Trillions of synapses connect the brain’s billions of neurons, but scientists still cannot define what makes a single synapse strong or weak—a concept called synaptic weight that is central to how we learn and remember. This international network of experts aims to finally pin down what synaptic weight actually is, from the molecules inside a single synapse to the behaviour of an entire animal. For over a century, researchers have lacked a clear definition, making it impossible to fully understand how neural circuits form, change, and drive actions. The team will combine advanced imaging techniques—including a new method called tomoSEM that captures synapse structure at nanoscale resolution across large tissue volumes—with optogenetics and computational tools to watch synapses change in real time. This is fundamental science with no immediate practical application. But a precise understanding of synaptic weight could eventually reshape how we approach brain disorders where synaptic function goes awry, such as Alzheimer’s disease, autism, or schizophrenia. Past discoveries about synaptic plasticity have already underpinned treatments for depression and chronic pain; a clearer definition of synaptic weight may unlock further breakthroughs in repairing or modulating neural circuits.
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Synapses form trillions of connections between billions of neurons in the brain to establish neural circuits that allow us to sense, think, act, learn, and remember. Synaptic weight is a crucial concept to understand the nervous system, yet its clear definition remains elusive, despite more than a century of searching. This NeuroNex Network assembles world experts to study synapses from molecules to behavior, in order to answer this fundamental and ambitious question: What constitutes synaptic weight and what role does it play in shaping neural circuits? How neuronal synapses control behaviour is a critical question in neuroscience. Behaviour is often a response to memories from prior experience. During learning, pre- and postsynaptic mechanisms of plasticity cooperate to elicit long-term changes in synaptic weight - broadly defined as the strength and influence of individual synapses or groups of synapses acting together to achieve a response. Revealing synaptic weight through a multi-modal analysis of synaptic molecules, subcellular composition, and morphology in the context of neural circuits is crucial to understand complex circuit function underlying behaviour. We need to study the diversity of synapses in different brain areas, across species, and in different functional states. For example, synaptic strength and other computational properties are affected by short-term or long-term changes in the probability of presynaptic transmitter release. Upon activation, presynaptic sites undergo dramatic changes as vesicles and other organelles appear, change morphology, relocate, and disappear on multiple time scales. The corresponding structural dynamics can now be captured with millisecond precision using a combination of optogenetics and electron microscopy. This exquisite timing allows characterization, at the spatial nanoscale, of dynamics of synapses undergoing plasticity, growth, or elimination in response to natural and experimental stimuli. The ideal goal of determining the structure, composition, and circuitry of virtually every synapse in the brain has driven new imaging and cell biology techniques. Our proposed international NeuroNex Network will build upon existing investments in methodology and technology, including the enhanced resolution for 3DEM analysis of synapses based on tomoSEM, a new method with great promise for wide field and high-throughput studies and with sufficient resolution to assess ultrastructural features of synapses throughout tissue volumes great enough to contain local circuits. Advanced labelling and tissue fixation provide new understanding about the ultrastructural features that reflect synaptic states established by molecular and physiological criteria. Our international NeuroNex Network brings expertise i) to integrate this transformative technology into the respective brain studies, ii) to combine and compare it with additional advanced methods, and to develop a more comprehensive, multi-scale understanding of the synapse across diverse brain circuits and species, and iii) to develop and combine computational tools to collect, analyze, and interpret the wealth of data. The complementary expertise covered by this international NeuroNex Network will generate unprecedented knowledge on the molecular and cellular mechanisms that establish synaptic weight and plasticity in individual synapses and how they translate to understanding synapses in circuits and behaviour.
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