Circuit Mechanisms Underlying Persistent Activity in a Neural Integrator

神经积分器持续活动背后的电路机制

• 批准号: 10704527
• 负责人: Emre R Aksay
• 金额: $ 69.9万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704527
• 关键词: 3-Dimensional; Address; Anatomy; Behavior; Biological; Biological Models; Brain region; Calcium; Cells; Conceptions; Couples; Coupling; Data; Decision Making; Dependence; Disease; Disparate; Exhibits; Experimental Designs; Eye; Eye Movements; Foundations; Functional Imaging; Future; Genotype; Heterogeneity; Image; Individual; Location; Maps; Mathematics; Measurement; Memory; Modeling; Neurons; Pattern; Physiological; Play; Population; Positioning Attribute; Preparation; Property; Recurrence; Resolution; Role; Short-Term Memory; Signal Transduction; Specificity; Speed; Stimulus; Synapses; System; Testing; Theoretical Studies; Theoretical model; Three-Dimensional Imaging; Time; Transgenic Organisms; Vision; Visual; Visual impairment; Work; Zebrafish; behavior change; cell type; experimental study; eye velocity; flexibility; gaze; imaging study; in silico; insight; motor control; network models; neural; neural patterning; oculomotor; optical imaging; optogenetics; postsynaptic; predictive modeling; reconstruction; response; simulation; theories; treatment strategy; two-photon

Abstract Short-term memory function is commonly supported through persistent activity, the sustained response of populations of neurons following the offset of a memorized stimulus. This form of activity underlies diverse tasks including navigation, motor control, and decision-making. Classic mechanistic theories have idealized such activity through models that assume strongly homogeneous populations of neurons that encode only a single variable and generate perfectly stable patterns of activity. This contrasts with recent work showing that neurons in real biological memory networks exhibit multiplexed encoding of multiple stimulus attributes, temporally varying responses across the population, and context dependence. Here we address the circuit mechanisms and role of this diversity in function through a combined experimental-theoretical approach. Experiments are conducted in a short-term memory circuit of the larval zebrafish gaze control system that contributes to stable vision by precisely maintaining the eyes on a visual target. Taking advantage of the quantitative precision and experimental tractability of this system, we combine whole-circuit, synapse-resolution anatomy with circuit-wide recordings and perturbations of activity at cellular resolution. In Aim 1, we combine these data into a model of the system in which neurons map in a one-to-one manner with experimentally recorded neurons. This enables us to infer the interactions within and between neurons of different anatomical, genotypic, and functional cell classes and form predictions for how these interactions govern circuit function. In Aim 2, we use 3D cellular resolution optical imaging and stimulating perturbations of neuronal activity to refine our model and test model predictions. In Aim 3, we expand our capacity to form precise characterizations of within and between cell-class interactions by developing and applying 3D suppression of neurons across the memory circuit. Altogether, this work promises to greatly expand our understanding of the circuit mechanisms and role of cell type diversity in persistent firing, short-term memory, and motor control.

抽象的 短期记忆功能通常通过持续的活动来支持，即持续的活动 记忆刺激抵消后神经元群体的反应。这种形式的 活动是各种任务的基础，包括导航、运动控制和决策。经典的 机械理论通过强烈假设的模型将这种活动理想化 只编码单个变量并完美生成的同质神经元群体 稳定的活动模式。这与最近的研究形成鲜明对比，该研究表明真实生物中的神经元 记忆网络表现出多种刺激属性的多路编码，随时间变化 整个人群的反应以及环境依赖性。这里我们解决电路 通过实验与理论相结合，研究这种功能多样性的机制和作用 方法。在斑马鱼幼虫凝视的短期记忆回路中进行实验 通过精确地将眼睛保持在视觉上来有助于稳定视力的控制系统 目标。利用该系统的定量精度和实验易处理性， 我们将全电路、突触分辨率解剖学与全电路记录相结合 细胞分辨率下的活动扰动。在目标 1 中，我们将这些数据组合成一个模型 系统中，神经元与实验记录的神经元以一对一的方式映射。这 使我们能够推断不同解剖学、基因型、 和功能细胞类别，并形成对这些相互作用如何控制电路功能的预测。 在目标 2 中，我们使用 3D 细胞分辨率光学成像并刺激神经元扰动 完善我们的模型并测试模型预测的活动。在目标 3 中，我们扩大了形成能力 通过开发和应用，精确表征细胞类内部和细胞类之间的相互作用 对记忆回路中神经元的 3D 抑制。总而言之，这项工作有望极大地 扩大我们对循环机制和细胞类型多样性在持久性中的作用的理解 放电、短期记忆和运动控制。