Basal Ganglia Pathways for Stopping and Switching

行为抑制是自我控制的核心。日常生活因一系列的曲目而变得无比轻松 习得的对刺激的反应，但我们需要中断和超越这样的反应，如环境和 目标变了。抑制功能问题是包括药物在内的一系列精神疾病的特征 成瘾、注意力缺陷多动障碍和多发性抽动症。尽管行为的重要性 抑制，我们对其中涉及的神经机制的了解仍然非常有限。 探测行为抑制的一个标准工具是停止信号任务。受试者被示意要 快速动作，以及在试验的子集中，后来被指示在开始之前取消这些动作。它有 长期以来，人们一直假设停止信号的性能反映了Go和Stop进程之间的竞争，但如何 这场比赛对应的大脑活动尚不清楚。尽管有大量证据表明大脑深处 被称为基底节的结构参与了止血，但很少有相应的研究 基底节采用时间分辨率最好的方法--单神经元电生理学。 我们最近发现了不同的基底节通路之间存在神经竞赛的证据。中的活动 感觉运动纹状体(STR)似乎对应于一个GO过程，而停止提示却激发了非常 丘脑底核(STN)的快速反应。这两个区域都投射到黑质部分。 网状结构(SNR)，它可以作为电机输出的门户。STR和STN触发的相对时序 确定SNR细胞是否对停止提示(在抑制成功时观察到)做出反应 (当抑制失败时)。 然而，我们的数据也表明，STN-SNR途径实际上提供了一个快速而短暂的 运动暂停，完全取消需要单独抑制STR输出。我们假设 这两种机制起着互补的作用，使行为抑制既快速又 有选择性的。为了进一步研究这些过程，我们提出了一系列实验，使用最先进的 监测和操纵基底神经节的技术。对于目标1，我们将比较与止损相关的活动 在STR、STN和SNR内的不同子区域，以更好地定义信息如何通过“马达”和 “认知”回路。对于目标2，我们将调查STN信号是否专用于停车，以及是否 它们是由层内丘脑驱动的，这是一个参与快速定向反应的区域。对于Aim 3，我们将使用 选择性光遗传抑制和刺激STN-SNR途径，以确认它提供了一个快速的 马达暂停。最后，对于目标4，我们将探索关键的神经调节剂乙酰胆碱和多巴胺是如何 有助于在成功取消的操作期间抑制STR输出。 总体而言，这个项目将在以前所未有的精度确定我们是如何的方面开辟新的天地 能够迅速压制不想要的或不适当的行为，以适应、灵活的行为。

Behavioral inhibition is central to self-control. Daily life is made immeasurably easier by a repertoire of learned responses to stimuli, yet we need to interrupt and override such responses as circumstances and goals change. Problems with inhibitory function characterize a range of psychiatric disorders including drug addiction, attention-deficit hyperactivity disorder, and Tourette Syndrome. Despite the importance of behavioral inhibition, our understanding of the neural mechanisms involved remains very limited. A standard tool to probe behavioral inhibition is the Stop-signal task. Subjects are signaled to make quick actions, and in a subset of trials are later instructed to cancel those movements before they begin. It has long been hypothesized that Stop-signal performance reflects a race between Go and Stop processes, but how this race corresponds to brain activity is not clear. Although there is a great deal of evidence that deep brain structures called the basal ganglia are involved in stopping, there has been little corresponding investigation of the basal ganglia using the method with the best temporal resolution - electrophysiology of single neurons. We have recently found evidence for a neural race between distinct basal ganglia pathways. Activity in sensorimotor striatum (STR) appeared to correspond to a Go process, while Stop cues instead provoked very fast responses in the subthalamic nucleus (STN). Both of these areas project to the substantia nigra pars reticulata (SNr), which can operate as a gateway to motor output. The relative timing of STR and STN firing determined whether SNr cells responded to the Stop cue (observed when inhibition was successful), or not (when inhibition failed). However, our data also suggest that the STN-SNr pathway actually provides a fast yet transient movement pause, with complete cancellation requiring a separate suppression of STR output. We hypothesize that these two mechanisms serve complementary functions, allowing behavioral inhibition to be both fast and selective. To investigate these processes further, we propose a series of experiments using state-of-the-art techniques for monitoring and manipulating the basal ganglia. For Aim 1 we will compare Stop-related activity in distinct subregions within STR, STN and SNr, to better define how information flows through "motor" and "cognitive" circuits. For Aim 2 we will investigate whether STN signals are specific to stopping, and whether they are driven by the intralaminar thalamus, an area involved in fast orienting reactions. For Aim 3 we will use selective optogenetic suppression and stimulation of the STN-SNr pathway to confirm that it provides a fast motor pause. Finally, for Aim 4 we will explore how the key neuromodulators acetylcholine and dopamine contribute to the suppression of STR output during successfully cancelled actions. Overall, this project would break new ground in determining with unprecedented precision how we are able to rapidly suppress unwanted or inappropriate actions, in the service of adaptive, flexible behavior.