Uncovering cell type-specific prefrontal neural mechanisms of visuospatial selective attention in freely behaving mice using a high-throughput touchscreen-based training system

使用基于高通量触摸屏的训练系统揭示自由行为小鼠视觉空间选择性注意的细胞类型特异性前额神经机制

• 批准号: 10527748
• 负责人: Shreesh P Mysore
• 金额: $ 24.56万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10527748
• 关键词: 3-Dimensional; 3D Print; Adaptive Behaviors; Address; Animals; Area; Attention; Attention deficit hyperactivity disorder; Behavior; Behavior Control; Behavioral; Behavioral Paradigm; Cells; Communication; Communities; Complex; Computer software; Cues; Data; Decision Making; Dissection; Electronics; Elements; Environment; Eye; Feeds; Functional disorder; Future; Goals; Head; Image; Impaired cognition; Impairment; Interneurons; Intuition; Investigation; Learning; Light; Literature; Location; Logic; Modeling; Mus; Neurons; Neurosciences; Online Systems; Prefrontal Cortex; Price; Primates; Process; Protocols documentation; Psychometrics; Raspberries; Readiness; Reporting; Research; Resources; Role; Schizophrenia; Sensory; Short-Term Memory; Somatostatin; Standardization; Stimulus; System; Testing; Time; Training; Visual attention; Visualization; Visuospatial; Work; addiction; analog; attentional control; base; behavior test; cell type; cingulate cortex; cognitive control; cognitive function; cost; design; experimental study; flexibility; frontal eye fields; graphical user interface; inhibitory neuron; motor deficit; neural circuit; neuromechanism; neurotechnology; novel; open source; open source tool; optogenetics; prototype; relating to nervous system; remote monitoring; response; selective attention; software systems; sustained attention; touchscreen; visual control; visual tracking; web site

PROJECT SUMMARY Selective spatial attention, the ability to select and preferentially process information at the most important spatial location, is essential for adaptive behavior. Although extensive research in primates has established the necessity of the prefrontal cortex (and specifically, the frontal eye field, FEF) for the control of selective visual attention, the underlying cell-type and projection-specific neural circuit mechanisms remain elusive. We recently developed rigorous touchscreen-based tasks for primate-like visuospatial selective attention in freely behaving mice in order to investigate circuit mechanistic questions in a genetically tractable model and in a naturalistic (unrestrained) setting. However, investigating the cell-type and projection-specific circuit logic of attention in mice (using these tasks) is a large-scale effort that critically requires an affordable, high-throughput system for the parallelized training of large numbers of mice. Specifically, for touchscreen behaviors, which are used extensively in the behavioral neuroscience community, such a system does not exist either commercially or as open-source. Here, in Aim 1, we propose to develop and establish a low cost, high-throughput, touchscreen-based hardware and software platform for parallelized training of 20 mice at a time on complex visually guided behaviors (including our attention tasks). We hypothesize that this open-source system will cost <1/10th the price, and occupy <1/3rd the space, of current commercial systems, and offer flexible, easy-to-use software for stimulus and experimental control. Preliminary data - hardware and software prototypes, establish viability of this aim. Next, in Aim 2, we will use this high-throughput system to investigate in freely behaving mice, the causal role of somatostatin-positive (SOM+) inhibitory neurons in the cingulate subdivision (Cg) of the mouse prefrontal cortex (considered to be an analog of the FEF), in the control of visuospatial selective attention. We will do so with cell- type specific chemogenetic silencing of SOM+ Cg interneurons in mice trained on our mouse flanker task of attention, which dissociates the locus of attention from the locus of behavioral report (total of 35 SOM-cre mice). We will combine behavioral testing with 3-D head-tracking (and eye-tracking). We hypothesize that Cg/SOM+ neurons control stimulus competition and target selection across space, and that their disruption will impair target selection accuracy without producing purely sensory or motor deficits. Results from this work will have three major impacts. (a) They will shed new light on the functional role of Cg/SOM+ interneurons in attention control. (b) They will set the stage for our planned R01 aimed at detailed cell-type and projection-specific dissection of cingulate sub-circuits (using optogenetics) and cingulate neuronal representations (using endoscopic Ca++ imaging) for visuospatial selective attention in freely behaving mice. (c) Equally importantly, the high-throughput touchscreen training platform developed here will be a potent open-source tool for the broader behavioral neuroscience community investigating the neural circuit basis of other visually guided cognitive functions and dysfunctions as well, such as cognitive control, decision-making, and addiction, in freely moving mice.

项目摘要 选择性空间注意力，在最重要的空间上选择和优先处理信息的能力 位置，对于自适应行为至关重要。尽管对灵长类动物的广泛研究已经建立了 前额叶皮层的必要性（特别是额叶眼场，FEF），以控制选择性视觉 注意，潜在的细胞类型和投影特异性的神经回路机制仍然难以捉摸。我们最近 开发了基于触摸屏的严格基于灵长类动物的视觉空间选择性关注 小鼠以研究遗传障碍模型中的电路机理问题和自然主义 （不受约束的）设置。但是，研究小鼠注意的细胞类型和投影特异性电路逻辑 （使用这些任务）是一项大规模的努力，非常需要负担得起的高通量系统 并行训练大量小鼠。具体而言，对于触摸屏行为，广泛使用 在行为神经科学社区中，这种系统在商业上或开源不存在。 在AIM 1中，我们建议开发和建立低成本，高通量，基于触摸屏的硬件 和软件平台，用于一次复杂的视觉指导行为，一次对20只小鼠进行并行训练 （包括我们的注意任务）。我们假设该开源系统的价格<1/10，并且 占用当前商业系统的空间<1/3，并提供灵活的，易于使用的软件用于刺激 和实验控制。初步数据 - 硬件和软件原型，建立此目标的可行性。 接下来，在AIM 2中，我们将使用此高通量系统来调查自由行为的小鼠 小鼠前额叶皮层的扣带细分（CG）中的生长抑素阳性（SOM+）抑制性神经元 （被认为是FEF的类似物），在控制视觉空间选择性关注的过程中。我们将使用细胞 - 类型在接受我们的小鼠侧翼任务训练的小鼠中的SOM+ CG中间神经元的特定化学发生沉默 注意，这将注意力的源头与行为报告源（总计35只SOM-CRE小鼠）分离。 我们将将行为测试与3-D头部跟踪（和眼球轨道）结合起来。我们假设CG/SOM+ 神经元控制刺激竞争和跨空间的目标选择，它们的破坏会损害目标 选择准确性，而无需产生纯粹的感觉或运动缺陷。这项工作的结果将有三个 主要影响。 （a）他们将为CG/SOM+中间神经元在注意力控制中的功能作用提供新的启示。 （b）他们将为我们计划的R01奠定舞台 扣带亚电路（使用光遗传学）和扣带神经元表示（使用内镜CA ++ 成像），以自由表现小鼠的视觉空间选择性关注。 （c）同样重要的是，高通量 在这里开发的触摸屏训练平台将是一个有效的开源工具，用于更广泛的行为 神经科学界调查了其他视觉引导的认知功能的神经回路基础和 自由移动的小鼠中的认知控制，决策和成瘾等功能障碍。