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

在自然界中，当面对多种相互竞争的刺激时，动物表现出一种非凡的能力，即有选择地处理最显著的目标位置，以指导行为。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，以及它们在精神疾病中的损害。然而，大脑如何实现空间目标选择仍然知之甚少。本研究将前沿技术与分析方法相结合，探索哺乳动物空间靶点选择的神经机制。具体来说，它关注的是老鼠的中脑，并揭示了“赢家通吃”选择的关键方面的生物学实现。与此同时，这项研究将实验神经科学与数学描述联系起来，教育、培训和推广目标，也将神经科学和数学培训结合起来。该提案支持扩展和改进最近为研究生和本科生开设的名为“脑科学定量方法”的课程，培训高中生在机器人车辆中对我们的神经回路模型进行“物理”模拟，与当地小学开展STEM推广活动，并为公众创建年度“机器人神经元”展示。总之，所提出的努力将促进对大脑如何在其神经硬件中实现选择的理解，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“赢者通吃”操作的生物实现的解构将为在混乱环境中（在导航、场景分析等过程中）进行目标选择的高效人工智能系统的设计提供信息。本研究采用电生理、光遗传学、钙成像等方法对小鼠空间靶点选择的机制逻辑进行剖析。这里测试的研究假设是受到最近对仓鸮研究的启发。具体来说，他们关注的是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，称为旁双侧外侧被盖核（pLTN）。目的1将利用电生理学研究SC （SCid）中间层和深层空间目标选择的神经相关性。假设是，SCid明确地发出了最显著的刺激信号（即，以赢家通吃的方式）。目的2使用光遗传学操作来研究这种SCid选择信号的抑制机制。假设是来自pLTN的甜甜圈样抑制模式控制了SC的空间靶标选择。目的3使用内窥镜钙成像来研究允许SCid在所有对刺激位置进行选择的机制。假设是由稀疏的pLTN神经元以一种不寻常的方式排列空间而制定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、决策和感知分类相关的长期悬而未决的问题，而且还将阐明选择的神经回路原理是否可能在脊椎动物物种中保守。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

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.