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。通过曲目的曲目使日常生活变得更加容易 学会了对刺激的反应，但是我们需要中断和覆盖情况和诸如环境和 目标改变。抑制功能的问题表征了包括药物在内的一系列精神疾病 成瘾，注意力缺陷多动障碍和图雷特综合征。尽管行为很重要 抑制作用，我们对所涉及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。受试者的信号是 快速行动，并在一部分中指示在开始之前取消这些动作。它有 长期以来，假设停止信号表现反映了GO和停止过程之间的竞赛，但是如何 该种族对应于大脑活动尚不清楚。尽管有很多证据表明大脑 称为基底神经节的结构参与停止，几乎没有相应的研究 使用该方法具有最佳时间分辨率 - 单神经元电生理学的基础神经节。 我们最近发现了不同基础神经节途径之间神经种族的证据。活动中的活动 感觉运动纹状体（STR）似乎与GO过程相对应，而停止提示则非常激发 丘脑下核（STN）中的快速反应。这两个区域都向黑泥人尼格拉 网状（SNR），可以用作通往电动机输出的门户。 STR和STN射击的相对时机 确定SNR细胞是否响应停止提示（在抑制成功时观察到） （抑制失败时）。 但是，我们的数据还表明STN-SNR途径实际上提供了快速而瞬态的 移动暂停，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，使行为抑制既快速又 选择性。为了进一步研究这些过程，我们提出了一系列使用最先进的实验 监测和操纵基底神经节的技术。对于目标1，我们将比较与停止相关的活动 在Str，STN和SNR中的不同子区域中，以更好地定义信息如何流过“电机”和 “认知”电路。对于AIM 2，我们将调查STN信号是否特定于停止，以及是否是否 它们是由腔内丘脑驱动的，丘脑是参与快速定向反应的区域。对于目标3，我们将使用 选择性的光遗传学抑制和STN-SNR途径的刺激，以确认它提供了快速 电机暂停。最后，对于AIM 4，我们将探讨关键神经调节剂乙酰胆碱和多巴胺如何 在成功取消动作过程中有助于抑制STR输出。 总体而言，该项目将以前所未有的精度确定我们的状况会破裂 能够快速抑制不需要或不适当的行动，以服务自适应，灵活的行为。