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.

项目总结 选择性空间注意，在最重要的空间选择和优先处理信息的能力 位置，对适应行为是必不可少的。尽管对灵长类动物的广泛研究已经确立了 前额叶皮质(特别是额叶眼野)对控制选择性视觉的必要性 注意，潜在的细胞类型和投射特定的神经回路机制仍然难以捉摸。我们最近 开发了严格的基于触摸屏的任务，用于自由行为中灵长类视觉空间的选择性注意 为了在遗传易驯化的模型和自然主义的模型中研究电路机制问题 (无拘无束的)环境。然而，研究小鼠注意的细胞类型和投射特定的电路逻辑 (使用这些任务)是一项大规模的工作，它迫切需要一个经济实惠的高吞吐量系统来 大量小鼠的并行训练。具体地说，对于广泛使用的触摸屏行为 在行为神经科学界，这样的系统既不是商业系统，也不是开源系统。 在这里，在目标1中，我们建议开发和建立一个低成本、高吞吐量、基于触摸屏的硬件 以及一次并行训练20只小鼠的复杂视觉引导行为的软件平台 (包括我们的注意力任务)。我们假设这个开源系统的成本是这个价格的十分之一，而且 占据当前商业系统1/3的空间，并提供灵活、易用的刺激软件 和实验对照。初步数据--硬件和软件原型，确立这一目标的可行性。 接下来，在目标2中，我们将使用这个高通量系统来研究在自由行为的小鼠中， 小鼠前额叶扣带回内生长抑素阳性抑制神经元 (被认为是FEF的类似物)，控制视觉空间选择性注意。我们会用细胞做到这一点- 在我们的小鼠侧翼任务中，SOM+CG中间神经元的类型特异性化学发生沉默 注意，它将注意力轨迹与行为报告轨迹分离(总共35只SOM-cre小鼠)。 我们将把行为测试与3-D头部跟踪(和眼球跟踪)结合起来。我们假设CG/SOM+ 神经元控制着整个空间的刺激竞争和目标选择，它们的破坏将损害目标 选择的准确性，而不会产生纯粹的感觉或运动缺陷。这项工作的结果将有三个 重大影响。(A)它们将为CG/SOM+中间神经元在注意控制中的功能角色提供新的线索。 (B)他们将为我们计划的R01奠定基础，旨在详细分析 扣带亚回路(使用光遗传学)和扣带神经元表示(使用内窥镜下的钙离子 成像)，用于自由行为小鼠的视觉空间选择性注意。(C)同样重要的是，高吞吐量 这里开发的触摸屏培训平台将是一个强大的开源工具，适用于更广泛的行为 神经科学界研究其他视觉引导认知功能的神经回路基础和 自由活动的小鼠也会出现认知控制、决策和成瘾等功能障碍。