Mechanisms of persistent neural activity

持续神经活动的机制

• 批准号: 10652453
• 负责人: Alexander C Huk
• 金额: $ 52.95万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10652453
• 关键词: Algorithms; Alzheimer' s Disease; Animals; Architecture; Area; Behavior; Behavioral Paradigm; Biological; Biological Models; Brain; Brain Diseases; Brain region; Calcium; Callithrix; Chronic; Code; Cognition; Complex; Computer Models; Data; Data Set; Development; Disease; Electrodes; Electrophysiology (science); Exhibits; FarGo; Genetic; Health; Human; Image; Individual; Intelligence; Knowledge; Link; Macaca; Maintenance; Maps; Measurement; Measures; Memory; Modeling; Modernization; Motor; Motor Activity; Neurons; Neurophysiology - biologic function; Output; Parietal; Parietal Lobe; Parkinson Disease; Performance; Primates; Recurrence; Resolution; Rodent; Role; Saccades; Schizophrenia; Sensory; Short-Term Memory; Signal Transduction; Specificity; Statistical Data Interpretation; Statistical Models; Techniques; Testing; Thalamic structure; Time; Training; Visual; Work; cell type; clinically relevant; cognitive neuroscience; data-driven model; density; experimental study; extracellular; flexibility; foot; insight; large scale data; motor behavior; network models; neural; neural circuit; neuronal circuitry; neurophysiology; nonhuman primate; novel; oculomotor; repaired; response; sensory input; theories; tool; two-photon

PROJECT SUMMARY / ABSTRACT Although many well-studied aspects of neural function involve activity driven by sensory inputs or occurring at the time of motor actions, the brain often links such fleeting sensory and motor signals with persistent activity. Somehow, neural circuits and individual neurons are capable of maintaining activity without additional input. This is a fundamental aspect of neural function and a critical building block of cognition. The mechanisms underlying persistent neural activity have long been considered in both experiment and theory, but there is little definitive mechanistic understanding of the circuit and cellular contributions to persistent activity. Indeed, theories of persistent activity are far more biologically nuanced than current empirical knowledge— especially in the nonhuman primate, from which our understanding should have greatest clinical relevance given the number of disorders that involve persistent activity. Here, we propose work that leverages advanced techniques for multiple scales (and specificities) of neural recordings with corresponding analyses of large- scale datasets to test detailed theories of how the brain generates and maintains persistent activity. Specific Aim 1. Establish the marmoset as a powerful complementary model system for dissecting persistent activity mechanisms in primate brains. We will demonstrate the viability of studying memory-guided saccades and persistent activity in the marmoset, using successful training approaches, electrophysiology, and calcium imaging to elicit the key behavior and to characterize the important brain areas in this exciting primate model system. Specific Aim 2. Characterize the large-scale circuitry underlying oculomotor persistent activity. Using large scale recordings of extracellular activity across multiple brain regions collecting during performance of a memory-guided saccade task, we will acquire a dataset of unprecedented scale to assess the large-scale circuitry underlying persistent activity. We will adapt, develop, and deploy advanced statistical models to capture the functional interactions between neurons and brain areas. Specific Aim 3. Test and refine theories of persistent activity with novel measurements at fine spatial and genetic resolution. We will perform both 2-photon imaging and high density electrophysiological measures of neural activity. The imaging will allow us to test the local circuit components of the theory, as well as to assess cell-type-specific contributions to persistent activity. High density electrophysiology will reveal the local circuit architecture and signal flow that are not accessible with coarser techniques. Integrated within our analysis framework, the resultant model of persistent activity will be supported and refined by multiple scales and forms of empirical evidence, all collected in the primate brain.

项目概要/摘要 尽管神经功能的许多经过充分研究的方面都涉及由感觉输入驱动的活动或发生在 在运动动作时，大脑经常将这种飞快的感觉和运动信号与持续的活动联系起来。 不知何故，神经回路和单个神经元能够在没有额外输入的情况下维持活动。 这是神经功能的一个基本方面，也是认知的关键组成部分。 长期以来，实验和理论都考虑了潜在的持续性神经活动，但很少有研究 事实上，对电路和细胞对持续活动的贡献有明确的机制理解。 持续活动的理论在生物学上比当前的经验知识更加微妙——尤其是 在非人类灵长类动物中，考虑到我们的理解应该具有最大的临床相关性 在此，我们提出了利用先进技术的工作。 用于神经记录的多尺度（和特异性）的技术以及对大尺度的相应分析 扩展数据集来测试大脑如何产生和维持持续活动的详细理论。 具体目标 1. 建立狨猴作为解剖的强大补充模型系统 灵长类动物大脑的持续活动机制。 我们将展示研究狨猴记忆引导的眼跳和持续活动的可行性， 使用成功的训练方法、电生理学和钙成像来引发关键行为并 描述这个令人兴奋的灵长类动物模型系统中重要大脑区域的特征。 具体目标 2. 描述动眼持续活动背后的大规模电路。 在收集过程中使用跨多个大脑区域的细胞外活动的大规模记录 为了评估记忆引导扫视任务的性能，我们将获取一个规模空前的数据集来评估 我们将适应、开发和部署先进的统计数据。 模型来捕捉神经元和大脑区域之间的功能相互作用。 具体目标 3. 通过精细空间的新颖测量来测试和完善持续活动理论 和遗传分辨率。 我们将对神经活动进行 2 光子成像和高密度电生理测量。 成像将使我们能够测试该理论的局部电路组件，以及评估细胞类型特异性 高密度电生理学的贡献将揭示局部电路结构和 无法使用更粗糙的技术访问的信号流集成在我们的分析框架中。 持续活动的最终模型将得到多种尺度和形式的实证支持和完善 证据全部收集在灵长类动物的大脑中。