CAREER: A cortex-basal forebrain loop enabling task-specific cognitive behavior

认知灵活性，即做出不同决定以满足环境不断变化的需求的能力，对人类和其他动物的生存至关重要。为了支持这一关键能力，大脑需要根据当前的行为背景重组其活动模式，但我们仍然对这种功能重组是如何完成的知之甚少。这个项目将通过询问多个小鼠大脑区域如何协同行动来支持任务切换来研究这个基本问题，任务切换是一种常见的灵活认知行为。除了更好地了解基本的大脑机制外，这项研究还可以为未来旨在治疗认知不灵活的工作提供信息。认知不灵活在自闭症、精神分裂症和痴呆症等大脑疾病中很普遍。该项目还将产生其他更广泛的社会影响。首先，它将为神经科学的本科生和研究生教育提供大量机会。其次，它将包括与学校教师和儿童进行接触，以提高人们对过度任务切换的危害的认识。随着智能手机等普及的数字技术的出现，过度任务切换的危害大大增加，尤其影响了学龄儿童的学习。这项提议的中心目标是对比大脑如何根据任务重组其活动模式的两个相互竞争的模型：在大脑皮层内模型中，任务特定的活动完全在大脑皮层内产生。在外部输入模型中，需要皮质外输入来主动重组皮质活动，从而实现新的认知计算。根据初步研究，假设前额叶皮质、胆碱能基底前脑和皮质其他部分之间的环路是一个关键的多区域环路，能够根据认知需求产生与外部输入模式兼容的皮质范围的活动模式。该项目将使用小鼠作为模型生物，因为它们将足够复杂的认知行为和实验工具的可用性独特地结合在一起。它将利用一种新的行为范式，让头部固定的老鼠在虚拟现实中做出导航决定，在行为会话中，它们会在简单和复杂的任务之间切换数十次。这一范例将与尖端的遗传和光学工具相结合，以细胞类型和投影专一性记录和干扰假想电路回路的不同节点。此外，统计和机械建模将被用来将神经活动模式与任务特定的行为联系起来，并从这个特定的电路中提取可概括的计算原理。因此，该项目将汇集行为、计算和电路解剖技术的最新发展，以获得对任务切换的机械性洞察，任务切换是灵活认知行为的典范形式。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。

Cognitive flexibility, or the ability to make different decisions to meet ever-changing demands from the environment, is essential for the survival of humans and other animals. To support this key ability, the brain needs to reorganize its activity patterns depending on the current behavioral context, but we still understand little about how this functional reorganization is accomplished. This project will investigate this fundamental question by asking how multiple mouse brain regions act in concert to support task switching, a common type of flexible cognitive behavior. Beyond leading to better understanding of basic brain mechanisms, this research could inform future work that aims to treat cognitive inflexibility, which is pervasive in brain disorders like autism, schizophrenia, and dementia. The project will also have other broader societal impacts. First, it will provide numerous opportunities for undergraduate and graduate education in neuroscience. Second, it will include outreach to schoolteachers and children to raise awareness about the detriments of excessive task switching, which has vastly increased with pervasive digital technologies like smartphones and particularly affects learning in school-aged children. The central goal of this proposal is to contrast two competing models of how the brain reorganizes its activity patterns task dependently: in the intracortical model, task-specific activity is fully generated within the cerebral cortex. In the external input model, extra-cortical input is required to actively reorganize cortical activity, enabling new cognitive computations. Based on preliminary studies, the hypothesis is that a loop between the prefrontal cortex, the cholinergic basal forebrain and the rest of the cortex is a key multi-region circuit that enables the generation of cortex-wide activity patterns depending on cognitive demands, compatible with the external input model. The project will use mice as the model organism due to their unique combination of sufficiently complex cognitive behavior and availability of experimental tools. It will leverage a new behavioral paradigm for head-fixed mice making navigational decisions in virtual reality, in which they switch between a simple and a complex task dozens of times within a behavioral session. This paradigm will be combined with cutting-edge genetic and optical tools to record and perturb different nodes of the hypothesized circuit loop, with cell-type and projection specificity. Further, statistical and mechanistic modeling will be employed to link neural activity patterns to task-specific behavior and extract generalizable computational principles from this specific circuit. Thus, this project will bring together recent developments in behavioral, computational, and circuit-dissection technologies to gain mechanistic insight into task switching, a canonical form of flexible cognitive behavior.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.