2024年12月6日 (五) 17:57的版本

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

1 概述

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。

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。

2 脑脊液 (Cerebrospinal Fluid, CSF)

CEREBROSPINAL FLUID

2.1 脑脊液充满脑室和蛛网膜下腔

CSF fills the ventricles and subarachnoid space

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

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

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

3 大脑细胞外间隙

BRAIN EXTRACELLULAR SPACE

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

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

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

4 血脑屏障 (BBB)

THE BLOOD-BRAIN BARRIER

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

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

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

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

5 胶质细胞 (Glial Cells)

GLIAL CELLS

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

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

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

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

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

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%。

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。

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

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。

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。

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