Principles of synapse-astrocyte networking in the brain (360G-Wellcome-212251_Z_18_Z)

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.