What is the physiological importance of bidirectional neuron–glia dynamic signaling in the brain? The amazing architecture of the brain consists of hundreds of billions of neurons, as well as trillions of supporting cells called glia which comprise approximately half the volume of the adult mammalian brain. Glial cells, divided into oligodendrocytes, microglia, and astrocytes, are organized into distinct non-overlapping domains whose boundaries are intimately in contact with synapses and cerebrovascular pathways. Since the first systematic studies of the central nervous system, the information communication and processing roles of neurons were clearly recognized, while the electrically non-excitable glial cells were investigated for their contribution to different physiological processes, such as differentiation, proliferation, and neurotrophic support. Astrocytes are now thought to go beyond these contributions, being involved in almost all aspects of the brain function. There is growing evidence that astrocytes are able to partition the extracellular space, altering and influencing the synaptic microenvironment, as well as neurons’ growth. Astrocytes can alter the positioning and the diffusion of neuroactive substances, attracting cells able to repair neurons. Moreover, astrocytes synergistically regulate neuronal activities and blood circulation, thus influencing the neuronal metabolism. It is worth mentioning the relationship between astrocytes and several neurological disorders, i.e., epilepsy, stroke, Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. In the mid-1990s, evidence demonstrated how astrocytes show a different form of excitability, undergoing elevations in intracellular calcium concentration in response to the release of synaptic neurotransmitters rather than electrical changes in the membrane potential. Many cells employ a network of biochemical reactions for calcium signaling to carry information from the extracellular side to internal targets. But what underlying information do the glia acquire from the synapse? Democritus of Abdera would say: “we know nothing really; for truth lies at the bottom.” Thus, many efforts have been recently devoted to understanding the functional role of the calcium response in order to decipher how this complex dynamical response is regulated by the biochemical network of signal transduction pathways in the central nervous system. Several experiments indicated how calcium signals are generated in response to external stimuli encoding information via frequency, amplitude, or both modulations. Consequently, these observations were captured by several models consisting of dynamical variables and/or intracellular diffusion mechanisms exhibiting the above-mentioned modulations as well as different and more advanced encoding modes. This demonstrated how astrocytes are active participants in brain information processing and key elements in the physiology of the nervous system. Going further, some authors are fascinated by an “astrocentric hypothesis,” where astrocytes are being considered as the final stage of conscious processing. Following these observations, some of the mechanisms underlying synaptic physiology are now becoming clearer. New reports are constantly enhancing our understanding of the bidirectional signaling between neurons and glia, opening fascinating new perspectives on their role. The underlying mechanisms and the crucial modulating role of glia are becoming clearer through the study of synaptic activities. Re-examinations and refinements of existing studies on the dynamics of neuron–glia interactions are under investigation with the aim to discover self-consistent models of the neuron–glia information processes able to capture the dynamical and computational properties of the synapse. All these efforts will have an impact both in brain neurophysiology and in network and nonlinear dynamics theory, defining a new path for neuroscience. The novel concept of the “tripartite synapse,” for the astrocyte processes’ close contact with the neuronal synapse, has been introduced. Astrocytes are considered to regulate the synaptic signaling currents between neurons, modulating the amount of neurotrasmitters, including glutamate or adenosine–triphosphate, in the synaptic cleft through inter- and intracellular calcium dynamics. The tripartite synapse involves a pre-synaptic neuron releasing neurotransmitters to activate or inhibit the activity of a post-synaptic neuron, the post-synaptic neuron, and the astrocyte that protects cells by taking up glutamate to prevent overexcitation and secretes growth factors. The astrocyte provides energy via glucose and modulates receptor function by locally released neurotrasmitters. They are accurate sensors of neuronal activity and respond to the synaptic release of glutamate with oscillations in the intracellular calcium concentration. Glutamate elevations in the astrocyte domain trigger the internal release of inositol 1,4,5-trisphosphate, which stimulates intracellular calcium dynamics. The properties of intracellular calcium oscillations generated in astrocytes, including their amplitude, frequency, and propagation, are governed by the intrinsic properties of both neuronal inputs and astrocytes. Astrocytes discriminate neuronal inputs of different origins and can integrate concomitant inputs responding to calcium elevations. Calcium dynamics is controlled by the interplay of calcium-induced calcium release, a nonlinear amplification method dependent on the calcium-dependent opening of channels to calcium stores such as the endoplasmic reticulum, and the action of active transporters that enable a reverse flux. The level of inositol 1,4,5-trisphosphate is directly controlled by signals impinging on the cell from its external environment. The elevation of the intracellular calcium level in astrocytes, promoted by the extracellular glutamate, triggers the release of glutamate from the astrocyte, modulating the pre-synaptic and post-synaptic neural activities by promoting a depolarizing current in neurons. As a reflection of the growing importance of neuron–glia investigations, the focus of this Special Issue of the Journal of Biological Physics is to publish outstanding recent results, challenging mathematical efforts, biophysically consistent models and in-depth analysis, as well as new perspectives, on neuron–glia interactions, roles, and signaling. This issue contains papers discussing a part of the brain that is largely unexplored and facing controversial neurophysiological processes. I definitely hope that this special issue will benefit, encourage, and inspire researchers looking beyond neurons, opening new exciting perspectives both in biological physics and in brain neurophysiology.

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关于神经元-胶质细胞相互作用的特刊

双向神经元-胶质细胞动态信号在大脑中的生理重要性是什么？大脑的惊人结构由数千亿个神经元以及数万亿个称为神经胶质的支持细胞组成，它们约占成年哺乳动物大脑体积的一半。胶质细胞分为少突胶质细胞、小胶质细胞和星形胶质细胞，被组织成不同的非重叠域，其边界与突触和脑血管通路密切接触。自从对中枢神经系统进行第一次系统研究以来，神经元的信息交流和处理作用得到了明确的认识，同时研究了电非兴奋性神经胶质细胞对不同生理过程的贡献，如分化、增殖、和神经营养支持。现在，星形胶质细胞被认为超越了这些贡献，几乎参与了大脑功能的所有方面。越来越多的证据表明，星形胶质细胞能够划分细胞外空间，改变和影响突触微环境以及神经元的生长。星形胶质细胞可以改变神经活性物质的定位和扩散，吸引能够修复神经元的细胞。此外，星形胶质细胞协同调节神经元活动和血液循环，从而影响神经元代谢。值得一提的是星形胶质细胞与几种神经系统疾病之间的关系，即癫痫、中风、阿尔茨海默病、帕金森病和肌萎缩侧索硬化症。在 1990 年代中期，证据表明星形胶质细胞如何表现出不同形式的兴奋性，细胞内钙浓度升高以响应突触神经递质的释放而不是膜电位的电变化。许多细胞利用钙信号的生化反应网络将信息从细胞外传递到内部目标。但是神经胶质从突触中获取了哪些潜在信息？Abdera 的德谟克利特会说：“我们真的什么都不知道；因为真相在底部。” 因此，最近许多努力致力于理解钙反应的功能作用，以破译这种复杂的动态反应是如何受中枢神经系统中信号转导通路的生化网络调节的。几个实验表明钙信号是如何通过频率、幅度或两者调制响应外部刺激而产生的。因此，这些观察结果被几个模型捕获，这些模型由表现出上述调制以及不同和更高级编码模式的动态变量和/或细胞内扩散机制组成。这证明了星形胶质细胞如何积极参与大脑信息处理和神经系统生理学的关键要素。更进一步，一些作者着迷于“以星为中心的假设”，其中星形胶质细胞被认为是意识处理的最后阶段。根据这些观察，突触生理学的一些机制现在变得更加清晰。新报告不断增强我们对神经元和神经胶质之间双向信号传导的理解，为它们的作用开辟了引人入胜的新视角。通过对突触活动的研究，神经胶质的潜在机制和关键调节作用变得更加清晰。正在研究对神经元-胶质细胞相互作用动力学的现有研究的重新检查和改进，目的是发现神经元-胶质细胞信息过程的自洽模型，能够捕捉突触的动力学和计算特性。所有这些努力都将对脑神经生理学以及网络和非线性动力学理论产生影响，为神经科学定义一条新途径。“三方突触”的新概念，用于星形胶质细胞过程与神经元突触的密切接触，已经介绍。星形胶质细胞被认为调节神经元之间的突触信号电流，通过细胞间和细胞内钙动力学调节突触间隙中神经递质的数量，包括谷氨酸或三磷酸腺苷。三联突触涉及突触前神经元释放神经递质以激活或抑制突触后神经元、突触后神经元和星形胶质细胞的活动，星形胶质细胞通过摄取谷氨酸以防止过度兴奋并分泌生长因子来保护细胞。星形胶质细胞通过葡萄糖提供能量并通过局部释放的神经递质调节受体功能。它们是神经元活动的准确传感器，并通过细胞内钙浓度的振荡响应谷氨酸的突触释放。星形胶质细胞域中谷氨酸的升高会触发 1,4,5-三磷酸肌醇的内部释放，从而刺激细胞内钙动力学。星形胶质细胞中产生的细胞内钙振荡的特性，包括它们的振幅、频率和传播，受神经元输入和星形胶质细胞的内在特性控制。星形胶质细胞区分不同来源的神经元输入，并且可以整合响应钙升高的伴随输入。钙动力学受钙诱导的钙释放的相互作用控制，这是一种非线性放大方法，依赖于钙依赖性通道向内质网等钙储存的开放，以及能够实现反向通量的主动转运蛋白的作用。肌醇 1,4 的水平，5-三磷酸受外部环境影响细胞的信号直接控制。细胞外谷氨酸促进星形胶质细胞细胞内钙水平的升高，触发星形胶质细胞释放谷氨酸，通过促进神经元中的去极化电流调节突触前和突触后神经活动。作为神经元-胶质细胞研究日益重要的反映，本期《生物物理学杂志》特刊的重点是发表杰出的近期成果、具有挑战性的数学研究、生物物理一致模型和深入分析，以及新观点，关于神经元-胶质细胞的相互作用、作用和信号。本期包含的论文讨论了大脑的一部分，该部分在很大程度上未被探索并面临着有争议的神经生理过程。我绝对希望这个特刊将有益于、鼓励和激励研究人员超越神经元，在生物物理学和脑神经生理学方面开辟新的令人兴奋的视角。