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，以建立神经回路，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，尽管经过了世纪的探索，它的明确定义仍然难以捉摸。这个NeuroNex网络聚集了世界各地的专家来研究从分子到行为的突触，以回答这个基本而雄心勃勃的问题：什么构成了突触重量，它在塑造神经回路中扮演着什么角色？神经元突触如何控制行为是神经科学中的一个关键问题。行为往往是对先前经历的记忆的反应。在学习过程中，突触前和突触后的可塑性机制共同作用，引起突触重量的长期变化-广义上定义为单个突触或突触组共同作用以实现反应的强度和影响。揭示突触重量通过突触分子，亚细胞组成的多模态分析，并在神经回路的背景下的形态是至关重要的理解复杂的电路功能的行为。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性质受到突触前递质释放概率的短期或长期变化的影响。在激活时，突触前位点经历了巨大的变化，囊泡和其他细胞器出现，改变形态，重新定位，并在多个时间尺度上消失。相应的结构动力学现在可以使用光遗传学和电子显微镜的组合以毫秒级的精度捕获。这种精确的计时技术可以在空间纳米尺度上表征突触的动态特性，这些突触在自然和实验刺激下经历可塑性、生长或消除。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的基础上，包括基于tomoSEM的突触3DEM分析的增强分辨率，这是一种新方法，具有广阔的领域和高通量研究的巨大前景，并具有足够的分辨率来评估整个组织体积的突触超微结构特征，足以包含局部电路。先进的标记和组织固定提供了对反映分子和生理标准建立的突触状态的超微结构特征的新理解。我们的国际NeuroNex网络带来了专业知识i）将这种变革性技术整合到相应的大脑研究中，ii）将其与其他先进方法联合收割机结合并进行比较，并开发更全面，跨不同脑回路和物种的突触的多尺度理解，以及iii）开发和联合收割机计算工具以收集、分析和解释大量数据。这个国际NeuroNex网络所涵盖的互补专业知识将产生前所未有的分子和细胞机制知识，这些机制在单个突触中建立突触重量和可塑性，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.