Role of Locus Coeruleus in Response Inhibition

蓝斑在反应抑制中的作用

• 批准号: 8463621
• 负责人: Gary S. Aston-Jones
• 金额: $ 31.86万
• 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 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8463621
• 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）：反应抑制 (RI) 是行为执行控制的核心，多种证据表明蓝斑-去甲肾上腺素 (LC-NE) 系统参与 RI。特定的皮质区域也与 RI 密切相关，包括大鼠 LC 神经元的主要目标——眶额皮质 (OFC)。 go-nogo (GNG) 和 stop signal (SS) 任务分别用于检查反应抑制和反应取消的神经基质。重要的是，人类和大鼠的这些任务几乎相同。此外，大鼠和人类额叶皮质区域的 NE 作用与 RI 以及注意力缺陷障碍/多动症 (ADHD) 受试者的 RI 缺陷有关。这些发现为我们提供了进行转化相关研究的机会，以检验 NE-LC 系统和 OFC 在 RI 中的具体作用。我们将在 GNG 和 SS 任务期间从大鼠 LC 和 OFC 神经元获得单位记录，以确定它们在 RI 中的作用。具体来说，我们将检验以下假设：LC 神经元的阶段性激活和 OFC 中的 NE 作用在这些抑制控制措施中发挥着重要作用。最近发现选择性 NE 再摄取抑制剂阿托莫西汀 (ATM) 可有效改善正常人和 ADHD 个体的 RI。我们推测，这可能至少部分归因于该化合物对 LC 神经元活动谱的影响以及对 OFC 细胞的 LC-NE 输入的影响。我们将通过在 ATM 管理后的 GNG 或 SS 任务期间记录 LC 和 OFC 神经元来测试这一点。最后，我们将使用新型病毒转导方法在 LC-NE 神经元中选择性表达光敏阳离子通道通道视紫红质 2 或氯离子泵盐视紫红质 3。我们将在这些任务的特定点分阶段光激活或抑制这些细胞或其在 OFC 中的末端，以测试 NE-LC 系统和 OFC 在 RI 功能中的因果作用。这些拟议的研究将通过对 LC-NE 系统和 OFC 对 RI 任务表现的贡献的新颖分析，极大地增进我们对抑制控制的理解。这些研究的结果还将提供一种新的药物设计方法，用于治疗涉及 RI 受损的人类疾病，包括 ADHD 和药物成瘾。