Astrocytes — star-shaped brain cells long dismissed as passive support cells — actively talk to neurons, but no one knows the rules of that conversation. This project tackles a fundamental gap in neuroscience. For decades, researchers assumed that only neurons handled information in the brain. Astrocytes were seen as glue or janitors. Recent evidence shows they respond to neuronal activity and release signals of their own, but how this two-way communication works, and whether it changes during learning, remains unknown. Without understanding these rules, models of brain function — and dysfunction — are incomplete. This is fundamental science. It will not produce a drug or a device. But it could rewrite the textbook on how brain circuits operate. By mapping the principles of astrocyte-neuron signalling, the work may eventually explain why certain brain disorders — epilepsy, Alzheimer’s, stroke — involve astrocyte dysfunction. Past fundamental discoveries about glial cells have already shifted understanding of brain energy use and waste clearance. Deeper knowledge of astrocyte signalling could, over time, open routes to therapies that target not just neurons but the cells that support them.
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Astrocytes are emerging as active contributors to the operation of synaptic circuits, in health and disease. Whilst important aspects of synapse-astroglia signalling are being revealed at a pace, the underlying principles are poorly understood. Whether this signal exchange system adapts to the changes associated with learning and memory remains an enigma. Building upon our recent findings and several methodological breakthroughs, the overall aim here is to establish the causality of cellular mechanisms engaging astroglia in brain circuit operation. We will focus on cortical circuitry, combining single-cell electrophysiology, two-photon excitation imaging and uncaging, time-resolved and super-resolution fluorescence microscopy, cell-targeted genetic optical sensors, in situ and in vivo, with high-end cell and network modelling. Firstly, we will establish rules that shape functional identities and co-operation among presynaptic sites carried by individual axonal circuits. Secondly, we will determine how these presynaptic identities are influenced by the astrocytes they trespass. Thirdly, we will find out how astroglial microenvironment contributes to use-dependent local circuit remodelling. Fourthly, we will unravel basic principles of functional micro-compartmentalisation and signal integration in astrocytes. Finally, we will explore models of astrocytes and neuron-astroglia networks, to reveal theoretical principles upon which astroglia can influence information handling by brain circuits.
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