Role of Locus Coeruleus in Response Inhibition

蓝斑在反应抑制中的作用

• 批准号: 8193802
• 负责人: Gary S. Aston-Jones
• 金额: $ 42.14万
• 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/8193802
• 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. PUBLIC HEALTH RELEVANCE: Response inhibition (RI) is an important cognitive function, and many disorders include an inability to inhibit inappropriate behavioral responses (e.g., attention deficit/hyperactivity disorder, obsessive-compulsive disorder and drug addiction). The proposed experiments will define the roles of key brain neurons in RI. This will facilitate development of better treatments for behavioral disorders that include deficient RI.

描述（由申请人提供）：反应抑制（RI）是行为执行控制的核心，多条证据表明蓝斑-去甲肾上腺素（LC-NE）系统参与RI。特定的皮质区域也强烈地牵涉到RI，包括大鼠LC神经元的主要目标，眶额皮质（OFC）。go-nogo（GNG）和停止信号（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，这些任务在人类和大鼠中几乎相同。此外，NE行动在大鼠和人类的额叶皮质区参与RI，以及在注意缺陷障碍/多动（ADHD）科目的RI赤字。这些研究结果为我们提供了机会，进行相关的研究，以检查的具体作用，NE-LC系统和OFC在RI。我们将在GNG和SS任务中获得大鼠LC和OFC神经元的单位记录，以确定它们在RI中的作用。具体来说，我们将测试的假设，LC神经元的阶段性激活，和NE的行动，在OFC中，重要的是参与这些措施的抑制控制。选择性NE再摄取抑制剂，托莫西汀（ATM），最近被发现有效地改善正常和ADHD个体的RI。我们推测，这可能是由于，至少部分地，这种化合物对LC神经元的活性曲线的影响，以及其对LC-NE输入到OFC细胞的影响。我们将通过记录ATM给药后GNG或SS任务期间的LC和OFC神经元来测试这一点。最后，我们将使用新的病毒转导方法来表达光敏阳离子通道通道视紫红质-2，或氯泵盐视紫红质-3，选择性地在LC NE神经元。我们将在这些任务中的特定点阶段性地光激活或抑制这些细胞或它们在OFC中的终端，以测试NE LC系统和OFC在RI功能中的因果作用。这些拟议的研究将大大推进我们的理解抑制控制通过新的分析的贡献LC-NE系统和OFC RI任务的性能。这些研究的结果也将提供一种新的方法来设计药物来治疗涉及RI受损的人类疾病，包括ADHD和药物成瘾。 公共卫生相关性：反应抑制（RI）是一种重要的认知功能，许多疾病包括无法抑制不适当的行为反应（例如，注意力缺陷/多动症、强迫症和药物成瘾）。拟议的实验将定义RI中的关键脑神经元的作用。这将有助于开发更好的治疗行为障碍，包括缺乏RI。