Stopping behavior and interrupting cognition via subthalamic nucleus

项目摘要 对几个物种的研究表明，快速停止动作会激活丘脑底核（subthalamic nucleus，简称ENA）。 基底神经节（BG）-并且可以通过来自前额叶的超直接通路（HDP）募集 皮质止结人类研究还表明，意外事件（如令人惊讶的音调）也 重新启动停止系统（包括工作记忆），并中断工作记忆（WM）。在这个问题的核心 一个建议是这样的想法，即WM是通过复发性皮质-BG环路维持的，并且这可以通过以下方式中断： 人民民主党招募了一批志愿者。中断是由停止信号和意外事件引起的， 功能是“清晰的认知”。这是一个激进的新理论：停止的额叶BG回路是认知的基础。 干扰。验证这一理论对于理解BG， 认知中断，以及帕金森病（PD）中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类-小鼠研究来系统地测试这一理论， 广泛的初步数据和使用几种新的方法，包括事件相关的脑深部电刺激 （eDBS）。目标1（运动停止）将在人类中使用DBS，在小鼠中使用光遗传学刺激，以测试是否 在因果关系上，该词对于停止动作是重要的。目标2（认知停止）将使用eDBS和功能性MRI， 人类和小鼠中的光遗传学，以测试该蛋白质是否对减少WM具有因果重要性。目标3 (HDP)将在小鼠中使用组合光遗传学， 在人类大脑中同时进行局部场记录，以测试运动和认知停止是否 通过HDP输入从额叶皮层到HDP来实现。在整个提案中，我们专注于设计 跨物种的互补实验，这样在小鼠身上学到的东西就可以直接告诉我们， 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.