Stopping behavior and interrupting cognition via subthalamic nucleus

项目总结 对几个物种的研究表明，快速停止动作激活了丘脑底核(STN)。 基底节(BG)--STN可能通过前额叶的超直接通路(HDP)招募 皮质停止结节。人类的研究还表明，意想不到的事件(如令人惊讶的语气)也 招募停机系统(包括STN)，并中断工作内存(WM)。在这件事的核心 建议的观点是，WM是通过反复的皮质-BG环路维持的，这种循环可以通过 HDP招募STN。中断是通过停止信号和意外事件引起的，并且可能 起到“理清认知”的作用。这是一种激进的新理论：一种用于停止的额叶-大脑皮层回路是认知的基础 被打断。验证这一理论对于理解BG、BG的机制具有广泛的意义 认知中断，以及帕金森病(PD)患者潜在的认知不足和过度灵活性 多动症。在这里，我们建议使用平行的人-鼠研究来系统地测试这一理论，基于 广泛的初步数据并使用几种新方法，包括事件相关的脑深部刺激 (EDBS)。目标1(运动停止)将在人类中使用STN eDBS，在小鼠中使用光遗传刺激来测试 STN对于停止动作具有重要的因果关系。AIM 2(认知停止)将使用eDBS和功能磁共振 人类和小鼠的光遗传学，以测试STN是否对减少WM具有因果重要性。目标3 (HDP)将在小鼠身上使用组合光遗传学和经颅磁刺激的新组合 用人类STN中的同步局部场记录来测试运动和认知停止是否 通过从额叶皮质到STN的HDP输入实现。在整个提案中，我们将重点放在设计 跨物种的互补性实验，因此在老鼠身上学到的东西可以直接告诉我们 了解人类神经回路的功能和行为。

PROJECT SUMMARY Research in several species shows that rapidly stopping action activates the subthalamic nucleus (STN) of the basal ganglia (BG) – and that the STN may be recruited via a hyperdirect pathway (HDP) from prefrontal cortical stopping nodes. Human research also shows that unexpected events (such as a surprising tones) also recruit the stopping system (including the STN), and interrupt working memory (WM). At the core of this proposal is the idea that WM is maintained via a recurrent cortico-BG loop, and that this can be interrupted via HDP recruitment of the STN. The interruption is induced via stop signals and unexpected events, and could function to `clear cognition'. This is a radical new theory: that a fronto-BG circuit for stopping underlies cognitive interruptions. Validating this theory has broad implications for understanding the BG, for mechanisms of cognitive interruptions, and for potential cognitive under-and-over flexibility in Parkinson's disease (PD) and ADHD. Here we propose to systematically test this theory using parallel human-mouse studies, based on extensive preliminary data and using several novel approaches, including event-related Deep Brain Stimulation (eDBS). Aim 1 (motor stop) will use STN eDBS in humans and optogenetic stimulation in mice to test whether the STN is causally important for stopping action. Aim 2 (cognitive stop) will use eDBS and functional MRI in humans and optogenetics in mice to test whether the STN is causally important for decrementing WM. Aim 3 (HDP) will use combinatorial optogenetics in mice and novel combinations of transcranial magnetic stimulation with concurrent local field recordings in human STN to test whether motor and cognitive Stops are implemented via HDP inputs to STN from frontal cortex. Throughout the proposal we focus on designing complementary experiments across species, so that what is learned in mice can directly inform our understanding of human neural circuit function and behavior.