Role for glia-neuron interaction in the brain ageing and longevity

保持大脑功能对个体的身心健康非常重要。大脑由两种主要类型的细胞组成：传递电信号的神经元和维持神经元健康和功能的胶质细胞。最近的发现强调了神经元和神经胶质细胞之间的相互作用对许多大脑功能（如记忆和认知）的重要性。神经胶质细胞在大脑中扮演着活跃的角色。它们可以相互交流，也可以与神经元交流。它们能够释放神经递质——一种在细胞间传递化学信号的小分子。神经胶质细胞也有这些神经递质的受体，这些神经递质是位于其膜上的特殊蛋白质。谷氨酸和腺苷-3-磷酸（ATP）是介导神经元和神经胶质细胞之间双向通讯的最重要的神经递质之一。在整个生命过程中，神经胶质细胞维持神经元的健康，并保护脑组织免受神经元过度兴奋。神经胶质功能障碍与许多脑部疾病有关，如缺血、中风、癫痫、阿尔茨海默病甚至药物滥用的影响。包括我们的初步结果在内，越来越多的证据表明，神经胶质细胞的功能及其与神经元的交流会随着年龄的增长而改变，而这些变化是老年大脑脆弱的基础。因此，神经胶质细胞之间的交流可能对大脑寿命和健康衰老至关重要。然而，星形胶质信号的年龄相关变化及其对大脑寿命的影响几乎尚未被探索。申请人领导的研究团队具有老龄动物全细胞脑电生理记录和荧光成像的经验。我们关于谷氨酸和ATP介导的神经胶质信号的年龄相关改变的数据最近发表在该领域的国际领先期刊《衰老细胞》上。我们还开发了一系列新的光遗传学和分子工具，用于研究星形胶质细胞与神经元之间的通讯。我们最近在《科学》杂志上发表的一篇论文说明了这种方法的力量，该论文展示了神经胶质细胞释放ATP在大脑呼吸控制中的另一个作用。我们希望利用这一潜力，并提出一项星形胶质细胞控制神经元和神经胶质细胞之间大脑信号传递中与年龄相关的变化的定量研究。这项研究的结果将对星形胶质细胞在脑功能和脑寿命中的作用有一个新的认识。获得的结果也将有助于进一步了解衰老的生理学，并将有助于开发神经系统疾病治疗干预的新方法和促进成功衰老的策略

Maintaining brain function is very important for mental and physical health of individuals. The brain is composed of two major types of cells: neurons which transmit electrical signals and glial cells which maintain the wellbeing and function of neurons.Recent discoveries highlighted the importance of interaction between neuronal and glial cells for many brain functions, like memory and cognition. Glial cells turned out to an active player in the brain. They can communicate with each other and neurons as well. They are capable to release neurotransmitters - small molecules transmitting chemical signals between cells. Glial cells also have receptors to these neurotransmitters - special proteins located in their membrane. One of the most important neurotransmitters that mediate bi-directional communication between neurons and glial cells are glutamate and adenosine-3-phosphate (ATP).Through the course of life, glial cells maintain the wellbeing of neurons and protect brain tissue from neuronal over-excitability. Glia malfunction is related to many brain disorders such as ischemia, stroke, epilepsy, Alzheimer's disease and even effects of drug abuse. There is growing evidence, including our preliminary results, that the function of glial cells and their communication with neurons can change with age and these changes underlie frailty of the aged brain. Thus, glia-neuron communication may be of crucial importance for brain longevity and healthy ageing. However, age-related changes in astroglial signalling and their impact on brain longevity remain almost unexplored. Research teams headed by the applicants have experience of whole-cell electrophysiological recordings and fluorescent imaging in brains of old animals. Our data on age-related alterations of glutamate- and ATP- mediated glial signalling have been recently published in the Ageing Cell - a leading international journal in the field. We have also developed a range of novel optogenetic and molecular tools for the study of astrocyte-to-neurone communication. The power of this approach is illustrated by our recent paper in Science which demonstrates another role for release of ATP from glial cells in the brain control of respiration. We wish to capitalise on this potential and propose a quantitative study of astrocytic control of age-related changes in communication between neurons and glial cells brain signaling.The outcome of this research will be a new understanding of the role of astroglial cells in brain function and brain longevity. Results obtained will also contribute to further understanding of the physiology of ageing and will help to develop novel approaches for therapeutic interventions in neurological disorders and strategies for promotion of successful ageing