The Role of Locus Coeruleus in Decision Execution and Adaptive Gain

首席调查员/项目主任(最后、第一、中间)：Vazey、Elena、M. 项目摘要/摘要 在许多精神疾病中，决策都会出错。相当多的证据支持 蓝斑去甲肾上腺素(LC-NE)在决策加工调制中的作用LC-NE功能障碍也是一个关键因素 决策受损的几种情况的特征，包括情绪障碍、注意力缺陷 多动症和痴呆症。阿斯顿-琼斯实验室和其他实验室的研究表明，LC-NE神经元 在决策任务期间做出阶段性反应，例如两个可供选择的强迫选择任务(2AFC)。相LC-NE 活动紧密且始终如一地先于行为结果，被认为是决策完成的信号。Ne 释放增加了皮层目标的增益，它被认为是整合任务相关的时间过滤器 信息和促进决策执行。这些证据大多来自观察。 研究和数学建模，并导致了一个强大的理论框架的发展- LC-NE函数的自适应增益假设。然而，选择性操作LC以测试精确的功能 去甲肾上腺素在皮质功能和行为表现的适应性增益中的作用一直缺乏，这是显著的 削弱这一重要框架。了解LC-NE功能的确切性质，通过监控和 控制系统，将完善和扩展这一假说，并将揭示关于 去甲肾上腺素调节对皮层加工及认知功能和功能障碍的影响。 在此K99/R00应用程序的指导阶段和独立阶段，我建议对其进行经验测试 决策过程中去甲肾上腺素适应性增益的概念框架。我将描述和描述 在2AFC任务中有选择地操纵LC-NE神经元的活动，以确定它们在决策中的作用 执行和最佳性能。蓝斑强烈投射到受累的许多额叶皮质区域 在决策处理中。我将具体描述LC-NE和运动前皮质之间的网络功能 (M2)。M2与运动和认知脑区紧密相连，并接受强大的NE神经支配 来自LC。由于M2已经牵涉到运动规划和行动选择/启动，它是 用来测试去甲肾上腺素对决策执行的调节作用。在颁奖的K99部分 我将接受进行2AFC的大鼠的行为电生理学记录方面的培训。通过使用同步 在LC和M2的多点记录中，我将确定这两者之间的内生时间关系 并确认这些区域的神经活动与最佳行为表现之间的关系。这 培训将与LC-NE生理和功能方面的著名专家Gary Aston-Jones博士一起进行， 使他成为提议的培训计划的最佳导师。 到目前为止，在阿斯顿-琼斯实验室，我已经开发并验证了选择性地 体内操纵LC-NE神经元。在独立的R00期间，我将使用这些技术来 在2AFC期间光遗传激活LC以确定LC-NE在信号决定完成中的因果作用 以及启动决策执行。我还将研究选择性操作LC-NE如何改变运动前状态 与行为执行有关的神经活动。我的初步数据显示，LC的光遗传激活可以 驱动大脑皮层传入感觉信息的自适应增益，NE信号对于最佳 在2AFC任务中的表现。另外，在R00中，我会相互测试任务是否存在光遗传抑制 与决策完成相关的诱发LC-NE放电可扰乱大鼠的任务相关神经活动 运动前皮质和准确的行为表现。拟议的实验将提供广泛的 接受认知神经科学和行为神经生理学培训，开启成功的独立之路 将强大的技术与强大的理论框架相结合的研究计划，以提高翻译能力 从这些发现和未来的研究中挖掘潜力。这项工作还将为高质量的出版物提供数据 以及R01多个竞争性应用研究去甲肾上腺素能调节的初步证据 大脑皮层网络在决策和其他认知功能中的作用。 项目说明第6页

Principal Investigator/Program Director (Last, first, middle): Vazey, Elena, M. Project Summary/Abstract Decision making goes awry in many psychiatric disorders. Considerable evidence supports a role for locus coeruleus norepinephrine (LC-NE) in modulation of decision processing. LC-NE dysfunction is also a key feature of several conditions with impaired decision making including mood disorders, attention deficit hyperactivity disorder and dementia. Work from the Aston-Jones lab and others has shown LC-NE neurons respond phasically during decision tasks such as the two alternative forced choice task (2AFC). Phasic LC-NE activity tightly and consistently precedes behavioral outcomes and is thought to signal decision completion. NE release increases gain in cortical targets which is posited to act as a temporal filter for integrating task relevant information and facilitating decision execution. The majority of this evidence has come from observational studies and mathematical modeling, and has led to the development of a strong theoretical framework – the Adaptive Gain hypothesis of LC-NE function. However, selective manipulation of LC to test the precise function of NE in adaptive gain of cortical function and behavioral performance has been lacking, significantly weakening this important framework. Understanding the exact nature of LC-NE function, by monitoring and controlling the system, will refine and extend this hypothesis and will reveal significant new knowledge about the influence of NE modulation on cortical processing as well as cognitive function and dysfunction. During the mentored and independent phases of this K99/R00 application I propose to empirically test the conceptual framework of noradrenergic adaptive gain in decision processing. I will characterize and selectively manipulate the activity of LC-NE neurons during a 2AFC task to identify their role in decision execution and optimal performance. Locus coeruleus projects strongly to many frontal cortical regions involved in decision processing. I will characterize network function specifically between LC-NE and premotor cortex (M2). M2 is heavily interconnected with motor and cognitive brain regions and receives strong NE innervation from LC. As M2 has been implicated in motor planning and action selection/initiation it is an ideal region in which to test noradrenergic mediated adaptive gain on decision execution. During the K99 portion of the award I will be trained in behavioral electrophysiology recordings from rats performing 2AFC. By using simultaneous multi-site recordings in LC and M2, I will identify the endogenous temporal relationship between these two regions and confirm how neural activity in these regions relates to optimal behavioral performance. This training will take place with Dr. Gary Aston-Jones, a renowned expert on LC-NE physiology and function, which makes him an optimal mentor for the proposed training plan. Thus far in the Aston-Jones laboratory I have developed and validated techniques for selectively manipulating LC-NE neurons in vivo. During the independent R00 period I will use these techniques to optogenetically activate LC during 2AFC to determine a causal role for LC-NE in signaling decision completion and initiating decision execution. I will also investigate how selective manipulation of LC-NE alters premotor neural activity related to behavioral execution. My preliminary data show that optogenetic activation of LC can drive adaptive gain for incoming sensory information in the cortex and that NE signaling is critical for optimal performance in the 2AFC task. Also in the R00 I will reciprocally test whether optogenetic inhibition of task evoked LC-NE discharge associated with decision completion can disrupt task related neural activity in premotor cortex, and accurate behavioral performance. The proposed experiments will provide extensive training in cognitive neuroscience and behavioral neurophysiology, jumpstarting a successful independent research program integrating powerful techniques with a strong theoretical framework to enhance translational potential from these findings and future studies. This work will also produce data for high quality publications and preliminary evidence for multiple competitive R01 applications investigating noradrenergic regulation of cortical networks in decision making and other cognitive functions. Project Description Page 6