CAREER: Neural circuit mechanisms of spatial target selection in the mammalian midbrain

职业：哺乳动物中脑空间目标选择的神经回路机制

• 批准号: 2047298
• 负责人: Shreesh Mysore
• 金额: $ 100万
• 依托单位: Johns Hopkins University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2047298&HistoricalAwards=false
• 关键词: CAREER; Neural; circuit; mechanisms; spatial

When faced with multiple competing stimuli in the natural world, animals display a remarkable ability to process selectively the most salient target location to guide behavior. Such stimulus selection is central to behavioral and cognitive functions such as spatial attention and decision-making, as well as their impairments in psychiatric conditions. However, how the brain achieves spatial target selection remains poorly understood. This proposal combines cutting-edge technologies and analytical methods to discover neural mechanisms underlying spatial target selection in mammals. Specifically, it focuses on the mouse midbrain and unravels the biological implementation of key aspects of ‘winner-take-all’ selection. In parallel with this research effort that links experimental neuroscience with mathematical descriptions, the educational, training and outreach goals, here, also couple neuroscience and mathematics training. This proposal supports the expansion and improvement of a recently created course for graduate students and undergraduate seniors called ‘Quantitative Methods for Brain Sciences’, trains high school students to perform ‘physical’ simulations of our neural circuit models in robot vehicles, engages in STEM outreach with local elementary schools, and creates an annual ‘Neurons in robots’ showcase for the public. In sum, the proposed efforts will advance understanding of how the brain implements selection in its neural hardware, and create a foundation for addressing the dysfunction of stimulus selection found in psychiatric disorders. Additionally, deconstruction of the biological implementation of the winner-take-all operation will inform the design of efficient artificial intelligence systems for target selection in cluttered environments (during navigation, scene analysis, etc.). The proposed research employs a combination of electrophysiological, optogenetic, and calcium imaging methods in mice to dissect the mechanistic logic of spatial target selection. The research hypotheses tested here are motivated by insights from recent work in barn owls. Specifically, they focus on the evolutionarily conserved midbrain sensorimotor hub, the superior colliculus (SC), and a group of satellite inhibitory neurons, called the periparabigeminal lateral tegmental nucleus (pLTN). Aim 1 will investigate the neural correlates of spatial target selection in the intermediate and deep layers of SC (SCid) using electrophysiology. The hypothesis is that SCid signals the most salient stimulus categorically (i.e., in a winner-take-all manner). Aim 2 uses optogenetic manipulations to investigate inhibitory mechanisms underlying this SCid selection signal. The hypothesis is that a donut-like pattern of inhibition from pLTN controls spatial target selection in SC. Aim 3 uses endoscopic calcium imaging to investigate the mechanisms that allow selection in SCid to operate at all pairs of stimulus locations. The hypothesis is that a combinatorial inhibitory strategy enacted by sparse pLTN neurons that tile space in an unusual manner achieves such selection. Uncovering neural mechanisms of spatial target selection in mice will not only address long-standing open questions pertinent to spatial attention, decision-making, and perceptual categorization, but also illuminate whether neural circuit principles underlying selection may be conserved across vertebrate species.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

当面对自然界中多种相互竞争的刺激时，动物表现出一种非凡的能力，能够选择性地处理最突出的目标位置来指导行为。这种刺激选择是行为和认知功能的核心，如空间注意力和决策，以及它们在精神状况下的损害。然而，大脑如何实现空间目标选择仍然知之甚少。这一建议结合了尖端技术和分析方法，以发现哺乳动物空间目标选择的神经机制。具体地说，它聚焦于小鼠的中脑，并揭示了“赢家通吃”选择的关键方面的生物学实现。在这项将实验神经科学与数学描述联系起来的研究工作的同时，教育、培训和推广目标也将神经科学和数学培训结合在一起。这项提议支持扩展和改进最近为研究生和本科生开设的一门名为《脑科学的量化方法》的课程，培训高中生在机器人车辆中对我们的神经电路模型进行‘物理’模拟，与当地小学开展STEM外联活动，并为公众创建一年一度的‘机器人中的神经元’展示。总而言之，拟议的努力将促进对大脑如何在其神经硬件中执行选择的理解，并为解决精神疾病中发现的刺激选择功能障碍奠定基础。此外，对赢家通吃操作的生物实现的解构将为在杂乱环境中(在导航、场景分析等期间)选择目标的高效人工智能系统的设计提供信息。这项拟议的研究结合了电生理学、光遗传学和钙成像方法，在小鼠身上剖析了空间目标选择的机制逻辑。这里测试的研究假设是受到最近对谷仓猫头鹰的研究的启发。具体地说，它们集中在进化上保守的中脑感觉运动中枢、上丘(SC)和一组卫星抑制神经元，称为延髓旁外侧被盖核(PLTN)。目的1用电生理学的方法研究SC(SCID)中层和深层空间靶点选择的神经关联。假设是，SCID明确地发出最显著的刺激信号(即，以赢家通吃的方式)。目的2利用光遗传操作来研究这种SCID选择信号的抑制机制。假设来自pLTN的甜甜圈状抑制模式控制着SC中的空间目标选择。AIM 3使用内窥镜钙成像来研究允许选择SCID在所有刺激位置进行操作的机制。假设是由稀疏的pLTN神经元以一种不寻常的方式瓦解空间的组合抑制策略实现了这种选择。揭示小鼠空间目标选择的神经机制不仅将解决与空间注意、决策和知觉分类相关的长期悬而未决的问题，还将阐明潜在选择的神经回路原理是否可以在脊椎动物物种中保留。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。