Role of Locus Coeruleus in Response Inhibition

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）系统参与了RI。特定的皮质区域也与RI密切相关，包括大鼠LC神经元的主要靶点，眶额皮质（OFC）。我们分别用go-nogo （GNG）和stop signal （SS）任务来考察反应抑制和反应抵消的神经基质。重要的是，这些任务在人类和老鼠身上几乎是相同的。此外，大鼠和人类额叶皮质区的NE活动都参与了RI，以及注意缺陷障碍/多动（ADHD）受试者的RI缺陷。这些发现为我们提供了进行翻译相关研究的机会，以检查NE-LC系统和OFC在RI中的具体作用。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，我们将验证LC神经元的相位激活和OFC中的NE行为在这些抑制控制措施中起重要作用的假设。选择性NE再摄取抑制剂阿托西汀（ATM）最近被发现对改善正常和ADHD个体的RI有效。我们假设这可能是由于，至少部分是由于这种化合物对LC神经元的活动谱的影响，以及它对LC- ne输入OFC细胞的影响。我们将通过在ATM管理后的GNG或SS任务中记录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在LC-NE神经元中选择性地表达光敏阳离子通道通道视紫红质-2或氯离子泵盐紫红质-3。我们将在这些任务的特定点上对这些细胞或它们在OFC中的末端进行阶段性光激活或抑制，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，极大地推进我们对抑制控制的理解。这些研究的结果还将为设计药物治疗包括多动症和药物成瘾在内的涉及RI受损的人类疾病提供一种新的方法。

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.