Role of Locus Coeruleus in Response Inhibition

蓝斑在反应抑制中的作用

• 批准号: 8659495
• 负责人: Gary S. Aston-Jones
• 金额: $ 33.19万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-22 至 2014-11-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8659495
• 关键词: Affect; Animals; Area; Attention deficit hyperactivity disorder; Autoreceptors; Behavior; Behavior Disorders; Behavioral; Brain; Cations; Cells; Cues; Decision Making; Development; Disease; Dopamine-beta-monooxygenase; Drug Addiction; Drug Design; Exhibits; Halorhodopsins; Human; Individual; Lentivirus Vector; Link; Measures; Methods; Neurons; Norepinephrine; Obsessive-Compulsive Disorder; Outcome; Patients; Performance; Pharmaceutical Preparations; Play; Pump; Rattus; Relative (related person); Role; Signal Transduction; System; Task Performances; Testing; Time; Training; Viral; Work; atomoxetine; cell cortex; cognitive function; executive function; frontal lobe; improved; in vivo; inhibitor/antagonist; locus ceruleus structure; norepinephrine system; novel; novel strategies; promoter; relating to nervous system; research study; response; restraint; reuptake; vector

DESCRIPTION (provided by applicant): Response inhibition (RI) is central to executive control of behavior, and multiple lines of evidence indicate that the locus coeruleus-norepinephrine (LC-NE) system is involved in RI. Specific cortical areas are also strongly implicated in RI, including a major target of LC neurons in rat, the orbitofrontal cortex (OFC). The go-nogo (GNG) and stop signal (SS) tasks are used to examine the neural substrates of response-restraint and response-cancellation, respectively. Importantly, these tasks are nearly identical in humans and rats. Moreover, NE actions in frontal cortical areas of both rats and humans are involved in RI, as well as in RI deficits in attention deficit disorder/hyperactivity (ADHD) subjects. These findings afford us the opportunity to conduct translationally relevant studies to examine the specific role of the NE-LC system and OFC in RI. We will obtain unit recordings from rat LC and OFC neurons during GNG and SS tasks to identify their roles in RI. Specifically, we will test the hypothesis that phasic activation of LC neurons, and NE actions in OFC, are importantly involved in these measures of inhibitory control. The selective NE reuptake inhibitor, atomoxetine (ATM), has recently been found effective for improving RI in normal and ADHD individuals. We hypothesize that this might be due, at least in part, to effects of this compound on the activity profile of LC neurons as well as its effect on LC-NE input to OFC cells. We will test this by recording LC and OFC neurons during GNG or SS tasks following ATM administration. Finally, we will use novel viral transduction methods to express the photosensitive cation channel channelrhodopsin-2, or choride pump halorhodopsin-3, selectively in LC-NE neurons. We will phasically photo-activate or -inhibit these cells, or their terminals in OFC, at specific points in these tasks to test a causal role for the NE-LC system and OFC in RI function. These proposed studies will substantially advance our understanding of inhibitory control through novel analyses of the contribution of the LC-NE system and OFC to RI task performance. The results of these studies will also provide a new approach to the design of drugs to treat human disorders involving impaired RI, including ADHD and drug addiction.

描述（由申请人提供）：响应抑制（RI）对于行为执行控制至关重要，多行证据表明，RI涉及的基因座 - 甲肾上腺素（LC-NE）系统。特定的皮质区域也与RI有很强的含义，其中包括大鼠（OFC）轨道额叶皮层的LC神经元的主要靶标。 GO-NOGO（GNG）和停止信号（SS）任务分别用于检查响应控制和响应局限性的神经底物。重要的是，这些任务在人类和大鼠中几乎相同。此外，大鼠和人类额叶皮质区域的NE作用都参与RI，以及注意力不足障碍/多动症（ADHD）受试者的RI缺陷。这些发现使我们有机会进行翻译相关的研究，以检查NE-LC系统和OFC在RI中的特定作用。在GNG和SS任务期间，我们将从大鼠LC和OFC神经元中获得单位记录，以识别其在RI中的作用。具体而言，我们将检验以下假设：LC神经元的阶段激活以及OFC中的NE作用重要地参与了这些抑制性控制的措施。选择性NE再摄取抑制剂Atomoxetine（ATM）最近被发现有效地改善了正常和多动症个体的RI。我们假设这至少部分是由于该化合物对LC神经元活性谱的影响以及对LC-NE输入对OFC细胞的影响。我们将通过在ATM给药后的GNG或SS任务期间记录LC和OFC神经元来测试这一点。最后，我们将使用新型的病毒转导方法来表达在LC-NE神经元中有选择地表达光敏的阳离子通道Ropopsin-2或胆碱泵的Halorhodopsin-3。我们将在这些任务中的特定点上进行图像激活或抑制它们在OFC中的终端，以测试NE-LC系统和RI功能中OFC的因果作用。这些提出的研究将通过对LC-NE系统和OFC对RI任务绩效的贡献进行新的分析来大大提高我们对抑制性控制的理解。这些研究的结果还将为治疗涉及RI受损的人类疾病的药物设计提供新的方法，包括ADHD和吸毒成瘾。