NeuroNex2: Enabling Identification and Impact of Synaptic Weight in Functional Networks; NSF reference 2014862

突触在大脑中数十亿个神经元之间形成数万亿个连接，建立神经回路，使我们能够感知、思考、行动、学习和记忆。突触重量是理解神经系统的一个关键概念，尽管一个多世纪以来一直在寻找，但它的明确定义仍然难以捉摸。这个NeuroNex网络汇集了世界各地的专家，从分子到行为来研究突触，以回答这个基本而雄心勃勃的问题：突触重量是由什么组成的？它在形成神经回路中起着什么作用？神经突触如何控制行为是神经科学中的一个关键问题。行为通常是对先前经验记忆的反应。在学习过程中，突触前和突触后的可塑性机制共同引起突触权重的长期变化，突触权重被广泛定义为单个突触或突触群共同作用以实现反应的强度和影响。在神经回路的背景下，通过对突触分子、亚细胞组成和形态的多模态分析来揭示突触的重量，对于理解复杂回路功能的潜在行为至关重要。我们需要研究不同大脑区域、不同物种和不同功能状态下突触的多样性。例如，突触强度和其他计算特性受到突触前递质释放概率的短期或长期变化的影响。激活后，突触前位点会随着囊泡和其他细胞器的出现、形态改变、重新定位和消失而发生剧烈变化。利用光遗传学和电子显微镜的结合，现在可以以毫秒级的精度捕获相应的结构动力学。这种精确的时间安排可以在空间纳米尺度上表征突触在自然和实验刺激下经历可塑性、生长或消除的动态。确定大脑中几乎每个突触的结构、组成和电路的理想目标推动了新的成像和细胞生物学技术。我们提出的国际NeuroNex网络将建立在现有的方法和技术投资基础上，包括基于tomoSEM的突触3DEM分析的增强分辨率，这是一种具有广泛领域和高通量研究前景的新方法，具有足够的分辨率来评估整个组织体积中突触的超微结构特征，大到足以包含局部电路。先进的标记和组织固定为反映分子和生理标准建立的突触状态的超微结构特征提供了新的认识。我们的国际NeuroNex网络带来了专业知识，1)将这种变革性技术整合到各自的大脑研究中，2)将其与其他先进方法相结合并进行比较，并对不同脑回路和物种的突触进行更全面，多尺度的理解，3)开发和结合计算工具来收集，分析和解释丰富的数据。这个国际NeuroNex网络所涵盖的互补专业知识将在分子和细胞机制方面产生前所未有的知识，这些机制建立了单个突触的突触重量和可塑性，以及它们如何转化为理解突触的电路和行为。

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.