Role of Locus Coeruleus in Response Inhibition

描述(申请人提供)：反应抑制(RI)是执行控制行为的中心，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--眶前叶皮质(OFC)。Go-nogo(GNG)和Stop Signal(SS)任务分别用于研究反应-抑制和反应-消除的神经基础。重要的是，这些任务在人类和大鼠身上几乎是相同的。此外，大鼠和人类额叶皮质的去甲肾上腺素活动都参与了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，以检验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。具体地说，我们将检验这一假设，即LC神经元的时相激活和去甲肾上腺素在OFC的作用，在这些抑制控制措施中起重要作用。选择性去甲肾上腺素再摄取抑制剂托莫西汀(ATM)最近被发现对改善正常和ADHD患者的RI有效。我们推测，这可能至少部分归因于该化合物对LC神经元活动的影响，以及它对LC-NE传入OFC细胞的影响。我们将通过记录ATM给药后在GNG或SS任务中的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在LC-NE神经元中选择性地表达光敏阳离子通道视紫红质-2或氯泵卤视紫红质-3。我们将在这些任务中的特定时间点对这些细胞或其在OFC中的终末进行阶段光激活或抑制，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任务绩效的贡献的新分析，极大地促进我们对抑制控制的理解。这些研究的结果还将为设计治疗包括ADHD和药物成瘾在内的RI受损的人类疾病的药物提供一种新的方法。 公共卫生相关性：反应抑制(RI)是一种重要的认知功能，许多障碍包括无法抑制不适当的行为反应(例如，注意力缺陷/多动障碍、强迫症和药物成瘾)。拟议的实验将确定关键脑神经元在RI中的作用。这将促进开发更好的治疗包括RI缺陷的行为障碍的方法。

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. 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.