会丧失。不可逆的神经细胞损伤可能在血流中断仅 5 到 10 分钟后发生。

[编辑] 2 脑脊液 (Cerebrospinal Fluid, CSF)

CEREBROSPINAL FLUID

CSF is a colorless, watery liquid. It fills the ventricles of the brain and forms a thin layer around the outside of the brain and spinal cord in the subarachnoid space. CSF is secreted within the brain by a highly vascularized epithelial structure called the choroid plexus and circulates to sites in the subarachnoid space, where it enters the venous blood system. The composition of CSF is highly regulated, and because it directly mixes with BECF, it helps regulate the composition of BECF. The choroid plexus can be thought of as the brain’s “kidney” in that it stabilizes the composition of CSF, just as the kidney stabilizes the composition of blood plasma.

CSF 是一种无色的水状液体。它充满大脑的心室，并在大脑外部和蛛网膜下腔的脊髓周围形成一层薄层。CSF 在大脑内由称为脉络丛的高度血管化的上皮结构分泌，并循环到蛛网膜下腔的部位，在那里进入静脉血系统。CSF 的成分受到高度调节，因为它直接与 BECF 混合，所以有助于调节 BECF 的成分。脉络丛可以被认为是大脑的“肾脏”，因为它稳定了脑脊液的组成，就像肾脏稳定血浆的组成一样。

[编辑] 2.1 脑脊液充满脑室和蛛网膜下腔

CSF fills the ventricles and subarachnoid space

The ventricles of the brain are four small compartments located within the brain (Fig. 11-1A). Each ventricle contains a choroid plexus and is filled with CSF. The ventricles are linked together by channels, or foramina, that allow CSF to move easily between them. The two lateral ventricles are the largest and are symmetrically located within the cerebral hemispheres. The choroid plexus of each lateral ventricle is located along the inner radius of this horseshoe-shaped structure (see Fig. 11-1B). The two lateral ventricles each communicate with the third ventricle, which is located in the midline between the thalami, through the two interventricular foramina of Monro. The choroid plexus of the third ventricle lies along the ventricle roof. The third ventricle communicates with the fourth ventricle by the cerebral aqueduct of Sylvius. The fourth ventricle is the most caudal ventricle and is located in the brainstem. It is bounded by the cerebellum superiorly and by the pons and medulla inferiorly. The choroid plexus of the fourth ventricle lies along only a portion of this ventricle’s tent-shaped roof. The fourth ventricle is continuous with the central canal of the spinal cord. CSF escapes from the fourth ventricle and flows into the subarachnoid space through three foramina: the two laterally placed foramina of Luschka and the midline opening in the roof of the fourth ventricle, called the foramen of Magendie. We shall see below how CSF circulates throughout the subarachnoid space of the brain and spinal cord, and how it moves through brain tissue itself.

大脑的心室是位于大脑内的四个小隔室（图 11-1A）。每个心室都包含一个脉络丛，并充满脑脊液。心室通过通道或孔连接在一起，使脑脊液能够在它们之间轻松移动。两个侧脑室最大，对称位于大脑半球内。每个侧脑室的脉络丛位于该马蹄形结构的内桡骨上（见图 11-1B）。两个侧脑室分别通过两个门罗室间孔与位于丘脑之间中线的第三脑室相通。第三脑室的脉络丛位于脑室顶部。第三脑室通过 Sylvius 的大脑导水管与第四脑室相通。第四脑室是最尾的脑室，位于脑干中。它上部以小脑为界，下部以脑桥和延髓为界。第四脑室的脉络丛仅位于该脑室帐篷形屋顶的一部分。第四脑室与脊髓中央管相连。CSF 从第四脑室逸出，通过三个孔流入蛛网膜下腔：两个外侧放置的 Luschka 孔和第四脑室顶部的中线开口，称为 Magendie 孔。我们将在下面看到 CSF 如何在大脑和脊髓的蛛网膜下腔中循环，以及它如何在脑组织本身中移动。

The brain and spinal cord are covered by two membranous tissue layers called the leptomeninges, which are in turn surrounded by a third, tougher layer. The innermost of these three layers is the pia mater; the middle is the arachnoid mater (or arachnoid membrane); and the outermost layer is the dura mater (Fig. 11-2). Between the arachnoid mater and pia mater (i.e., the leptomeninges) is the subarachnoid space, which is filled with CSF that flows from the fourth ventricle. The CSF in the subarachnoid space completely surrounds the brain and spinal cord. In adults, the subarachnoid space and the ventricles with which they are continuous contain ~150 mL of CSF, 30 mL in the ventricles and 120 mL in the subarachnoid spaces of the brain and spinal cord.

大脑和脊髓被两层称为软脑膜的膜组织层覆盖，而软脑膜又被第三层更坚韧的组织层包围。这三层中最里面的是软脑膜;中间是蛛网膜（或蛛网膜）;最外层是硬脑膜（图 11-2）。蛛网膜和软脑膜（即软脑膜）之间是蛛网膜下腔，它充满了从第四脑室流出的脑脊液。蛛网膜下腔的 CSF 完全围绕着大脑和脊髓。在成人中，蛛网膜下腔及其连续的脑室含有 ~150 mL 的脑脊液，脑室中含有 30 mL，大脑和脊髓的蛛网膜下腔中含有 120 mL。

The pia mater (Latin for “tender mother”) is a thin layer of connective tissue cells that is very closely applied to the surface of the brain and covers blood vessels as they plunge through the arachnoid into the brain. A nearly complete layer of astrocytic endfeet (see p. 286)—the glia limitans— abuts the pia from the brain side and is separated from the pia by a basement membrane. The pia adheres so tightly to the associated glia limitans in some areas that the two seem to be continuous with each other; this combined structure is sometimes called the pial-glial membrane or layer. This layer does not restrict diffusion of substances between the BECF and the CSF.

pia mater（拉丁语为“温柔的母亲”）是一层薄薄的结缔组织细胞，非常紧密地贴在大脑表面，并在血管通过蛛网膜进入大脑时覆盖血管。几乎完整的星形胶质细胞终足层（见第 286 页）——极限胶质细胞——从大脑一侧紧邻软脑膜，并通过基底膜与软脑膜隔开。软脑膜在某些区域与相关的神经胶质限制素紧密粘附，以至于两者似乎彼此连续;这种组合结构有时称为软脑膜-胶质细胞膜或层。该层不限制物质在 BECF 和 CSF 之间的扩散。

The arachnoid membrane (from the Greek arachnoeides [cobweb-like]) is composed of layers of cells, resembling those that make up the pia, linked together by tight junctions. The arachnoid isolates the CSF in the subarachnoid space from blood in the overlying vessels of the dura mater. The cells that constitute the arachnoid and the pia are continuous in the trabeculae that span the subarachnoid space. These arachnoid and pial layers are relatively avascular; thus, the leptomeningeal cells that form them probably derive nutrition from the CSF that they enclose as well as from the ECF that surrounds them. The leptomeningeal cells can phagocytose foreign material in the subarachnoid space.

蛛网膜（来自希腊语 arachnoeides [蜘蛛网状]）由细胞层组成，类似于构成软脑膜的细胞，通过紧密的连接连接在一起。蛛网膜将蛛网膜下腔的 CSF 与硬脑膜上覆血管中的血液分离出来。构成蛛网膜和软脑膜的细胞在跨越蛛网膜下腔的小梁中是连续的。这些蛛网膜和软脑膜层相对无血管;因此，形成它们的软脑膜细胞可能从它们所包围的 CSF 以及它们周围的 ECF 中获取营养。软脑膜细胞可以吞噬蛛网膜下腔中的异物。

The dura mater is a thick, inelastic membrane that forms an outer protective envelope around the brain. The dura has two layers that split to form the intracranial venous sinuses. Blood vessels in the dura mater are outside the BBB (see below), and substances could easily diffuse from dural capillaries into the nearby CSF if it were not for the blood-CSF barrier created by the arachnoid.

硬脑膜是一层厚的、无弹性的膜，在大脑周围形成一个外部保护膜。硬脑膜有两层，它们分裂形成颅内静脉窦。硬脑膜中的血管位于 BBB 之外（见下文），如果不是蛛网膜形成的血液-CSF 屏障，物质很容易从硬脑膜毛细血管扩散到附近的 CSF。

[编辑] 2.2 大脑漂浮在脑脊液中，脑脊液起到减震器的作用

The brain floats in CSF, which acts as a shock absorber

An important function of CSF is to buffer the brain from mechanical injury. The CSF that surrounds the brain reduces the effective weight of the brain from ~1400 g to <50 g. This buoyancy is a consequence of the difference in the specific gravities of brain tissue (1.040) and CSF (1.007). The mechanical buffering that the CSF provides greatly diminishes the risk of acceleration-deceleration injuries in the same way that wearing a bicycle helmet reduces the risk of head injury. As you strike a tree, the foam insulation of the helmet gradually compresses and reduces the velocity of your head. Thus, the deceleration of your head is not nearly as severe as the deceleration of the outer shell of your helmet. The importance of this fluid suspension system is underscored by the consequences of reduced CSF pressure, which sometimes happens transiently after the diagnostic procedure of removal of CSF from the spinal subarachnoid space (Box 11-1). Patients with reduced CSF pressure experience severe pain when they try to sit up or stand because the brain is no longer cushioned by shock-absorbing fluid and small gravity-induced movements put strain on pain-sensitive structures. Fortunately, the CSF leak that can result from lumbar puncture is only temporary; the puncture hole easily heals itself, with prompt resolution of all symptoms.

CSF 的一个重要功能是缓冲大脑免受机械损伤。围绕大脑的 CSF 将大脑的有效重量从 ~1400 克降低到 <50 克。这种浮力是脑组织 （1.040） 和 CSF （1.007） 比重差异的结果。CSF 提供的机械缓冲大大降低了加速-减速损伤的风险，就像佩戴自行车头盔可以降低头部受伤的风险一样。当您撞到一棵树时，头盔的泡沫绝缘材料会逐渐压缩并降低头部的速度。因此，头部的减速并不像头盔外壳的减速那么严重。这种液体悬浮系统的重要性因降低 CSF 压力的后果而得到强调，这有时会在从脊髓蛛网膜下腔去除 CSF 的诊断程序后短暂发生（框 11-1）。脑脊液压力降低的患者在尝试坐起来或站起来时会感到剧烈疼痛，因为大脑不再被减震液缓冲，而重力诱导的小运动会对疼痛敏感结构造成压力。幸运的是，腰椎穿刺可能导致的脑脊液漏只是暂时的;穿刺孔很容易自愈，所有症状都能迅速消退。

[编辑] 2.3 脉络丛将脑脊液分泌到脑室中，蛛网膜颗粒吸收它

The choroid plexuses secrete CSF into the ventricles, and the arachnoid granulations absorb it

Total CSF production is ~500 mL/day. Because the entire volume of CSF is ~150 mL, the CSF “turns over” about three times each day. Most of the CSF is produced by the choroid plexuses, which are present in four locations (see Fig. 11-1): the two lateral ventricles, the third ventricle, and the fourth ventricle. The capillaries within the brain appear to form as much as 30% of the CSF.

CSF 总产量为 ~500 mL/天。因为 CSF 的整个体积为 ~150 mL，所以 CSF 每天大约“翻转”3 次。大部分脑脊液由脉络丛产生，脉络丛存在于四个位置（见图 11-1）：两个侧脑室、第三脑室和第四脑室。大脑内的毛细血管似乎构成了多达 30% 的 CSF。

Secretion of new CSF creates a slight pressure gradient, which drives the circulation of CSF from its ventricular sites of origin into the subarachnoid space through three openings in the fourth ventricle, as discussed above. CSF percolates throughout the subarachnoid space and is finally absorbed into venous blood in the superior sagittal sinus, which lies between the two cerebral hemispheres (see Fig. 11-2). The sites of absorption are specialized evaginations of the arachnoid membrane into the venous sinus (Fig. 11-3A). These absorptive sites are called pacchionian granulations N11-1 or simply arachnoid granulations when they are large (up to 1 cm in diameter) and arachnoid villi if their size is microscopic. These structures act as pressuresensitive one-way valves for bulk CSF clearance; CSF can cross into venous blood but venous blood cannot enter CSF. The actual mechanism of CSF absorption may involve transcytosis (see pp. 477–487), or the formation of giant fluidcontaining vacuoles that cross from the CSF side of the arachnoid epithelial cells to the blood side (see Fig. 11-3A). CSF may also be absorbed into spinal veins from herniations of arachnoid cells into these venous structures.

如上所述，新脑脊液的分泌会产生轻微的压力梯度，这驱动脑脊液从其起源的心室部位循环到蛛网膜下腔，通过第四脑室的三个开口。CSF 渗透到整个蛛网膜下腔，最后被吸收到位于两个大脑半球之间的矢状窦上部的静脉血中（见图 11-2）。吸收部位是蛛网膜专门逃逸到静脉窦中（图 11-3A）。这些吸收部位称为 PACCHIONIAN 颗粒 N11-1，当它们较大（直径可达 1 cm）时简称为蛛网膜颗粒，如果它们的大小是微观的，则简称为蛛网膜绒毛。这些结构充当用于大量 CSF 清除的压敏单向阀;CSF 可以进入静脉血，但静脉血不能进入 CSF。CSF 吸收的实际机制可能涉及转胞吞作用（参见第 477-487 页），或形成从蛛网膜上皮细胞的 CSF 侧穿过血液侧的含液巨大液泡（参见图 11-3A）。CSF 也可能从蛛网膜细胞疝吸收到脊髓静脉中，进入这些静脉结构。

The pressure of the CSF, which is higher than that of the venous blood, promotes net CSF movement into venous blood. When intracranial pressure (equivalent to CSF pressure) exceeds ~70 mm H2O, absorption commences and increases in a graded fashion with further intracranial pressure (see Fig. 11-3B). In contrast to CSF absorption, CSF formation is not sensitive to intracranial pressure. This arrangement helps stabilize intracranial pressure. Thus, if intracranial pressure increases, CSF absorption selectively increases as well, so that absorption exceeds formation. This response lowers CSF volume and tends to counteract the increased intracranial pressure. However, if absorption of CSF is impaired even at an initially normal intracranial pressure (Box 11-2), CSF volume increases and causes an increase in intracranial pressure, which can lead to a disturbance in brain function.

CSF 的压力高于静脉血的压力，促进 Net CSF 进入静脉血。当颅内压（相当于 CSF 压力）超过 ~70 mm H2O 时，吸收开始并随着颅内压的进一步而逐渐增加（见图 11-3B）。与 CSF 吸收相反，CSF 形成对颅内压不敏感。这种安排有助于稳定颅内压。因此，如果颅内压升高，CSF 吸收也会选择性增加，从而使吸收超过形成。这种反应会降低 CSF 体积，并倾向于抵消增加的颅内压。然而，如果在最初正常的颅内压下，脑脊液的吸收也受损（框 11-2），脑脊液体积增加并导致颅内压升高，这可能导致脑功能紊乱。

Some subarachnoid CSF flows into “sleeves” around arteries that dive from the subarachnoid space (see Fig. 11-2) deeply into the substance of the brain. This CSF appears to exit the sleeve by flowing across the pia/glia limitans and into brain extracellular space (BECS), where it mixes with BECF. Moving by convection, the BECF eventually appears to cross the pia/glia limitans that surrounds veins, enter via perivenous sleeves, and return to the subarachnoid space. This parenchymal CSF circuit—termed the glymphatic system N11-2—may be an efficient pathway to rid the brain of extracellular debris, including glutamate and potentially dangerous peptides such as amyloid beta.

一些蛛网膜下腔 CSF 流入动脉周围的“袖子”，这些动脉从蛛网膜下腔（见图 11-2）深入大脑物质。这种 CSF 似乎通过流经 pia/神经胶质限制体进入大脑细胞外空间 （BECS） 而离开袖状物，在那里它与 BECF 混合。通过对流移动，BECF 最终似乎穿过围绕静脉的软脑膜/神经胶质限制体，通过静脉周围袖状进入，并返回蛛网膜下腔。这种实质 CSF 回路（称为淋巴系统 N11-2）可能是清除大脑细胞外碎片（包括谷氨酸和潜在危险肽，如 β 淀粉样蛋白）的有效途径。

[编辑] 2.4 脉络丛的上皮细胞分泌脑脊液

The epithelial cells of the choroid plexus secrete the CSF

Each of the four choroid plexuses is formed during embryological development by invagination of the tela choroidea into the ventricular cavity (Fig. 11-4). The tela choroidea consists of a layer of ependymal cells covered by the pia mater and its associated blood vessels. The choroid epithelial cells (see Fig. 11-4, first inset) are specialized ependymal cells and therefore contiguous with the ependymal lining of the ventricles at the margins of the choroid plexus. Choroid epithelial cells are cuboidal and have an apical border with microvilli and cilia that project into the ventricle (i.e., into the CSF). The plexus receives its blood supply from the anterior and posterior choroidal arteries; blood flow to the plexuses—per unit mass of tissue—is ~10-fold greater than the average cerebral blood flow. Sympathetic and parasympathetic nerves innervate each plexus, and sympathetic input appears to inhibit CSF formation. A high density of relatively leaky capillaries is present within each plexus; as discussed below, these capillaries are outside the BBB. The choroid epithelial cells are bound to one another by tight junctions that completely encircle each cell, an arrangement that makes the epithelium an effective barrier to free diffusion. Thus, although the choroid capillaries are outside the BBB, the choroid epithelium insulates the ECF around these capillaries (which has a composition more similar to that of arterial blood) from the CSF. Moreover, the thin neck that connects the choroid plexus to the rest of the brain isolates the ECF near the leaky choroidal capillaries from the highly protected BECF in the rest of the brain.

四个脉络丛中的每一个都是在胚胎发育过程中通过将 tela 绒毛膜内陷到心室腔中形成的（图 11-4）。tela choroidea 由一层室管膜细胞组成，该细胞被软脑膜及其相关血管覆盖。脉络膜上皮细胞（见图 11-4，第一插图）是专门的室管膜细胞，因此与脉络丛边缘的室管膜衬里相邻。脉络膜上皮细胞是立方体的，顶端边界有微绒毛和纤毛，伸入脑室（即脑脊液）。神经丛从脉络膜前动脉和后脉络膜动脉接收血液供应;流向神经丛的血流量（每单位质量的组织）比平均脑血流量大 ~10 倍。交感神经和副交感神经支配每个神经丛，交感神经输入似乎抑制了 CSF 的形成。每个神经丛内都存在高密度的相对渗漏的毛细血管;如下所述，这些毛细血管位于 BBB 之外。脉络膜上皮细胞通过完全包围每个细胞的紧密连接相互结合，这种排列使上皮成为自由扩散的有效屏障。因此，尽管脉络膜毛细血管位于 BBB 之外，但脉络膜上皮将这些毛细血管周围的 ECF（其成分更类似于动脉血的成分）与 CSF 隔离开来。此外，将脉络丛与大脑其他部分相连的细颈将渗漏的脉络膜毛细血管附近的 ECF 与大脑其他部分高度受保护的 BECF 隔离开来。

The composition of CSF differs considerably from that of plasma; thus, CSF is not just an ultrafiltrate of plasma (Table 11-1). For example, CSF has lower concentrations of K+ and amino acids than plasma does, and it contains almost no protein. Moreover, the choroid plexuses rigidly maintain the concentration of ions in CSF in the face of large swings in ion concentration in plasma. This ion homeostasis includes K+, H+ /HCO3−, Mg2+, Ca2+, and, to a lesser extent, Na+ and Cl−. All these ions can affect neural function, hence the need for tight homeostatic control. The neuronal microenvironment is so well protected from the blood by the choroid plexuses and the rest of the BBB that essential micronutrients, such as vitamins and trace elements that are needed in very small amounts, must be selectively transported into the brain. Some of these micronutrients are transported into the brain primarily by the choroid plexus and others primarily by the endothelial cells of the blood vessels. In comparison, the brain continuously metabolizes relatively large amounts of “macronutrients,” such as glucose and some amino acids. CSF forms in two sequential stages. First, ultrafiltration of plasma occurs across the fenestrated capillary wall (see p. 462) into the ECF beneath the basolateral membrane of the choroid epithelial cell. Second, choroid epithelial cells secrete fluid into the ventricle. CSF production occurs with a net transfer of NaCl and NaHCO3 that drives water movement isosmotically (see Fig. 11-4, right inset, large white arrow labeled “Transepithelial fluxes”). The renal proximal tubule (see p. 761) and small intestine (see p. 903) also perform near-isosmotic transport, but in the direction of absorption rather than secretion. In addition, the choroid plexus conditions CSF by absorbing K+ (see Fig. 11-4, right inset, thin black arrow labeled “Transepithelial fluxes”) and certain other substances (e.g., 5-hydroxyindoleacetic acid, a metabolite of serotonin).

CSF 的成分与血浆的成分有很大不同;因此，CSF 不仅仅是血浆的超滤液（表 11-1）。例如，CSF 的 K+ 和氨基酸浓度低于血浆，并且几乎不含蛋白质。此外，面对血浆中离子浓度的大幅波动，脉络丛刚性地保持 CSF 中离子的浓度。这种离子稳态包括 K+、H+ /HCO3−、Mg2+、Ca2+，以及较小程度的 Na+ 和 Cl−。所有这些离子都会影响神经功能，因此需要严格的稳态控制。神经元微环境受到脉络丛和 BBB 其余部分的良好保护，不受血液的影响，因此必须选择性地将必需的微量营养素，例如非常少量所需的维生素和微量元素输送到大脑中。其中一些微量营养素主要通过脉络丛运输到大脑中，而另一些主要通过血管的内皮细胞运输。相比之下，大脑不断代谢相对大量的“宏量营养素”，例如葡萄糖和一些氨基酸。CSF 分两个连续阶段形成。首先，血浆超滤穿过有孔毛细血管壁（见第 462 页）进入脉络膜上皮细胞基底外侧膜下的 ECF。其次，脉络膜上皮细胞将液体分泌到心室中。CSF 的产生是通过 NaCl 和 NaHCO3 的净转移发生的，该转移驱动水的同向运动（参见图 11-4，右插图，标记为“跨上皮通量”的白色大箭头）。肾近端小管（见第 761 页）和小肠（见第 903 页）也进行近等渗运输，但方向是吸收而不是分泌。此外，脉络丛通过吸收 K+（见图 11-4，右插图，标记为“跨上皮通量”的黑色细箭头）和某些其他物质（例如，5-羟基吲哚乙酸，5-羟色胺的代谢物）来调节 CSF。

The upper portion of the right inset of Figure 11-4 summarizes the ion transport processes that mediate CSF secretion. The net secretion of Na+ from plasma to CSF is a two-step process. The Na-K pump in the choroid plexus, unlike that in other epithelia (see pp. 137–138), is unusual in being located on the apical membrane, where it moves Na+ out of the cell into the CSF—the first step. This active movement of Na+ out of the cell generates an inward Na+ gradient across the basolateral membrane, energizing basolateral Na+ entry—the second step—through Na-H exchange and Na+- coupled HCO3− transport. In the case of Na-H exchange, the limiting factor is the availability of intracellular H+, which carbonic anhydrase generates, along with HCO3− , from CO2 and H2O. Thus, blocking of the Na-K pump with ouabain halts CSF formation, whereas blocking of carbonic anhydrase with acetazolamide slows CSF formation.

图 11-4 右插图的上半部分总结了介导 CSF 分泌的离子传输过程。Na+ 从血浆到 CSF 的净分泌是一个两步过程。与其他上皮细胞不同（参见第 137-138 页），脉络丛中的 Na-K 泵不寻常，它位于顶膜上，它将 Na+ 从细胞中移出进入 CSF——第一步。Na+ 的这种主动运动出细胞，在基底外侧膜上产生向内的 Na + 梯度，通过 Na-H 交换和 Na + 偶联的 HCO3 − 转运，为基底外侧 Na + 进入提供动力，这是第二步。在 Na-H 交换的情况下，限制因素是细胞内 H+ 的可用性，碳酸酐酶与 HCO3− 一起从 CO2 和 H2O 中产生。因此，用哇巴因阻断 Na-K 泵会阻止 CSF 形成，而用乙酰唑胺阻断碳酸酐酶会减慢 CSF 的形成。

The net secretion of Cl−, like that of Na+, is a two-step process. The first step is the intracellular accumulation of Cl− by the basolateral Cl-HCO3 exchanger. Note that the net effect of parallel Cl-HCO3 exchange and Na-H exchange is NaCl uptake. The second step is efflux of Cl− across the apical border into the CSF through either a Cl− channel or a K/Cl cotransporter.

Cl− 的净分泌与 Na+ 一样，是一个两步过程。第一步是基底外侧 Cl-HCO3 交换剂在细胞内积累 Cl−。请注意，平行 Cl-HCO3 交换和 Na-H 交换的净效应是 NaCl 摄取。第二步是 Cl− 通过 Cl− 通道或 K/Cl 协同转运蛋白穿过顶端边界流入 CSF。

HCO3− secretion into CSF is important for neutralizing acid produced by CNS cells. At the basolateral membrane, the epithelial cell probably takes up HCO3− directly from the plasma filtrate through electroneutral Na/HCO3 cotransporters (see Fig. 5-11F) and the Na+-driven Cl-HCO3 exchanger (see Fig. 5-13C). As noted before, HCO3− can also accumulate inside the cell after CO2 entry. The apical step, movement of intracellular HCO3− into the CSF, probably occurs by an electrogenic Na/HCO3 cotransporter (see Fig. 5-11D) and Cl− channels (which may be permeable to HCO3−).

HCO3− 分泌到 CSF 中对于中和 CNS 细胞产生的酸很重要。在基底外侧膜，上皮细胞可能通过电中性 Na/HCO3 协同转运蛋白（见图 5-11F）和 Na+ 驱动的 Cl-HCO3 交换蛋白（见图 5-13C）直接从血浆滤液中吸收 HCO3−。如前所述，HCO3− 在 CO2 进入后也会在细胞内积累。顶端步骤，即细胞内 HCO3− 向 CSF 的运动，可能是由电生 Na/HCO3 协同转运蛋白（见图 5-11D）和 Cl− 通道（可能对 HCO3− 具有渗透性）发生的。

The lower portion of the right inset of Figure 11-4 summarizes K+ absorption from the CSF. The epithelial cell takes up K+ by the Na-K pump and the Na/K/Cl cotransporter at the apical membrane (see Fig. 5-11G). Most of the K+ recycles back to the CSF, but a small amount exits across the basolateral membrane and enters the blood. The concentration of K+ in freshly secreted CSF is ~3.3 mM. Even with very large changes in plasma [K+], the [K+] in CSF changes very little. The value of [K+] in CSF is significantly lower in the subarachnoid space than in choroid secretions, which suggests that brain capillary endothelial cells remove extracellular K+ from the brain.

图 11-4 右侧插图的下半部分总结了 CSF 的 K+ 吸收。上皮细胞被 Na-K 泵和顶膜上的 Na/K/Cl 协同转运蛋白吸收 K+（见图 5-11G）。大部分 K+ 循环回到 CSF，但有一小部分穿过基底外侧膜流出并进入血液。新鲜分泌的 CSF 中 K+ 的浓度为 ~3.3 mM。即使血浆 [K+] 的变化非常大，CSF 中的 [K+] 变化也很小。蛛网膜下腔 CSF 中 [K+] 的值明显低于脉络膜分泌物，这表明脑毛细血管内皮细胞从大脑中去除细胞外 K+。

Water transport across the choroid epithelium is driven by a small osmotic gradient favoring CSF formation. This water movement is facilitated by the water channel aquaporin 1 (AQP1; see p. 110) on both the apical and basal membranes as in the renal proximal tubule (see pp. 761–762).

水通过脉络膜上皮的运输是由有利于 CSF 形成的小渗透压梯度驱动的。与肾近端小管一样，顶端和基底膜上的水通道水通道蛋白 1（AQP1;见第 110 页）促进了这种水的运动（见第 761-762 页）。

[编辑] 3 大脑细胞外间隙

BRAIN EXTRACELLULAR SPACE

[编辑] 3.1 神经元、神经胶质细胞和毛细血管在 CNS 中紧密堆积在一起

Neurons, glia, and capillaries are packed tightly together in the CNS

The average width of the space between brain cells is ~20 nm, which is about three orders of magnitude smaller than the diameter of either a neuron or a glial cell body (Fig. 11-5). However, because the surface membranes of neurons and glial cells are highly folded (i.e., have a large surface-to- volume ratio), the BECF in toto has a sizable volume fraction, ~20%, of total brain volume. The fraction of the brain occupied by BECF varies somewhat in different areas of the CNS and increases during sleep. Moreover, because brain cells can increase volume rapidly during intense neural activity, the BECF fraction can reversibly decrease within seconds from ~20% to ~17% of brain volume.

脑细胞之间空间的平均宽度为 ~20 nm，比神经元或神经胶质细胞体的直径小约三个数量级（图 11-5）。然而，由于神经元和神经胶质细胞的表面膜高度折叠（即具有较大的表面积与体积比），因此 toto 中的 BECF 具有相当大的体积分数，占总脑体积的 ~20%。BECF 占据的大脑部分在 CNS 的不同区域略有不同，并在睡眠期间增加。此外，由于脑细胞可以在强烈的神经活动期间迅速增加体积，因此 BECF 分数可以在几秒钟内从脑体积的 ~20% 可逆地降低到 ~17%。

Even though the space between brain cells is extremely small, diffusion of ions and other solutes within this thin BECF space is reasonably high. However, a particle that diffuses through the BECF from one side of a neuron to the other must take a circuitous route that is described by a parameter called tortuosity. For a normal width of the cell-to-cell spacing, this tortuosity reduces the rate of diffusion by ~60% compared with movement in free solution. Decreases in cell-to-cell spacing can further slow diffusion. For example, brain cells, especially glial cells, swell under certain pathological conditions and sometimes with intense neural activity. Cell swelling is associated with a reduction in BECF because water moves from the BECF into cells. The intense cell swelling associated with acute anoxia, for example, can reduce BECF volume from ~20% to ~5% of total brain volume. By definition, this reduced extracellular volume translates to reduced cell-to-cell spacing, which further slows the extracellular movement of solutes between the blood and brain cells (Box 11-3).

尽管脑细胞之间的空间非常小，但离子和其他溶质在这个薄的 BECF 空间内的扩散相当高。然而，通过 BECF 从神经元的一侧扩散到另一侧的粒子必须采用由称为迂曲度的参数描述的迂回路线。对于细胞间间距的正常宽度，与自由溶液中的移动相比，这种弯曲使扩散速率降低了 ~60%。细胞间间距的减小会进一步减慢扩散。例如，脑细胞，尤其是神经胶质细胞，在某些病理条件下会肿胀，有时还会伴有强烈的神经活动。细胞肿胀与 BECF 的减少有关，因为水从 BECF 进入细胞。例如，与急性缺氧相关的强烈细胞肿胀可以将 BECF 体积从总脑体积的 ~20% 降低到 ~5%。根据定义，这种细胞外体积的减少转化为细胞间间距的减小，这进一步减慢了溶质在血液和脑细胞之间的细胞外运动（框 11-3）。

The BECF is the route by which important molecules such as oxygen, glucose, and amino acids reach brain cells and by which the products of metabolism, including CO2 and catabolized neurotransmitters, leave the brain. The BECF also permits molecules that are released by brain cells to diffuse to adjacent cells. Neurotransmitter molecules released at synaptic sites, for example, can spill over from the synaptic cleft and contact nearby glial cells and neurons, in addition to their target postsynaptic cell. Glial cells express neurotransmitter receptors, and neurons have extrajunctional receptors; therefore, these cells are capable of receiving “messages” sent through the BECF. Numerous trophic molecules (see p. 292) secreted by brain cells diffuse in the BECF to their targets. Intercellular communication by way of the BECF is especially well suited for the transmission of tonic signals that are ideal for longer-term modulation of the behavior of aggregates of neurons and glial cells. The chronic presence of variable amounts of neurotransmitters in the BECF supports this idea.

BECF 是氧、葡萄糖和氨基酸等重要分子到达脑细胞的途径，以及包括 CO2 和分解代谢的神经递质在内的新陈代谢产物离开大脑的途径。BECF 还允许脑细胞释放的分子扩散到邻近细胞。例如，在突触部位释放的神经递质分子可以从突触间隙溢出，除了接触目标突触后细胞外，还可以接触附近的神经胶质细胞和神经元。神经胶质细胞表达神经递质受体，神经元具有连接外受体;因此，这些信元能够接收通过 BECF 发送的 “消息”。脑细胞分泌的许多营养分子（见第 292 页）在 BECF 中扩散到其目标。通过 BECF 进行的细胞间通讯特别适合于强直信号的传输，这些信号非常适合长期调节神经元和神经胶质细胞聚集体的行为。BECF 中长期存在不同数量的神经递质支持了这一想法。

[编辑] 3.2 脑脊液与脑细胞外液 (BECF) 自由交流，从而稳定神经元微环境的组成

The CSF communicates freely with the BECF, which stabilizes the composition of the neuronal microenvironment

CSF in the ventricles and the subarachnoid space can exchange freely with BECF across two borders, the pia mater and ependymal cells. The pial-glial membrane (see Fig. 11-2, upper inset) has paracellular gaps through which substances can equilibrate between the subarachnoid space and BECF. Ependymal cells (see Fig. 11-2, lower inset) are special glial cells that line the walls of the ventricles and form the cellular boundary between the CSF and the BECF. These cells form gap junctions (see p. 45) between themselves that mediate intercellular communication, but they do not create a tight epithelium (see p. 137). Thus, macromolecules and ions can also easily pass through this cellular layer through paracellular openings (some notable exceptions to this rule are considered below) and equilibrate between the CSF in the ventricle and the BECF.

脑室和蛛网膜下腔的 CSF 可以跨越软脑膜和室管膜细胞两个边界与 BECF 自由交换。软脑膜-胶质膜（见图 11-2，上插图）具有细胞旁间隙，物质可以通过这些间隙在蛛网膜下腔和 BECF 之间保持平衡。室管膜细胞（见图 11-2，下插图）是特殊的神经胶质细胞，排列在脑室壁上，形成 CSF 和 BECF 之间的细胞边界。这些细胞在它们之间形成间隙连接（见第 45 页），介导细胞间通讯，但它们不会形成紧密的上皮（见第 137 页）。因此，大分子和离子也可以很容易地通过细胞旁开口穿过该细胞层（下面将考虑此规则的一些显着例外）并在心室中的 CSF 和 BECF 之间达到平衡。

Because CSF and BECF can readily exchange with one another, it is not surprising that they have a similar chemical composition. For example, [K+] is ~3.3 mM in freshly secreted CSF and ~3 mM in both the CSF of the subarachnoid space (see Table 11-1) and BECF. The [K+] of blood is ~4.5 mM. However, because of the extent and vast complexity of the extracellular space, changes in the composition of CSF are reflected slowly in the BECF and probably incompletely.

因为 CSF 和 BECF 可以很容易地相互交换，所以它们具有相似的化学成分也就不足为奇了。例如，[K+] 在新鲜分泌的 CSF 中为 ~3.3 mM，在蛛网膜下腔的 CSF 中为 ~3 mM（见表 11-1）和 BECF。血液的 [K+] 为 ~4.5 mM。然而，由于细胞外空间的范围和巨大复杂性，CSF 组成的变化在 BECF 中反映得很慢，而且可能不完全。

CSF is an efficient waste-management system because of its high rate of production, its circulation over the surface of the brain, and the free exchange between CSF and BECF. Products of metabolism and other substances released by cells, perhaps for signaling purposes, can diffuse into the chemically stable CSF and ultimately be removed on a continuous basis either by bulk resorption into the venous sinuses or by active transport across the choroid plexus into the blood. For example, the choroid plexus actively absorbs the breakdown products of the neurotransmitters serotonin (i.e., 5-hydroxyindoleacetic acid) and dopamine (i.e., homovanillic acid).

CSF 是一种高效的废物管理系统，因为它的生产率高，在大脑表面循环，以及 CSF 和 BECF 之间的自由交换。细胞释放的新陈代谢产物和其他物质，可能出于信号传输目的，可以扩散到化学稳定的 CSF 中，并最终通过大量再吸收到静脉窦中或通过脉络丛主动转运到血液中连续去除。例如，脉络丛积极吸收神经递质血清素（即 5-羟基吲哚乙酸）和多巴胺（即高香草酸）的分解产物。

[编辑] 3.3 伴随神经活动的离子通量导致细胞外离子浓度发生较大变化

The ion fluxes that accompany neural activity cause large changes in extracellular ion concentration

As discussed in Chapter 7, ionic currents through cell membranes underlie the synaptic and action potentials by which neurons communicate. These currents lead to changes in the ion concentrations of the BECF. It is estimated that even a single action potential can transiently lower [Na+]o by ~0.75 mM and increase [K+]o by a similar amount. Repetitive neuronal activity causes larger perturbations in these extracellular ion concentrations. Because ambient [K+]o is much lower than [Na+]o, activity-induced changes in [K+]o are proportionately larger and are of special interest because of the important effect that [K+]o has on membrane potential (Vm). For example, K+ accumulation in the vicinity of active neurons depolarizes nearby glial cells. In this way, neurons signal to glial cells the pattern and extent of their activity. Even small changes in [K+]o can alter metabolism and ionic transport in glial cells and may be used for signaling. Changes in the extracellular concentrations of certain common amino acids, such as glutamate and glycine, can also affect neuronal Vm and synaptic function by acting at specific receptor sites. If the nervous system is to function reliably, its signaling elements must have a regulated environment. Glial cells and neurons both function to prevent excessive extracellular accumulation of K+ and neurotransmitters.

如第 7 章所述，通过细胞膜的离子电流是神经元交流的突触电位和动作电位的基础。这些电流导致 BECF 的离子浓度发生变化。据估计，即使是单个动作电位也可以暂时使 [Na+]o 降低 ~0.75 mM，并将 [K+]o 增加相似的量。重复的神经元活动会导致这些细胞外离子浓度的较大扰动。由于环境 [K+]o 远低于 [Na+]o，因此活性诱导的 [K+]o 变化成比例地更大，并且由于 [K+]o 对膜电位 （Vm） 有重要影响，因此具有特别的兴趣。例如，活跃神经元附近的 K+ 积累会使附近的神经胶质细胞去极化。通过这种方式，神经元向神经胶质细胞发出信号，表明其活动的模式和程度。即使是 [K+]o 的微小变化也可以改变神经胶质细胞中的代谢和离子转运，并可用于信号传导。某些常见氨基酸（如谷氨酸和甘氨酸）的细胞外浓度变化也可以通过作用于特定受体位点来影响神经元 Vm 和突触功能。如果神经系统要可靠地运作，其信号元件必须有一个受监管的环境。神经胶质细胞和神经元都有助于防止 K+ 和神经递质的过度细胞外积累。

[编辑] 4 血脑屏障 (BBB)

THE BLOOD-BRAIN BARRIER

[编辑] 4.1 血脑屏障阻止一些血液成分进入大脑细胞外间隙

The blood-brain barrier prevents some blood constituents from entering the brain extracellular space

The unique protective mechanism now called the BBB was first demonstrated by Ehrlich in 1885. He injected aniline dyes intravenously and discovered that the soft tissues of the body, except for the brain, were uniformly stained. Aniline dyes, such as trypan blue, extensively bind to serum albumin, and the dye-albumin complex passes across capillaries in most areas of the body, but not the brain. This ability to exclude certain substances from crossing CNS blood vessels into the brain tissue is due to the blood-brain barrier. We now recognize that a BBB is present in all vertebrates and many invertebrates as well.

现在称为 BBB 的独特保护机制由 Ehrlich 于 1885 年首次演示。他静脉注射苯胺染料，发现身体的软组织，除了大脑，都是均匀染色的。苯胺染料（如台盼蓝）与血清白蛋白广泛结合，染料-白蛋白复合物穿过身体大多数部位的毛细血管，但不穿过大脑。这种排除某些物质穿过 CNS 血管进入脑组织的能力是由于血脑屏障。我们现在认识到 BBB 存在于所有脊椎动物和许多无脊椎动物中。

The need for a BBB can be understood by considering that blood is not a suitable environment for neurons. Blood is a complex medium that contains a large variety of solutes, some of which can vary greatly in concentration, depending on factors such as diet, metabolism, illness, and age. For example, the concentration of many amino acids increases significantly after a protein-rich meal. Some of these amino acids act as neurotransmitters within the brain, and if these molecules could move freely from the blood into the neuronal microenvironment, they would nonselectively activate receptors and disturb normal neurotransmission. Similarly, strenuous exercise can increase plasma concentrations of K+ and H+ substantially. If these ionic changes were communicated directly to the microenvironment of neurons, they could disrupt ongoing neural activity. Running a foot race might temporarily lower your IQ. Increases in [K+]o would depolarize neurons and thus increase their likelihood of firing and releasing transmitter. H+ can nonspecifically modulate neuronal excitability and influence the action of certain neurotransmitters. A broad range of blood constituents—including hormones, other ions, and inflammatory mediators such as cytokines—can influence the behavior of neurons or glial cells, which can express receptors for these molecules. For the brain to function efficiently, it must be spared such influences.

通过考虑血液不适合神经元的环境，可以理解对 BBB 的需求。血液是一种复杂的介质，含有多种溶质，其中一些溶质的浓度会有很大差异，具体取决于饮食、新陈代谢、疾病和年龄等因素。例如，在富含蛋白质的膳食后，许多氨基酸的浓度会显着增加。其中一些氨基酸在大脑中充当神经递质，如果这些分子可以从血液中自由移动到神经元微环境中，它们就会非选择性地激活受体并干扰正常的神经传递。同样，剧烈运动可以显着增加血浆中 K+ 和 H+ 的浓度。如果这些离子变化直接传达给神经元的微环境，它们可能会破坏正在进行的神经活动。跑步可能会暂时降低您的智商。[K+]o 的增加会使神经元去极化，从而增加它们发射和释放递质的可能性。H+ 可以非特异性调节神经元兴奋性并影响某些神经递质的作用。广泛的血液成分（包括激素、其他离子和炎症介质，如细胞因子）可以影响神经元或神经胶质细胞的行为，而神经元或神经胶质细胞可以表达这些分子的受体。为了让大脑有效运作，它必须免受这种影响。

The choroid plexus and several restricted areas of the brain lack a BBB; that is, they are supplied by leaky capillaries. Intra-arterially injected dyes can pass into the BECS at these sites through gaps between endothelial cells. The BECF in the vicinity of these leaky capillaries is more similar to blood plasma than to normal BECF. The small brain areas that lack a BBB are called the circumventricular organs because they surround the ventricular system; these areas include the area postrema, posterior pituitary, median eminence, organum vasculosum laminae terminalis, subfornical organ, subcommissural organ, and pineal gland (Fig. 11-7). The ependymal cells that overlie the leaky capillaries in some of these regions (e.g., the choroid plexus) are linked together by tight junctions that form a barrier between the local BECF and the CSF, which must be insulated from the variability of blood composition. Whereas dyes with molecular weights up to 5000 can normally pass from CSF across the ependymal cell layer into the BECF, they do not pass across the specialized ependymal layer at the median eminence, area postrema, and infundibular recess. At these points, the localized BECF-CSF barrier is similar to the one in the choroid plexus. These specialized ependymal cells often have long processes that extend to capillaries within the portal circulation of the pituitary. Although the function of these cells is not known, it has been suggested that they may form a special route for neurohumoral signaling; molecules secreted by hypothalamic cells into the third ventricle could be taken up by these cells and transmitted to the general circulation or to cells in the pituitary.

脉络丛和大脑的几个受限区域缺乏 BBB;也就是说，它们是由渗漏的毛细血管供应的。动脉内注射的染料可以通过内皮细胞之间的间隙进入这些部位的 BECS。这些渗漏的毛细血管附近的 BECF 比正常 BECF 更类似于血浆。缺乏 BBB 的小脑区称为脑室周围器官，因为它们围绕着心室系统;这些区域包括极后区、垂体后叶、正中隆起、器官血管终板、穹窿下器官、连合下器官和松果体（图 11-7）。在其中一些区域（例如脉络丛）中覆盖渗漏毛细血管的室管膜细胞通过紧密连接连接在一起，这些连接在局部 BECF 和 CSF 之间形成屏障，CSF 必须与血液成分的变化隔离。虽然分子量高达 5000 的染料通常可以从 CSF 穿过室管膜细胞层进入 BECF，但它们不会穿过正中隆起、极后区和漏斗部隐窝处的特化室管膜层。在这些点上，定位的 BECF-CSF 屏障类似于脉络丛中的屏障。这些特化的室管膜细胞通常具有延伸到垂体门静脉循环内的毛细血管的长过程。虽然这些细胞的功能尚不清楚，但有人认为它们可能形成神经体液信号传导的特殊途径;下丘脑细胞分泌到第三脑室的分子可以被这些细胞吸收并传递到全身循环或垂体中的细胞。

Neurons within the circumventricular organs are directly exposed to blood solutes and macromolecules; this arrangement is believed to be part of a neuroendocrine control system for maintaining such parameters as osmolality (see p. 844) and appropriate hormone levels, among other things. Humoral signals are integrated by connections of circumventricular organ neurons to endocrine, autonomic, and behavioral centers within the CNS. In the median eminence, neurons discharge “releasing hormones,” which diffuse into leaky capillaries for carriage through the pituitary portal system to the anterior pituitary (see p. 978). The lack of a BBB in the posterior pituitary is necessary to allow hormones that are released there to enter the general circulation (see p. 979). In the organum vasculosum laminae terminalis, leakiness is important in the action of cytokines from the periphery, which act as signals to temperature control centers that are involved in fever (see p. 1202).

脑室周围器官内的神经元直接暴露于血液溶质和大分子;这种安排被认为是神经内分泌控制系统的一部分，用于维持渗透压（见第 844 页）和适当的激素水平等参数。体液信号通过脑室周围器官神经元与 CNS 内的内分泌、自主神经和行为中心的连接进行整合。在正中隆起处，神经元释放“释放激素”，这些激素扩散到渗漏的毛细血管中，通过垂体门系统到达垂体前叶（见第 978 页）。垂体后叶缺乏 BBB 是允许在那里释放的激素进入全身循环所必需的（见第 979 页）。在器官血管终梢层中，渗漏在来自外周的细胞因子的作用中很重要，这些细胞因子充当与发烧有关的温度控制中心的信号（见第 1202 页）。

[编辑] 4.2 连续的紧密连接连接大脑毛细血管内皮细胞

Continuous tight junctions link brain capillary endothelial cells

The BBB should be thought of as a physical barrier to diffusion from blood to BECF and as a selective set of regulatory transport mechanisms that determine how certain organic solutes move between the blood and brain. Thus, the BBB contributes to stabilization and protection of the neuronal microenvironment by facilitating the entry of needed substances, removing waste metabolites, and excluding toxic or disruptive substances.

BBB 应被视为从血液扩散到 BECF 的物理屏障，以及一组选择性的调节运输机制，用于确定某些有机溶质如何在血液和大脑之间移动。因此，BBB 通过促进所需物质的进入、去除废物代谢物以及排除有毒或破坏性物质，有助于稳定和保护神经元微环境。

The structure of brain capillaries differs from that of capillaries in other organs (Fig. 11-8A). Capillaries in other organs generally have small, simple openings—or clefts— between their endothelial cells. In some of these other organs, windows, or fenestrae, provide a pathway that bypasses the cytoplasm of capillary endothelial cells. Thus, in most capillaries outside the CNS, solutes can easily diffuse through the clefts and fenestrae. The physical barrier to solute diffusion in brain capillaries (see Fig. 11-8B) is provided by the capillary endothelial cells, which are fused to each other by continuous tight junctions (or zonula occludens; see pp. 43–44). The tight junctions prevent watersoluble ions and molecules from passing from the blood into the brain through the paracellular route. Not surprisingly, the electrical resistance of the cerebral capillaries is 100 to 200 times higher than that of most other systemic capillaries.

脑毛细血管的结构与其他器官的毛细血管不同（图 11-8A）。其他器官的毛细血管通常在其内皮细胞之间有小而简单的开口或裂缝。在一些其他器官中，窗户或门口提供了绕过毛细血管内皮细胞细胞质的通路。因此，在 CNS 外的大多数毛细血管中，溶质很容易通过裂隙和孔隙扩散。溶质在脑毛细血管中扩散的物理屏障（见图 11-8B）由毛细血管内皮细胞提供，它们通过连续的紧密连接（或小带闭塞;见第 43-44 页）相互融合。紧密连接可防止水溶性离子和分子通过细胞旁途径从血液进入大脑。毫不奇怪，大脑毛细血管的电阻比大多数其他全身毛细血管的电阻高 100 到 200 倍。

Elsewhere in the systemic circulation, molecules may traverse the endothelial cell by the process of transcytosis (see p. 467). In cerebral capillaries, transcytosis is uncommon, and brain endothelial cells have fewer endocytic vesicles than do systemic capillaries. However, brain endothelial cells have many more mitochondria than systemic endothelial cells do, which may reflect the high metabolic demands imposed on brain endothelial cells by active transport.

在体循环的其他地方，分子可能通过转胞吞作用过程穿过内皮细胞（见第 467 页）。在脑毛细血管中，转胞吞作用不常见，脑内皮细胞的内吞囊泡比全身毛细血管少。然而，脑内皮细胞的线粒体比全身内皮细胞多得多，这可能反映了主动运输对脑内皮细胞的高代谢需求。

Other interesting features of brain capillaries are the thick basement membrane that underlies the endothelial cells, the presence of occasional pericytes within the basement membrane sheath, and the astrocytic endfeet (or processes) that provide a nearly continuous covering of the capillaries and other blood vessels. Astrocytes may play a crucial role in forming tight junctions between endothelial cells; experiments have shown that these glial cells can induce the formation of tight junctions between endothelial cells derived from capillaries outside the CNS. The close apposition of the astrocyte endfoot to the capillary also could facilitate transport of substances between these cells and blood.

脑毛细血管的其他有趣特征是内皮细胞下方的厚基底膜、基底膜鞘内偶尔存在的周细胞，以及提供几乎连续覆盖毛细血管和其他血管的星形胶质细胞终足（或过程）。星形胶质细胞可能在内皮细胞之间形成紧密连接方面起关键作用;实验表明，这些神经胶质细胞可以诱导来源于 CNS 外毛细血管的内皮细胞之间形成紧密连接。星形胶质细胞终足与毛细血管的紧密结合也可以促进这些细胞和血液之间的物质运输。

[编辑] 4.3 不带电和脂溶性分子更容易通过血脑屏障

Uncharged and lipid-soluble molecules more readily pass through the blood-brain barrier

The capacity of the brain capillaries to exclude large molecules is strongly related to the molecular mass of the molecule and its hydrated diameter (Table 11-2). With a mass of 61 kDa, prealbumin is 14 times as concentrated in blood as in CSF (essentially equivalent to BECF for purposes of this comparison), whereas fibrinogen, which has a molecular mass of 340 kDa, is ~5000 times more concentrated in blood than in CSF. Diffusion of a solute is also generally limited by ionization at physiological pH, by low lipid solubility, and by binding to plasma proteins. For example, gases such as CO2 and O2 and drugs such as ethanol, caffeine, nicotine, heroin, and methadone readily cross the BBB. However, ions such as K+ or Mg2+ and protein-bound metabolites such as bilirubin have restricted access to the brain. Finally, the BBB is permeable to water mainly because of the presence of AQP4 in the astrocytic endfeet (see Fig. 11-8A). Thus, water moves across the BBB in response to changes in plasma osmolality. When dehydration raises the osmolality of blood plasma (see Box 11-3), the increased osmolality of the CSF and BECF can affect the behavior of brain cells.

脑毛细血管排除大分子的能力与分子的分子量及其水合直径密切相关（表 11-2）。质量为 61 kDa，前白蛋白在血液中的浓度是 CSF 中的14倍（基本上相当于本比较中的BECF），而纤维蛋白原的分子量为 340 kDa，在血液中的浓度是 CSF 中的 ~5000 倍。溶质的扩散通常也受到生理 pH 值下电离、低脂质溶解度以及与血浆蛋白结合的限制。例如，CO2 和 O2 等气体以及乙醇、咖啡因、尼古丁、海洛因和美沙酮等药物很容易穿过 BBB。然而，离子（如 K+ 或 Mg2+）和蛋白质结合的代谢物（如胆红素）对大脑的访问受到限制。最后，BBB 对水具有渗透性，主要是因为星形胶质细胞终足中存在 AQP4（见图 11-8A）。因此，水响应血浆渗透压的变化而穿过 BBB。当脱水提高血浆的渗透压时（见框 11-3），CSF 和 BECF 的渗透压增加会影响脑细胞的行为。

Cerebral capillaries also express enzymes that can affect the movement of substances from blood to brain and vice versa. Peptidases, acid hydrolases, monoamine oxidase, and other enzymes are present in CNS endothelial cells and can degrade a range of biologically active molecules, including enkephalins, substance P, proteins, and norepinephrine. Orally administered dopamine is not an effective treatment of Parkinson disease (see p. 313), a condition in which CNS dopamine is depleted, because dopamine is rapidly broken down by monoamine oxidase in the capillaries. Fortunately, the dopamine precursor compound L-DOPA is effective for this condition. Neutral amino-acid transporters in capillary endothelial cells move L-DOPA to the BECF, where presynaptic terminals take up the L-DOPA and convert it to dopamine in a reaction that is catalyzed by DOPA decarboxylase.

脑毛细血管还表达酶，这些酶可以影响物质从血液到大脑的运动，反之亦然。肽酶、酸性水解酶、单胺氧化酶和其他酶存在于 CNS 内皮细胞中，可以降解一系列生物活性分子，包括脑啡肽、P 物质、蛋白质和去甲肾上腺素。口服多巴胺不是帕金森病的有效治疗方法（见第 313 页），帕金森病是一种 CNS 多巴胺耗尽的情况，因为多巴胺在毛细血管中被单胺氧化酶迅速分解。幸运的是，多巴胺前体化合物 L-DOPA 对这种情况有效。毛细血管内皮细胞中的中性氨基酸转运蛋白将 L-DOPA 移动到 BECF，在那里突触前末端吸收 L-DOPA 并在 DOPA 脱羧酶催化的反应中将其转化为多巴胺。

[编辑] 4.4 毛细血管内皮细胞的运输有助于血脑屏障

Transport by capillary endothelial cells contributes to the blood-brain barrier

Two classes of substances can pass readily between blood and brain. The first consists of the small, highly lipid-soluble molecules discussed in the preceding section. The second group consists of water-soluble compounds—either critical nutrients entering or metabolites exiting the brain—that traverse the BBB by specific transporters. Examples include glucose, several amino acids and neurotransmitters, nucleic acid precursors, and several organic acids. Two major transporter groups provide these functions: the SLC superfamily (see pp. 111–114) and ABC transporters (see pp. 119–120). N11-3 As is the case for other epithelial cells, capillary endothelial cells selectively express these and other membrane proteins on either the luminal or basal surface.

两类物质可以很容易地在血液和大脑之间传递。第一个由上一节中讨论的高脂溶性小分子组成。第二组由水溶性化合物组成——进入大脑的关键营养物质或离开大脑的代谢物——它们通过特定的转运蛋白穿过 BBB。例子包括葡萄糖、几种氨基酸和神经递质、核酸前体和几种有机酸。两个主要的转运蛋白组提供这些功能：SLC 超家族（参见第 111-114 页）和 ABC 转运蛋白（参见第 119-120 页）。N11-3 与其他上皮细胞一样，毛细血管内皮细胞选择性地在管腔或基底表面表达这些和其他膜蛋白。

Although the choroid plexuses secrete most of the CSF, brain endothelial cells produce some interstitial fluid with a composition similar to that of CSF. Transporters such as those shown in Figure 11-8C are responsible for this CSFlike secretion as well as for the local control of [K+] and pH in the BECF.

虽然脉络丛分泌大部分脑脊液，但脑内皮细胞会产生一些成分类似于脑脊液的间质液。如图 11-8C 所示的转运蛋白负责这种 CSF 样分泌以及 BECF 中 [K+] 和 pH 值的局部控制。

[编辑] 5 胶质细胞 (Glial Cells)

GLIAL CELLS

[编辑] 5.1 神经胶质细胞占大脑体积的一半，数量超过神经元

Glial cells constitute half the volume of the brain and outnumber neurons

The three major types of glial cells in the CNS are astrocytes, oligodendrocytes, and microglial cells (Fig. 11-9, Table 11-3). As discussed in Chapter 10, the peripheral nervous system (PNS) contains other, distinctive types of glial cells, including satellite cells, Schwann cells, and enteric glia. Glial cells represent about half the volume of the brain and are more numerous than neurons. Unlike neurons, which have little capacity to replace themselves when lost, neuroglial (or simply glial) cells can proliferate throughout life. An injury to the nervous system is the usual stimulus for proliferation.

CNS 中的三种主要神经胶质细胞类型是星形胶质细胞、少突胶质细胞和小胶质细胞（图 11-9、表 11-3）。如第 10 章所述，周围神经系统 （PNS） 包含其他独特类型的神经胶质细胞，包括卫星细胞、雪旺细胞和肠道神经胶质细胞。神经胶质细胞约占大脑体积的一半，比神经元多。与神经元不同，神经元在丢失时几乎没有自我替换的能力，神经胶质细胞（或简称神经胶质细胞）可以在一生中增殖。神经系统损伤是增殖的常见刺激因素。

Historically, glial cells were viewed as a type of CNS connective tissue whose main function was to provide support for the true functional cells of the brain, the neurons. This firmly entrenched concept remained virtually unquestioned for the better part of a century after the early description of these cells by Virchow in 1858. Knowledge about glial cells has accumulated slowly because these cells have proved far more difficult to study than neurons. Because glial cells do not exhibit easily recorded action potentials or synaptic potentials, these cells were sometimes referred to as silent cells. However, glial cells are now recognized as intimate partners with neurons in virtually every function of the brain.

从历史上看，神经胶质细胞被视为一种 CNS 结缔组织，其主要功能是为大脑的真正功能细胞神经元提供支持。在 1858 年 Virchow 对这些细胞进行早期描述后的大部分时间里，这个根深蒂固的概念几乎没有受到质疑。关于神经胶质细胞的知识积累得很慢，因为事实证明这些细胞比神经元更难研究。由于神经胶质细胞不表现出容易记录的动作电位或突触电位，因此这些细胞有时被称为沉默细胞。然而，神经胶质细胞现在被认为与大脑几乎所有功能的神经元紧密结合。

[编辑] 5.2 星形胶质细胞以乳酸的形式为神经元提供燃料

Astrocytes supply fuel to neurons in the form of lactic acid

Astrocytes have great numbers of extremely elaborate processes that closely approach both blood vessels and neurons. This arrangement led to the idea that astrocytes transport substances between the blood and neurons. This notion may be true, but it has not been proved. Throughout the brain, astrocytes envelop neurons, and both cells bathe in a common BECF. Therefore, astrocytes are ideally positioned to modify and to control the immediate environment of neurons. Most astrocytes in the brain are traditionally subdivided into fibrous and protoplasmic types (see Table 11-3). Fibrous astrocytes (found mainly in white matter) have long, thin, and well-defined processes, whereas protoplasmic astrocytes (found mainly in gray matter) have shorter, frilly processes (see Fig. 11-9). Astrocytes are evenly spaced. In cortical regions, the dense processes of an individual astrocyte define its spatial domain, into which adjacent astrocytes do not encroach. The cytoskeleton of these and other types of astrocytes contains an identifying intermediate filament (see p. 23) that is composed of a unique protein called glial fibrillar acidic protein (GFAP). The basic physiological properties of both types of astrocyte are similar, but specialized features, such as the expression of neurotransmitter receptors, vary among astrocytes from different brain regions.

星形胶质细胞具有大量极其复杂的过程，它们紧密接近血管和神经元。这种安排导致了星形胶质细胞在血液和神经元之间运输物质的想法。这个概念可能是正确的，但尚未得到证实。在整个大脑中，星形胶质细胞包裹着神经元，两个细胞都沐浴在共同的 BECF 中。因此，星形胶质细胞非常适合修饰和控制神经元的直接环境。大脑中的大多数星形胶质细胞传统上分为纤维型和原生质型（见表 11-3）。纤维星形胶质细胞（主要存在于白质中）具有长而薄且界限分明的突起，而原生质星形胶质细胞（主要存在于灰质中）具有较短的褶边突起（见图 11-9）。星形胶质细胞分布均匀。在皮质区域，单个星形胶质细胞的致密突定义了它的空间域，相邻的星形胶质细胞不会侵入该空间域。这些和其他类型的星形胶质细胞的细胞骨架包含一个识别中间丝（见第 23 页），它由一种称为神经胶质纤维酸性蛋白 （GFAP） 的独特蛋白质组成。两种星形胶质细胞的基本生理特性相似，但来自不同大脑区域的星形胶质细胞的特殊特征（例如神经递质受体的表达）各不相同。

During development, another type of astrocyte called the radial glial cell (see pp. 263–265) is also present. As discussed on p. 267, these cells create an organized “scaffolding” by spanning the developing forebrain from the ventricle to the pial surface. Astrocytes in the retina and cerebellum are similar in appearance to radial glial cells. Like astrocytes elsewhere, these cells contain the intermediate filament GFAP. Retinal astrocytes, called Müller cells, are oriented so that they span the entire width of the retina. Bergmann glial cells in the cerebellum have processes that run parallel to the processes of Purkinje cells.

在发育过程中，还存在另一种称为放射状胶质细胞的星形胶质细胞（参见第 263-265 页）。如第 267 页所述，这些细胞通过将发育中的前脑从心室跨越到软脑膜表面来创建一个有组织的“支架”。视网膜和小脑中的星形胶质细胞在外观上与放射状神经胶质细胞相似。与其他地方的星形胶质细胞一样，这些细胞包含中间丝 GFAP。视网膜星形胶质细胞，称为 Müller 细胞，其定向使其跨越视网膜的整个宽度。小脑中的 Bergmann 神经胶质细胞具有与浦肯野细胞平行的过程。

Astrocytes store virtually all the glycogen present in the adult brain. They also contain all the enzymes needed for metabolizing glycogen. The brain’s high metabolic needs are primarily met by glucose transferred from blood because the brain’s glucose supply in the form of glycogen is very limited. In the absence of glucose from blood, astrocytic glycogen could sustain the brain for only 5 to 10 minutes. As implied, astrocytes can share with neurons the energy stored in glycogen, but not by the direct release of glucose into the BECF. Instead, astrocytes break glycogen down to glucose and even further to lactate, which is transferred to nearby neurons where it can be aerobically metabolized (Fig. 11-10). The extent to which this metabolic interaction takes place under normal conditions is not known, but it may be important during periods of intense neuronal activity, when the demand for glucose exceeds the supply from blood.

星形胶质细胞几乎储存了成人大脑中存在的所有糖原。它们还包含代谢糖原所需的所有酶。大脑的高代谢需求主要由从血液中转移的葡萄糖来满足，因为大脑以糖原形式提供的葡萄糖供应非常有限。在血液中没有葡萄糖的情况下，星形胶质细胞糖原只能维持大脑 5 到 10 分钟。正如暗示的那样，星形胶质细胞可以与神经元共享储存在糖原中的能量，但不能通过将葡萄糖直接释放到 BECF 中。相反，星形胶质细胞将糖原分解成葡萄糖，甚至进一步分解成乳酸，乳酸被转移到附近的神经元，在那里可以进行有氧代谢（图 11-10）。这种代谢相互作用在正常情况下发生的程度尚不清楚，但在神经元活动激烈期间可能很重要，此时对葡萄糖的需求超过血液的供应。

Astrocytes can also provide fuel to neurons in the form of lactate derived directly from glucose, independent of glycogen. Glucose entering the brain from blood first encounters the astrocytic endfoot. Although it can diffuse past this point to neurons, glucose may be preferentially taken up by astrocytes and shuttled through astrocytic glycolysis to lactic acid, a significant portion of which is excreted into the BECF surrounding neurons. Several observations support the notion that astrocytes provide lactate to neurons. First, astrocytes have higher anaerobic metabolic rates and export much more lactate than do neurons. Second, neurons and their axons function normally when glucose is replaced by lactate, and some neurons seem to prefer lactate to glucose as fuel. Note that when they are aerobically metabolized, the two molecules of lactate derived from the breakdown of one molecule of glucose provide nearly as much ATP (28 molecules) as the complete oxidation of glucose itself (30 molecules of ATP; see Table 58-4). The advantage of this scheme for neuronal function is that it provides a form of substrate buffering, a second energy reservoir that is available to neurons. The availability of glucose in the neuronal microenvironment depends on moment-to-moment supply from the blood and varies as a result of changes in neural activity. The concentration of extracellular lactate, however, is buffered against such variability by the surrounding astrocytes, which continuously shuttle lactate to the BECF by metabolizing glucose or by breaking down glycogen.

星形胶质细胞还可以以直接来自葡萄糖的乳酸形式为神经元提供燃料，与糖原无关。葡萄糖从血液进入大脑首先遇到星形胶质细胞型末端足。尽管葡萄糖可以扩散到神经元，但葡萄糖可能优先被星形胶质细胞吸收并通过星形胶质细胞糖酵解转化为乳酸，其中很大一部分排泄到神经元周围的 BECF 中。一些观察结果支持星形胶质细胞为神经元提供乳酸的观点。首先，星形胶质细胞具有更高的厌氧代谢率，并且比神经元输出更多的乳酸。其次，当葡萄糖被乳酸取代时，神经元及其轴突功能正常，一些神经元似乎更喜欢乳酸而不是葡萄糖作为燃料。请注意，当它们被有氧代谢时，由一个葡萄糖分子分解产生的两个乳酸分子提供的 ATP（28 个分子）几乎与葡萄糖本身的完全氧化（30 个 ATP 分子;见表 58-4）一样多。这种神经元功能方案的优势在于它提供了一种底物缓冲形式，即神经元可用的第二个能量库。神经元微环境中葡萄糖的可用性取决于血液的即时供应，并因神经活动的变化而变化。然而，细胞外乳酸的浓度被周围的星形胶质细胞缓冲到这种变化，星形胶质细胞通过代谢葡萄糖或分解糖原不断将乳酸穿梭到 BECF。

[编辑] 5.3 星形胶质细胞主要可渗透 K+，也有助于调节 [K+]o

Astrocytes are predominantly permeable to K+ and also help regulate [K+]o

The membrane potential of glial cells is more negative than that of neurons. For example, astrocytes have a Vm of about −85 mV, whereas the resting neuronal Vm is about −65 mV. Because the equilibrium potential for K+ is about −90 mV in both neurons and glia, the more negative Vm in astrocytes indicates that glial membranes have higher K+ selectivity than neuronal membranes do (see p. 148). Although glial cells express a variety of K+ channels, inwardly rectifying K+ channels seem to be important in setting the resting potential. These channels are voltage gated and are open at membrane potentials that are more negative than about −80 mV, close to the observed resting potential of astrocytes. Astrocytes express many other voltage-gated ion channels that were once thought to be restricted to neurons. The significance of voltage-gated Na+ and Ca2+ channels in glial cells is unknown. Because the ratio of Na+ to K+ channels is low in adult astrocytes, these cells are not capable of regenerative electrical responses such as the action potential.

神经胶质细胞的膜电位比神经元的膜电位更负。例如，星形胶质细胞的 Vm 约为 -85 mV，而静息神经元的 Vm 约为 -65 mV。因为 K+ 的平衡电位在神经元和神经胶质细胞中约为 -90 mV，所以星形胶质细胞中更多的负 Vm 表明神经胶质细胞膜具有比神经元膜更高的 K+ 选择性（见第 148 页）。尽管神经胶质细胞表达多种 K+ 通道，但向内整流 K+ 通道似乎在设置静息电位方面很重要。这些通道是电压门控的，并且在比约 -80 mV 更负的膜电位处开放，接近观察到的星形胶质细胞的静息电位。星形胶质细胞表达许多其他电压门控离子通道，这些离子通道曾经被认为仅限于神经元。电压门控 Na + 和 Ca2 + 通道在神经胶质细胞中的意义尚不清楚。由于成年星形胶质细胞中 Na + 与 K + 通道的比率较低，因此这些细胞无法产生再生电反应，例如动作电位。

One consequence of the higher K+ selectivity of astrocytes is that the Vm of astrocytes is far more sensitive than that of neurons to changes in [K+]o. For example, when [K+]o is raised from 4 to 20 mM, astrocytes depolarize by ~25 mV versus only ~5 mV for neurons. This relative insensitivity of neuronal resting potential to changes in [K+]o in the “physiological” range may have emerged as an adaptive feature that stabilizes the resting potential of neurons in the face of the transient increases in [K+]o that accompany neuronal activity. In contrast, natural stimulation, such as viewing visual targets of different shapes or orientations, can cause depolarizations of up to 10 mV in astrocytes of the visual cortex. The accumulation of extracellular K+ that is secondary to neural activity may serve as a signal—to glial cells—that is proportional to the extent of the activity. For example, small increases in [K+]o cause astrocytes to increase their glucose metabolism and to provide more lactate for active neurons. In addition, the depolarization that is triggered by the increased [K+]o leads to the influx of HCO3− into astrocytes by the electrogenic Na/HCO3 cotransporter (see p. 122); this influx of bicarbonate in turn causes a fall in extracellular pH that may diminish neuronal excitability. N11-4

星形胶质细胞较高的 K+ 选择性的一个结果是，星形胶质细胞的 Vm 比神经元对 [K+]o 的变化更敏感。例如，当 [K+]o 从 4 mM 升高到 20 mM 时，星形胶质细胞去极化 ~25 mV，而神经元的去极化仅为 ~5 mV。神经元静息电位对“生理”范围内 [K+]o 变化的这种相对不敏感可能已成为一种适应性特征，当神经元活动伴随 [K+]o 的瞬时增加时，它可以稳定神经元的静息电位。相比之下，自然刺激，例如观察不同形状或方向的视觉目标，可导致视觉皮层星形胶质细胞出现高达 10 mV 的去极化。继发于神经活动的细胞外 K+ 积累可能作为神经胶质细胞的信号，该信号与活动程度成正比。例如，[K+]o 的小幅增加会导致星形胶质细胞增加其葡萄糖代谢并为活跃的神经元提供更多的乳酸。此外，由增加的 [K+]o 触发的去极化导致 HCO3− 通过电原 Na/HCO3 协同转运蛋白流入星形胶质细胞（见第 122 页）;碳酸氢盐的流入反过来会导致细胞外 pH 值下降，这可能会降低神经元的兴奋性。编号 N11-4

Not only do astrocytes respond to changes in [K+]o, they also help regulate it (Fig. 11-11A). The need for homeostatic control of [K+]o is clear because changes in brain [K+]o can influence transmitter release, cerebral blood flow, cell volume, glucose metabolism, and neuronal activity. Active neurons lose K+ into the BECF, and the resulting increased [K+]o tends to act as a positive-feedback signal that increases excitability by further depolarizing neurons. This potentially unstable situation is opposed by efficient mechanisms that expedite K+ removal and limit its accumulation to a maximum level of 10 to 12 mM, the so-called ceiling level. [K+]o would rise far above this ceiling with intense neural activity if K+ clearance depended solely on passive redistribution of K+ in the BECF. Neurons and blood vessels can contribute to K+ homeostasis, but glial mechanisms are probably most important. Astrocytes can take up K+ in response to elevated [K+]o by three major mechanisms: the Na-K pump, the Na/K/Cl cotransporter, and the uptake of K+ and Cl− through channels. Conversely, when neural activity decreases, K+ and Cl− leave the astrocytes through ion channels.

星形胶质细胞不仅对 [K+]o 的变化做出反应，还有助于调节它（图 11-11A）。对 [K+]o 进行稳态控制的需求是显而易见的，因为大脑 [K+]o 的变化会影响递质释放、脑血流量、细胞体积、葡萄糖代谢和神经元活动。活跃的神经元将 K+ 丢失到 BECF 中，由此产生的 [K+]o 增加往往充当正反馈信号，通过进一步去极化神经元来增加兴奋性。这种潜在的不稳定情况与加速 K+ 去除并将其积累限制在 10 至 12 mM 的最大水平（即所谓的上限水平）的有效机制相反。如果 K+ 清除仅取决于 BECF 中 K+ 的被动重新分配，则 [K+]o 将远远超过这个上限。神经元和血管可促进 K+ 稳态，但神经胶质机制可能是最重要的。星形胶质细胞可以通过三种主要机制响应 [K+]o 升高而摄取 K+：Na-K 泵、Na/K/Cl 协同转运蛋白以及通过通道摄取 K+ 和 Cl−。相反，当神经活动降低时，K+ 和 Cl− 通过离子通道离开星形胶质细胞。

[编辑] 5.4 间隙连接将星形胶质细胞彼此偶联，允许小溶质扩散

Gap junctions couple astrocytes to one another, allowing diffusion of small solutes

The anatomical substrate for cell-cell coupling among astrocytes is the gap junction, which is composed of membrane proteins called connexins that form large aqueous pores connecting the cytoplasm of two adjacent cells (see pp. 158– 159). Coupling between astrocytes is strong because hundreds of gap junction channels may be present between two astrocytes. Astrocytes may also be weakly coupled to oligodendrocytes. Ions and organic molecules that are up to 1 kDa in size, regardless of charge, can diffuse from one cell into another through these large channels. Thus, a broad range of biologically important molecules, including nucleotides, sugars, amino acids, small peptides, cAMP, Ca2+, and inositol 1,4,5-trisphosphate (IP3), have access to this pathway.

星形胶质细胞之间细胞-细胞偶联的解剖基质是间隙连接，它由称为连接蛋白的膜蛋白组成，这些膜蛋白形成连接两个相邻细胞的细胞质的大水孔（参见第 158-159 页）。星形胶质细胞之间的偶联性很强，因为两个星形胶质细胞之间可能存在数百个间隙连接通道。星形胶质细胞也可能与少突胶质细胞弱偶联。大小高达 1 kDa 的离子和有机分子，无论电荷如何，都可以通过这些大通道从一个细胞扩散到另一个细胞。因此，广泛的生物学重要分子，包括核苷酸、糖、氨基酸、小肽、cAMP、Ca2+ 和肌醇 1,4,5-三磷酸 （IP3），都可以进入该途径。

Gap junctions may coordinate the metabolic and electrical activities of cell populations, amplify the consequences of signal transduction, and control intrinsic proliferative capacity. The strong coupling among astrocytes ensures that all cells in the aggregate have similar intracellular concentrations of ions and small molecules and similar membrane potentials. Thus, the network of astrocytes functionally behaves like a syncytium, much like the myocytes in the heart (see p. 483). In ways that are not yet clear, gap junctional communication can be important for the control of cellular proliferation. The most common brain cell–derived tumors in the CNS arise from astrocytes. Malignant astrocyte tumors, like malignant neoplasms derived from other cells that are normally coupled (e.g., liver cells), lack gap junctions. N11-5

间隙连接可以协调细胞群的代谢和电活动，放大信号转导的后果，并控制内在的增殖能力。星形胶质细胞之间的强偶联确保聚集体中的所有细胞都具有相似的细胞内离子和小分子浓度以及相似的膜电位。因此，星形胶质细胞网络在功能上表现得像合胞体，很像心脏中的肌细胞（见第 483 页）。以尚不清楚的方式，间隙连接通信对于控制细胞增殖可能很重要。CNS 中最常见的脑细胞来源肿瘤起源于星形胶质细胞。恶性星形胶质细胞肿瘤，如源自正常偶联的其他细胞（例如肝细胞）的恶性肿瘤，缺乏间隙连接。编号 N11-5

The coupling among astrocytes may also play an important role in controlling [K+]o by a mechanism known as spatial buffering. The selective K+ permeability of glia, together with their low-resistance cell-cell connections, permits them to transport K+ from focal areas of high [K+]o, where a portion of the glial syncytium would be depolarized, to areas of normal [K+]o, where the glial syncytium would be more normally polarized (see Fig. 11-11B). Redistribution of K+ proceeds by way of a current loop in which K+ enters glial cells at the point of high [K+]o and leaves them at sites of normal [K+]o, with the extracellular flow of Na+ completing this circuit. At a site of high neuronal activity, [K+]o might rise to 12 mM, which would produce a very large depolarization of an isolated, uncoupled astrocyte. However, because of the electrical coupling among astrocytes, the Vm of the affected astrocyte remains more negative than the equilibrium potential for K+ (EK) predicted for a [K+]o of 12 mM. Thus, K+ would tend to passively enter coupled astrocytes through channels at sites of high [K+]o. N11-6 As discussed in the preceding section, K+ may also enter the astrocyte by transporters.

星形胶质细胞之间的偶联也可能通过一种称为空间缓冲的机制在控制 [K+]o 中发挥重要作用。神经胶质细胞的选择性 K+ 通透性，以及它们的低电阻细胞间连接，使它们能够将 K+ 从高 [K+]o 的局灶区域（其中一部分神经胶质合胞体会去极化）转运到正常 [K+]o 的区域，在那里神经胶质细胞合胞体会更正常地极化（见图 11-11B）。K+ 的重新分布通过电流回路进行，其中 K+ 在高 [K+]o 点进入神经胶质细胞，并将它们留在正常 [K+]o 的位点，Na+ 的细胞外流动完成该回路。在神经元活性高的位点，[K+]o 可能会上升到 12 mM，这将产生分离的、未偶联的星形胶质细胞的非常大的去极化。然而，由于星形胶质细胞之间的电耦合，受影响的星形胶质细胞的 Vm 仍然比预测的 [K+]o 为 12 mM 的 K+ （EK） 的平衡电位更负。因此，K+ 倾向于通过高 [K+]o 位点的通道被动进入偶联的星形胶质细胞。N11-6 如上一节所述，K+ 也可能通过转运蛋白进入星形胶质细胞。

[编辑] 5.5 星形胶质细胞合成神经递质，从细胞外间隙吸收它们，并具有神经递质受体

Astrocytes synthesize neurotransmitters, take them up from the extracellular space, and have neurotransmitter receptors

Astrocytes synthesize at least 20 neuroactive compounds, including both glutamate and gamma-aminobutyric acid (GABA). Neurons can manufacture glutamate from glucose or from the immediate precursor molecule glutamine (Fig. 11-12). The glutamine pathway appears to be the primary one in the synthesis of synaptically released glutamate. Glutamine, however, is manufactured only in astrocytes by use of the astrocyte-specific enzyme glutamine synthetase to convert glutamate to glutamine. Astrocytes release this glutamine into the BECF through the SNAT3 and SNAT5 transporters (SLC38 family, see Table 5-4) for uptake by neurons through SNAT1 and SNAT2. Consistent with its role in the synthesis of glutamate for neurotransmission, glutamine synthetase is localized to astrocytic processes surrounding glutamatergic synapses. In the presynaptic ter- minals of neurons, glutaminase converts the glutamine to glutamate for release into the synaptic cleft by the presynaptic terminal. Finally, astrocytes take up much of the synaptically released glutamate to complete this glutamateglutamine cycle. Disruption of this metabolic interaction between astrocytes and neurons can depress glutamatedependent synaptic transmission.

星形胶质细胞合成至少 20 种神经活性化合物，包括谷氨酸和 γ-氨基丁酸 （GABA）。神经元可以从葡萄糖或直接前体分子谷氨酰胺中制造谷氨酸（图 11-12）。谷氨酰胺途径似乎是合成突触释放的谷氨酸的主要途径。然而，谷氨酰胺仅在星形胶质细胞中通过使用星形胶质细胞特异性酶谷氨酰胺合成酶将谷氨酸转化为谷氨酰胺而制造。星形胶质细胞通过 SNAT3 和 SNAT5 转运蛋白（SLC38 家族，见表 5-4）将这种谷氨酰胺释放到 BECF 中，以便神经元通过 SNAT1 和 SNAT2 摄取。与其在谷氨酸合成神经传递中的作用一致，谷氨酰胺合成酶定位于谷氨酸能突触周围的星形胶质细胞过程。在神经元的突触前末端，谷氨酰胺酶将谷氨酰胺转化为谷氨酸，由突触前末端释放到突触间隙中。最后，星形胶质细胞吸收大部分突触释放的谷氨酸以完成这个谷氨酸谷氨酰胺循环。星形胶质细胞和神经元之间这种代谢相互作用的破坏会抑制谷氨酸依赖性突触传递。

Glutamine derived from astrocytes is also important for synthesis of the brain’s most prevalent inhibitory neurotransmitter, GABA. In the neuron, the enzyme glutamic acid decarboxylase converts glutamate (generated from glutamine) to GABA (see Fig. 13-8A). Because astrocytes play such an important role in the synthesis of synaptic transmitters, these glial cells are in a position to modulate synaptic efficacy.

源自星形胶质细胞的谷氨酰胺对于合成大脑最普遍的抑制性神经递质 GABA 也很重要。在神经元中，谷氨酸脱羧酶将谷氨酸（由谷氨酰胺产生）转化为 GABA（见图 13-8A）。由于星形胶质细胞在突触递质的合成中起着如此重要的作用，因此这些神经胶质细胞能够调节突触功效。

Astrocytes have high-affinity uptake systems for the excitatory transmitter glutamate and the inhibitory transmitter GABA. In the case of glutamate uptake, mediated by EAAT1 and EAAT2 (SLC1 family, see Table 5-4), astrocytes appear to play the dominant role compared with neurons or other glial cells. Glutamate moves into cells accompanied by two Na+ ions and an H+ ion, with one K+ ion moving in the opposite direction (see Fig. 11-12). Because a net positive charge moves into the cell, glutamate uptake causes membrane depolarization. The presynaptic cytoplasm may contain glutamate at a concentration as high as 10 mM, and vesicles may contain as much as 100 mM glutamate. Nevertheless, the glutamate uptake systems can maintain extracellular glutamate at concentrations as low as ~1 μM, which is crucial for normal brain function.

星形胶质细胞具有兴奋性递质谷氨酸和抑制性递质 GABA 的高亲和力摄取系统。在由 EAAT1 和 EAAT2 （SLC1 家族，见表 5-4） 介导的谷氨酸摄取的情况下，与神经元或其他神经胶质细胞相比，星形胶质细胞似乎起主导作用。谷氨酸在两个 Na+ 离子和一个 H+ 离子的陪伴下进入细胞，其中一个 K+ 离子沿相反方向移动（见图 11-12）。因为净正电荷进入细胞，谷氨酸摄取导致膜去极化。突触前细胞质可能含有浓度高达 10 mM 的谷氨酸，囊泡可能含有高达 100 mM 的谷氨酸。然而，谷氨酸摄取系统可以将细胞外谷氨酸维持在低至 ~1 μM 的浓度，这对正常的大脑功能至关重要。

Neurotransmitter uptake systems are important because they help terminate the action of synaptically released neurotransmitters. Astrocyte processes frequently surround synaptic junctions and are ideally placed for this function. Under pathological conditions in which transmembrane ion gradients break down, high-affinity uptake systems may work in reverse and release transmitters, such as glutamate, into the BECF (Box 11-4).

神经递质摄取系统很重要，因为它们有助于终止突触释放的神经递质的作用。星形胶质细胞突起经常围绕突触连接，是实现此功能的理想位置。在跨膜离子梯度分解的病理条件下，高亲和力摄取系统可以反向工作并将谷氨酸等递质释放到 BECF 中（框 11-4）。

Astrocytes express a wide variety of ionotropic and metabotropic neurotransmitter receptors that are similar or identical to those present on neuronal membranes. As in neurons, activation of these receptors can open ion channels or generate second messengers. In most astrocytes, glutamate produces depolarization by increasing Na+ permeability, whereas GABA hyperpolarizes cells by opening Cl− channels, similar to the situation in neurons (see pp. 326–327). Transmitter substances released by neurons at synapses can diffuse in the BECF to activate nearby receptors on astrocytes, thus providing, at least theoretically, a form of neuronal-glial signaling.

星形胶质细胞表达多种离子型和代谢型神经递质受体，这些受体与神经元膜上的受体相似或相同。与神经元一样，这些受体的激活可以打开离子通道或产生第二信使。在大多数星形胶质细胞中，谷氨酸通过增加 Na+ 通透性产生去极化，而 GABA 通过打开 Cl− 通道使细胞超极化，类似于神经元中的情况（参见第 326-327 页）。神经元在突触处释放的递质物质可以在 BECF 中扩散以激活星形胶质细胞上的附近受体，从而至少在理论上提供一种神经元-神经胶质细胞信号传导形式。

Astrocytes apparently can actively enhance or depress neuronal discharge and synaptic transmission by releasing neurotransmitters that they have taken up or synthesized. The release mechanisms are diverse and include stimulation by certain neurotransmitters, a fall in [Ca2+]o, or depolarization by elevated [K+]o. Applying glutamate to cultured astrocytes increases [Ca2+]i, which may oscillate. Moreover, these increases in [Ca2+]i can travel in waves from astrocyte to astrocyte through gap junctions or through a propagated front of extracellular ATP release that activates astrocytic purinergic receptors, thereby increasing [Ca2+]i and releasing more ATP. These [Ca2+]i waves—perhaps by triggering the release of a neurotransmitter from the astrocyte—can lead to changes in the activity of nearby neurons. This interaction represents another form of glial-neuronal communication.

星形胶质细胞显然可以通过释放它们已经吸收或合成的神经递质来主动增强或抑制神经元放电和突触传递。释放机制多种多样，包括某些神经递质的刺激、[Ca2+]o 的下降或 [K+]o 升高的去极化。将谷氨酸应用于培养的星形胶质细胞会增加 [Ca2+]i，这可能会振荡。此外，这些 [Ca2+]i 的增加可以通过间隙连接或通过激活星形胶质细胞嘌呤能受体的细胞外 ATP 释放的传播前沿，从而增加 [Ca2+]i 并释放更多的 ATP。这些 [Ca2+]i 波（可能是通过触发星形胶质细胞释放神经递质）可导致附近神经元活动的变化。这种相互作用代表了另一种形式的神经胶质-神经元通讯。

[编辑] 5.6 星形胶质细胞分泌营养因子，促进神经元存活和突触生成

Astrocytes secrete trophic factors that promote neuronal survival and synaptogenesis

Astrocytes, and other glial cell types, are a source of important trophic factors and cytokines, including brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), basic fibroblast growth factor (bFGF), and ciliary neurotrophic factor (CNTF). Moreover, both neurons and glial cells express receptors for these molecules, which are crucial for neuronal survival, function, and repair. The expression of these substances and their cognate receptors can vary during development and with injury to the nervous system.

星形胶质细胞和其他神经胶质细胞类型是重要营养因子和细胞因子的来源，包括脑源性神经营养因子 （BDNF）、神经胶质细胞源性神经营养因子 （GDNF）、碱性成纤维细胞生长因子 （bFGF） 和睫状神经营养因子 （CNTF）。此外，神经元和神经胶质细胞都表达这些分子的受体，这对神经元的生存、功能和修复至关重要。这些物质及其同源受体的表达在发育过程中和神经系统损伤过程中会发生变化。

The development of fully functional excitatory synapses in the brain requires the presence of astrocytes, which act at least in part by secreting proteins called thrombospondins. Indeed, synapses in the developing CNS do not form in substantial numbers before the appearance of astrocytes. In the absence of astrocytes, only ~20% of the normal number of synapses form.

大脑中功能齐全的兴奋性突触的发育需要星形胶质细胞的存在，星形胶质细胞至少部分是通过分泌称为血小板反应蛋白的蛋白质发挥作用的。事实上，在星形胶质细胞出现之前，发育中的 CNS 中的突触并没有大量形成。在没有星形胶质细胞的情况下，仅形成正常突触数量的 ~20%。

[编辑] 5.7 星形胶质细胞终足调节脑血流

Astrocytic endfeet modulate cerebral blood flow

Astrocytic endfeet (see p. 286) surround not only capillaries but also small arteries. Neuronal activity can lead to astrocytic [Ca2+]i waves—as previously described on pages 291– 292 that spread to the astrocytic endfeet, or to isolated increases in endfoot [Ca2+]i. In either case, the result is a rapid increase in blood vessel diameter and thus in local blood flow. A major mechanism of this vasodilation is the stimulation of phospholipase A2 in the astrocyte, the formation of arachidonic acid, and the liberation through cyclooxygenase 1 (see Fig. 3-11) of a potent vasodilator that acts on vascular smooth muscle. This is one mechanism of neuron-vascular coupling—a local increase in neuronal activity that leads to a local increase in blood flow. Radiologists exploit this physiological principle in a form of functional magnetic resonance imaging (fMRI) called blood oxygen level–dependent (BOLD) MRI, which uses blood flow as an index of neuronal activity.

星形胶质细胞终足（见第 286 页）不仅围绕毛细血管，还围绕小动脉。神经元活动可导致星形胶质细胞 [Ca2+]i 波——如前面第 291-292 页所述，扩散到星形胶质细胞末足，或导致末足 [Ca2+]i 的孤立增加。在任何一种情况下，结果都是血管直径迅速增加，从而增加局部血流量。这种血管舒张的一个主要机制是刺激星形胶质细胞中的磷脂酶 A2，形成花生四烯酸，以及通过环氧合酶 1（见图 3-11）释放作用于血管平滑肌的强效血管扩张剂。这是神经元-血管耦合的一种机制——神经元活动的局部增加导致血流的局部增加。放射科医生以一种称为血氧水平依赖性 （BOLD） MRI 的功能性磁共振成像 （fMRI） 形式利用这一生理原理，它使用血流作为神经元活动的指标。

Astrocytic modulation of blood flow is complex, and increases in [Ca2+]i in endfeet can sometimes lead to vasoconstriction.

星形胶质细胞对血流的调节很复杂，末端足中 [Ca2+]i 的增加有时会导致血管收缩。

[编辑] 5.8 少突胶质细胞和雪旺细胞制造并维持髓鞘

Oligodendrocytes and Schwann cells make and sustain myelin

The primary function of oligodendrocytes as well as of their PNS equivalent, the Schwann cell, is to provide and to maintain myelin sheaths on axons of the central and peripheral nervous systems, respectively. As discussed on p. 199, myelin is the insulating “electrical tape” of the nervous system (see Fig. 7-21B). Oligodendrocytes are present in all areas of the CNS, although their morphological appearance is highly variable and depends on their location within the brain. In regions of the brain that are dominated by myelinated nerve tracts, called white matter, the oligodendrocytes responsible for myelination have a distinctive appearance (Fig. 11-13A). Such an oligodendrocyte has 15 to 30 processes, each of which connects a myelin sheath to the oligodendrocyte’s cell body. Each myelin sheath, which is up to 250 μm wide, wraps many times around the long axis of one axon. The small exposed area of axon between adjacent myelin sheaths is called the node of Ranvier (see pp. 200–201). In gray matter, oligodendrocytes do not produce myelin and exist as perineuronal satellite cells.

少突胶质细胞及其 PNS 等效物雪旺细胞的主要功能是分别在中枢和周围神经系统的轴突上提供和维持髓鞘。如第 199 页所述，髓鞘是神经系统的绝缘“电胶带”（见图 7-21B）。少突胶质细胞存在于 CNS 的所有区域，尽管它们的形态外观变化很大，并且取决于它们在大脑中的位置。在大脑中以髓鞘神经束（称为白质）为主的区域，负责髓鞘形成的少突胶质细胞具有独特的外观（图 11-13A）。这种少突胶质细胞有 15 到 30 个过程，每个过程将髓鞘连接到少突胶质细胞的细胞体。每个髓鞘宽达 250 μm，围绕一个轴突的长轴缠绕多次。相邻髓鞘之间的轴突小暴露区域称为 Ranvier 节点（见第 200-201 页）。在灰质中，少突胶质细胞不产生髓鞘，以神经元周围卫星细胞的形式存在。

During the myelination process, the leading edge of one of the processes of the oligodendrocyte cytoplasm wraps around the axon many times (see Fig. 11-13A, upper axon). The cytoplasm is then squeezed out of the many cell layers surrounding the axon in a process called compaction. This process creates layer upon layer of tightly compressed membranes that is called myelin. The myelin sheaths remain continuous with the parent glial cells, which nourish them.

在髓鞘形成过程中，少突胶质细胞细胞质的一个过程的前缘多次缠绕轴突（参见图 11-13A，上轴突）。然后，细胞质在称为压缩的过程中从轴突周围的许多细胞层中挤出。这个过程会产生一层又一层的紧密压缩膜，称为髓鞘。髓鞘与母本神经胶质细胞保持连续，从而滋养它们。

In the PNS, a single Schwann cell provides a single myelin segment to a single axon of a myelinated nerve (see Fig. 11-13B). This situation stands in contrast to that in the CNS, where one oligodendrocyte myelinates many axons. The process of myelination that occurs in the PNS is analogous to that outlined for oligodendrocytes. Axons of unmyelinated nerves are also associated with Schwann cells. In this case, the axons indent the surface of the Schwann cell and are completely surrounded by Schwann cell cytoplasm (Fig. 11-14).

在 PNS 中，单个雪旺细胞为有髓神经的单个轴突提供单个髓鞘段（见图 11-13B）。这种情况与 CNS 的情况形成鲜明对比，在 CNS 中，一个少突胶质细胞髓鞘化许多轴突。PNS 中发生的髓鞘形成过程类似于少突胶质细胞概述的过程。无髓神经的轴突也与雪旺细胞有关。在这种情况下，轴突压入雪旺细胞表面，并完全被雪旺细胞细胞质包围（图 11-14）。

Myelin has a biochemical composition different from that of the oligodendrocyte or Schwann cell plasma membrane from which it arose. Although PNS myelin and CNS myelin look similar, some of the constituent proteins are different (Table 11-4). For example, proteolipid protein is the most common protein in CNS myelin (~50% of total protein) but is absent in PNS myelin. Conversely, P0 is found almost exclusively in PNS myelin.

髓鞘的生化成分不同于它产生的少突胶质细胞或雪旺细胞质膜的生化成分。尽管 PNS 髓鞘和 CNS 髓鞘看起来相似，但一些组成蛋白是不同的（表 11-4）。例如，蛋白脂蛋白是 CNS 髓鞘中最常见的蛋白质（占总蛋白的 ~50%），但在 PNS 髓鞘中不存在。相反，P0 几乎只存在于 PNS 髓鞘中。

Myelination greatly enhances conduction of the action potential down the axon because it allows the regenerative electrical event to skip from one node to the next rather than gradually spreading down the whole extent of the axon. This process is called saltatory conduction (see pp. 200–201). Besides being responsible for CNS myelin, oligodendrocytes play another key role in saltatory conduction: they induce the clustering of Na+ channels at the nodes (see Fig. 12-5C), which is essential for saltatory conduction.

髓鞘形成极大地增强了动作电位沿轴突的传导，因为它允许再生电事件从一个节点跳到另一个节点，而不是逐渐沿着轴突的整个范围扩散。这个过程称为盐传导（见第 200-201 页）。除了负责 CNS 髓鞘外，少突胶质细胞在盐性传导中还起着另一个关键作用：它们诱导 Na+ 通道在节点处聚集（见图 12-5C），这对于盐性传导至关重要。

It is well known that severed axons in the PNS can regenerate with restoration of lost function. Regrowth of these damaged axons is coordinated by the Schwann cells in the distal portion of the cut nerve. Severed axons in the CNS do not show functional regrowth, in part because of the growth-retarding nature of myelin-associated glycoproteins (see pp. 267–268).

众所周知，PNS 中被切断的轴突可以通过恢复失去的功能而再生。这些受损轴突的再生由切割神经远端的雪旺细胞协调。CNS 中切断的轴突不显示功能性再生，部分原因是髓鞘相关糖蛋白的生长延缓性质（参见第 267-268 页）。

[编辑] 5.9 少突胶质细胞参与大脑中的 pH 调节和铁代谢

Oligodendrocytes are involved in pH regulation and iron metabolism in the brain

Oligodendrocytes and myelin contain most of the enzyme carbonic anhydrase within the brain. The appearance of this enzyme during development closely parallels the maturation of these cells and the formation of myelin. Carbonic anhydrase rapidly catalyzes the reversible hydration of CO2 and may thus allow the CO2 /HCO3- buffer system to be maximally effective in dissipating pH gradients in the brain. The pH regulation in the brain is important because it influences neuronal excitability. The classic example of the brain’s sensitivity to pH is the reduced seizure threshold caused by the respiratory alkalosis secondary to hyperventilation (see p. 634).

少突胶质细胞和髓鞘含有大脑内的大部分碳酸酐酶。这种酶在发育过程中的出现与这些细胞的成熟和髓鞘的形成密切相关。碳酸酐酶可快速催化 CO2 的可逆水合，因此可能使 CO2 /HCO3- 缓冲系统在消散大脑中的 pH 梯度方面发挥最大作用。大脑中的 pH 调节很重要，因为它会影响神经元的兴奋性。大脑对 pH 值敏感的典型例子是由过度换气继发的呼吸性碱中毒引起的癫痫发作阈值降低（见第 634 页）。

Oligodendrocytes are the cells in the brain most involved with iron metabolism. They contain the iron storage protein ferritin and the iron transport protein transferrin. Iron is necessary as a cofactor for certain enzymes and may catalyze the formation of free radicals (see pp. 1238–1239) under pathological circumstances, such as disruption of blood flow to the brain.

少突胶质细胞是大脑中与铁代谢最相关的细胞。它们含有铁储存蛋白铁蛋白和铁转运蛋白转铁蛋白。铁作为某些酶的辅助因子是必需的，并且在病理情况下可能会催化自由基的形成（参见第 1238-1239 页），例如破坏流向大脑的血流。

Oligodendrocytes, like astrocytes, have a wide variety of neurotransmitter receptors. Unmyelinated axons can release glutamate when they conduct action potentials, and in principle, this glutamate could signal nearby oligodendrocytes. Ischemia readily injures oligodendrocytes, in part by releasing toxic levels of glutamate. Even white matter, therefore, can suffer excitotoxicity.

少突胶质细胞和星形胶质细胞一样，具有多种神经递质受体。无髓轴突在传导动作电位时可以释放谷氨酸，原则上，这种谷氨酸可以向附近的少突胶质细胞发出信号。缺血很容易损伤少突胶质细胞，部分原因是释放有毒水平的谷氨酸。因此，即使是白质也会遭受兴奋性毒性。

[编辑] 5.10 小胶质细胞是中枢神经系统的巨噬细胞

Microglial cells are the macrophages of the CNS

Microglial cells are of mesodermal origin and derive from cells related to the monocyte-macrophage lineage. Microglia represent ~20% of the total glial cells within the mature CNS. These cells are rapidly activated by injury to the brain, which causes them to proliferate, to change shape, and to become phagocytic (Fig. 11-15). When activated, they are capable of releasing substances that are toxic to neurons, including free radicals and nitric oxide. It is believed that microglia are involved in most brain diseases, not as initiators but as highly reactive cells that shape the brain’s response to any insult.

小胶质细胞起源于中胚层，来源于与单核细胞-巨噬细胞谱系相关的细胞。小胶质细胞占成熟 CNS 内神经胶质细胞总数的 ~20%。这些细胞因大脑损伤而迅速激活，导致它们增殖、改变形状并成为吞噬细胞（图 11-15）。当被激活时，它们能够释放对神经元有毒的物质，包括自由基和一氧化氮。据信，小胶质细胞与大多数脑部疾病有关，不是作为引发剂，而是作为高度反应性的细胞，塑造大脑对任何损伤的反应。

Microglia are also the most effective antigen-presenting cells within the brain. Activated T lymphocytes are able to breech the BBB and enter the brain. To become mediators of tissue-specific disease or to destroy an invading infectious agent, T lymphocytes must recognize specific antigenic targets. Such recognition is accomplished through the process of antigen presentation, which is a function of the microglia.

小胶质细胞也是大脑中最有效的抗原呈递细胞。活化的 T 淋巴细胞能够破坏 BBB 并进入大脑。为了成为组织特异性疾病的介质或破坏侵袭的感染因子，T 淋巴细胞必须识别特定的抗原靶标。这种识别是通过抗原呈递过程完成的，这是小胶质细胞的一个功能。

[编辑] 6 Reference

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

• Smith et al. Insights into inner ear function and disease through novel visualizatio of the ductus reuniens, a semila communication between hearing and balance mechanisms. JARO (2022)
• http://www.cochlea.eu/en/cochlea
• http://www.cochlea.eu/en/cochlea/cochlear-fluids