Basal Ganglia Pathways for Stopping and Switching

基底神经节通路的停止和切换

• 批准号: 8630262
• 负责人: JOSHUA D BERKE
• 金额: $ 37.74万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-26 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8630262
• 关键词: Accounting; Acetylcholine; Affect; Area; Attention; Attention deficit hyperactivity disorder; Basal Ganglia; Behavior; Behavioral; Behavioral inhibition; Brain; Cell Nucleus; Cells; Clinical; Cognitive; Corpus striatum structure; Cues; Data; Disease; Dopamine; Drug Addiction; Electrophysiology (science); Equus caballus; Event; Failure; Generations; Gilles de la Tourette syndrome; Goals; Human; Individual; Investigation; Learning; Life; Measurement; Mental disorders; Methods; Modeling; Monitor; Motor; Motor output; Movement; Neuromodulator; Neurons; Obesity; Optics; Output; Pathway interactions; Performance; Physiologic pulse; Population; Preparation; Process; Race; Rattus; Reaction; Relative (related person); Resolution; Role; STN stimulation; Self-control as a personality trait; Series; Services; Signal Transduction; Stimulus; Structure; Structure of subthalamic nucleus; Substantia nigra structure; Techniques; Testing; Thalamic structure; Time; cognitive control; design; drug abuser; flexibility; frontal lobe; improved; innovation; insight; neurochemistry; neuromechanism; neuroregulation; novel; optogenetics; public health relevance; relating to nervous system; research study; response; theories; tool

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.

行为抑制是自我控制的核心。日常生活变得无比简单， 学习对刺激的反应，但我们需要中断和覆盖这些反应，如环境和 目标会变抑制功能的问题表征了一系列精神障碍，包括药物依赖性精神障碍。 成瘾、注意力缺陷多动障碍和图雷特综合征。尽管行为的重要性 虽然我们对抑制的神经机制的理解仍然非常有限。 探测行为抑制的标准工具是停止信号任务。受试者被告知 快速动作，并且在试验的子集中，稍后被指示在这些动作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 称为基底神经节的结构参与停止，很少有相应的研究， 基底神经节使用最佳时间分辨率的方法-单个神经元的电生理学。 我们最近发现了不同基底神经节通路之间的神经竞赛的证据。活性 感觉运动纹状体（STR）似乎对应于Go过程，而Stop提示反而引起了非常 丘脑底核（subthalamic nucleus，简称STN）。这两个区域都投射到黑质部分 reticulata（SNr），其可以作为通向运动输出的通道。STR和STR触发的相对时间 确定SNr细胞是否响应停止提示（当抑制成功时观察）， (when抑制失败）。 然而，我们的数据也表明，STN-SNr通路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 这两种机制具有互补的功能，使行为抑制既快速， 选择性的为了进一步研究这些过程，我们提出了一系列使用最先进技术的实验 用于监测和操纵基底神经节的技术。对于目标1，我们将比较停止相关活动 在短信息量、短信息量和短信息量内的不同次区域，更好地界定信息如何通过“运动”流动， “认知”回路对于目标2，我们将研究停止信号是否特定于停止，以及 它们由板内丘脑（一个参与快速定向反应的区域）驱动。对于目标3，我们使用 STN-SNr通路的选择性光遗传学抑制和刺激，以证实它提供了快速的 运动暂停。最后，对于目标4，我们将探讨关键的神经调节剂乙酰胆碱和多巴胺 在成功取消动作期间有助于抑制STR输出。 总的来说，这个项目将以前所未有的精确度确定我们是如何工作的。 能够迅速抑制不想要的或不适当的行为，以适应性，灵活的行为服务。