The Role of Locus Coeruleus in Decision Execution and Adaptive Gain

描述（由申请人提供）：在许多精神疾病中，决策出错。相当多的证据支持蓝斑去甲肾上腺素（LC-NE）在决策过程的调制中的作用。LC-NE功能障碍也是具有决策受损的几种病症的关键特征，包括情绪障碍、注意力缺陷多动障碍和痴呆。Aston-Jones实验室和其他人的工作表明，LC-NE神经元在决策任务（如两个选择强迫选择任务（2AFC））中会产生阶段性反应。阶段性LC-NE活动紧密且一致地先于行为结果，并被认为是决定完成的信号。NE释放增加皮层目标的增益，这被认为是作为一个时间过滤器，用于整合任务相关信息和促进决策执行。这些证据大部分来自观测研究和数学建模，并导致了一个强大的理论框架的发展-LC-NE功能的自适应增益假设。然而，选择性操作LC测试NE在皮层功能和行为表现的自适应增益中的精确功能一直缺乏，显着削弱了这一重要框架。了解LC-NE功能的确切性质，通过监测和控制系统，将细化和扩展这一假设，并将揭示重要的新知识NE调制对皮层处理以及认知功能和功能障碍的影响。在指导和独立的阶段，这K99/R 00的应用程序，我建议实证测试的概念框架去甲肾上腺素能自适应增益的决策处理。我将在2AFC任务中表征和选择性地操纵LC-NE神经元的活动，以确定它们在决策执行和最佳性能中的作用。蓝斑强烈投射到许多参与决策处理的额叶皮层区域。我将专门描述LC-NE和运动前皮质（M2）之间的网络功能。M2与运动和认知脑区域紧密相连，并接受来自LC的强NE神经支配。由于M2与运动规划和动作选择/启动有关，因此它是测试去甲肾上腺素能介导的决策执行适应性增益的理想区域。在奖励的K99部分期间，我将接受来自执行2AFC的大鼠的行为电生理学记录的培训。通过使用同时多站点记录在LC和M2，我将确定这两个区域之间的内源性时间关系，并确认如何在这些地区的神经活动与最佳的行为表现。该培训将与LC-NE生理学和功能方面的著名专家加里·阿斯顿-琼斯博士一起进行，这使他成为拟议培训计划的最佳导师。到目前为止，在Aston-Jones实验室，我已经开发并验证了在体内选择性操纵LC-NE神经元的技术。在独立R 00期间，我将使用这些技术在2AFC期间光遗传学激活LC，以确定LC-NE在信号决定完成和启动决定执行中的因果作用。我还将研究如何选择性地操纵LC-NE改变与行为执行相关的运动前神经活动。我的初步数据表明，LC的光遗传学激活可以驱动皮层中传入感觉信息的自适应增益，NE信号传导对于2AFC任务中的最佳表现至关重要。同样在R 00中，我将验证与决策完成相关的任务诱发的LC-NE放电的光遗传学抑制是否可以破坏前运动皮层中的任务相关神经活动和准确的行为表现。拟议的实验将提供认知神经科学和行为神经生理学的广泛培训，启动一个成功的独立研究计划，将强大的技术与强大的理论框架相结合，以增强这些发现和未来研究的转化潜力。这项工作还将为高质量的出版物提供数据，并为研究决策和其他认知功能中皮质网络的去甲肾上腺素能调节的多个竞争性R 01应用提供初步证据。

DESCRIPTION (provided by applicant): 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 o 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.