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

维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神经胶质细胞。最近的发现突显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的重要性，如记忆和认知。结果表明，神经胶质细胞是大脑中活跃的参与者。它们可以相互通信，也可以与神经元通信。它们能够释放神经递质--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--位于细胞膜上的特殊蛋白质。谷氨酸和三磷酸腺苷(ATP)是调节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，在生命过程中，神经胶质细胞维持神经元的健康，保护脑组织免受神经元过度兴奋的影响。胶质细胞功能障碍与许多大脑疾病有关，如缺血、中风、癫痫、阿尔茨海默病，甚至药物滥用的影响。越来越多的证据，包括我们的初步结果，表明胶质细胞的功能及其与神经元的沟通可以随着年龄的增长而改变，这些变化是衰老大脑脆弱的基础。因此，神经胶质细胞与神经元之间的交流对于大脑的长寿和健康衰老可能至关重要。然而，星形胶质信号与年龄相关的变化及其对大脑寿命的影响仍然几乎没有被研究过。申请者领导的研究团队拥有在老年动物大脑中进行全细胞电生理记录和荧光成像的经验。我们关于谷氨酸和三磷酸腺苷介导的神经胶质信号与年龄相关的变化的数据最近发表在该领域的领先国际期刊《老化细胞》上。我们还开发了一系列新的光遗传学和分子工具来研究星形胶质细胞到神经元的通讯。我们最近在《科学》杂志上的一篇论文证明了这种方法的力量，这篇论文证明了神经胶质细胞释放ATP在大脑控制呼吸中的另一个作用。我们希望利用这一潜力，并建议对星形胶质细胞控制与年龄相关的神经元和神经胶质细胞之间的通讯变化脑信号进行定量研究。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理解。所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疾病治疗干预的新方法和促进成功老龄化的战略

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