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

职业：皮层基底前脑环路实现特定任务的认知行为

• 批准号: 2337351
• 负责人: Lucas Pinto
• 金额: $ 125万
• 依托单位: Northwestern University at Chicago
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-03-01 至 2029-02-28
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2337351&HistoricalAwards=false
• 关键词: CAREER; cortex; basal; forebrain; loop

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.

认知灵活性或做出不同决策以满足环境不断变化的需求的能力对于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环境重新组织其活动模式，但我们仍然对如何完成这种功能重组的理解几乎没有理解。该项目将通过询问多个小鼠大脑区域如何共同支持任务切换，这是一种常见的灵活认知行为类型，来研究这个基本问题。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的工作提供旨在治疗认知僵化性的工作，这在自闭症，精神分裂症和痴呆等脑部疾病中无处不在。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和研究生教育提供许多机会。其次，它将包括向学校老师和儿童的宣传，以提高人们对任务转换过度转换的损害的认识，这随着智能手机（例如智能手机）的普遍数字技术的大大增加，尤其会影响学龄儿童的学习。该提案的核心目标是对比两个竞争模型，即大脑如何重新组织其活动模式任务：在心脏内模型中，特定于任务的活动是在大脑皮层中充分生成的。在外部输入模型中，需要皮层输入来积极重组皮质活动，从而实现新的认知计算。基于初步研究，假设是，前额叶皮层，胆碱能基础前脑和皮质的其余部分之间的循环是一个关键的多区域电路，可以根据认知需求的认知需求，与外部输入模型相吻合。由于其独特的认知行为和实验工具的可用性，该项目将使用小鼠作为模型生物体。它将利用一种新的行为范式来用于头固定的小鼠在虚拟现实中做出导航决策，其中它们在行为会话中的简单和复杂任务之间进行了数十次。该范式将与尖端的遗传和光学工具结合使用，以记录和扰动假设电路环的不同节点，并具有细胞类型和投影特异性。此外，将采用统计和机械建模将神经活动模式与特定于任务的行为联系起来，并从该特定电路中提取可概括的计算原理。因此，该项目将汇总行为，计算和电路拆卸技术的最新发展，以获取对任务切换的机械洞察力，这是一种柔性认知行为的规范形式。该奖项反映了NSF的法定任务，并被认为是值得通过基金会的知识分子和更广泛影响的评估来通过评估来获得支持的审查审查审查的审查标准。