Nigro Marco, Tortorelli Lucas Silva, Garad Machhindra, Zlebnik Natalie E, Yang Hongdian
Department of Molecular, Cell and Systems Biology, University of California, Riverside, CA 92521, USA.
Division of Biomedical Sciences, School of Medicine, University of California, Riverside, CA 92521, USA.
bioRxiv. 2025 Feb 4:2023.12.13.571356. doi: 10.1101/2023.12.13.571356.
Behavioral flexibility, the ability to adjust behavioral strategies in response to changing environmental contingencies and internal demands, is fundamental to cognitive functions. Despite a large body of pharmacology and lesion studies, the precise neurophysiological mechanisms that underlie behavioral flexibility are still under active investigations. This work is aimed to determine the role of a brainstem-to-prefrontal cortex circuit in flexible rule switching. We trained mice to perform a set-shifting task, in which they learned to switch attention to distinguish complex sensory cues. Using chemogenetic inhibition, we selectively targeted genetically-defined locus coeruleus (LC) neurons or their input to the medial prefrontal cortex (mPFC). We revealed that suppressing either the LC or its mPFC projections severely impaired switching behavior, establishing the critical role of the LC-mPFC circuit in supporting attentional switching. To uncover the neurophysiological substrates of the behavioral deficits, we paired endoscopic calcium imaging of the mPFC with chemogenetic inhibition of the LC in task-performing mice. We found that mPFC prominently responded to attentional switching and that LC inhibition not only enhanced the engagement of mPFC neurons but also broadened single-neuron tuning in the task. At the population level, LC inhibition disrupted mPFC dynamic changes and impaired the encoding capacity for switching. Our results highlight the profound impact of the ascending LC input on modulating prefrontal dynamics and provide new insights into the cellular and circuit-level mechanisms that support behavioral flexibility.
行为灵活性，即根据不断变化的环境情况和内部需求调整行为策略的能力，是认知功能的基础。尽管有大量的药理学和损伤研究，但行为灵活性背后的确切神经生理机制仍在积极研究中。这项工作旨在确定脑干到前额叶皮层回路在灵活规则切换中的作用。我们训练小鼠执行一种转换任务，在该任务中它们学会转移注意力以区分复杂的感觉线索。使用化学遗传学抑制，我们选择性地靶向基因定义的蓝斑（LC）神经元或其到内侧前额叶皮层（mPFC）的输入。我们发现抑制LC或其mPFC投射都会严重损害转换行为，确立了LC-mPFC回路在支持注意力转换中的关键作用。为了揭示行为缺陷的神经生理基础，我们在执行任务的小鼠中将mPFC的内窥镜钙成像与LC的化学遗传学抑制相结合。我们发现mPFC对注意力转换有显著反应，并且LC抑制不仅增强了mPFC神经元的参与度，还拓宽了任务中单个神经元的调谐范围。在群体水平上，LC抑制破坏了mPFC的动态变化并损害了转换的编码能力。我们的结果突出了LC上行输入对调节前额叶动态的深远影响，并为支持行为灵活性的细胞和回路水平机制提供了新的见解。
