The Role of Locus Coeruleus in Decision Execution and Adaptive Gain

描述(由申请人提供)：在许多精神障碍中决策出现问题。相当多的证据支持蓝斑去甲肾上腺素(LC-NE)在调节决策过程中的作用。LC-NE功能障碍也是决策受损的几种情况的关键特征，包括情绪障碍、注意力缺陷多动障碍和痴呆症。阿斯顿-琼斯实验室和其他实验室的研究表明，LC-NE神经元在决策任务中有阶段性反应，例如两个可供选择的强迫选择任务(2AFC)。时相LC-NE活动紧密而一致地先于行为结果，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信息和促进决策执行的时间过滤器。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-LC-NE函数的自适应增益假设。然而，选择性地操作LC来测试NE在皮质功能和行为表现的适应性获得中的精确功能一直是缺乏的，显著削弱了这一重要框架。了解LC-NE功能的确切性质，通过监测和控制该系统，将完善和扩展这一假说，并将揭示关于NE调节对皮质加工以及认知功能和功能障碍的影响的重要新知识。在K99/R00应用程序的指导和独立阶段，我建议对去甲肾上腺素能自适应增益在决策过程中的概念框架进行经验测试。我将描述和选择性地操纵LC-NE神经元在2AFC任务中的活动，以确定它们在决策执行和最佳表现中的作用。蓝斑强烈投射到参与决策处理的许多额叶皮质区域。我将具体描述LC-NE和运动前皮质(M2)之间的网络功能。M2与运动和认知脑区紧密相连，并接受来自LC的强大的NE神经支配。由于M2参与了运动计划和动作选择/启动，因此它是测试去甲肾上腺素调节的决策执行适应性增益的理想区域。在K99颁奖部分，我将接受2AFC大鼠的行为电生理学录音培训。通过使用LC和M2的同步多点记录，我将确定这两个区域之间的内生时间关系，并确认这些区域的神经活动如何与最佳行为表现相关。这项培训将与加里·阿斯顿-琼斯博士一起进行，他是LC-NE生理和功能方面的著名专家，这使他成为拟议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在体内选择性操作LC-NE神经元的技术。在独立的R00期间，我将使用这些技术在2AFC期间光基因激活LC，以确定LC-NE在发出决策完成信号和启动决策执行中的因果作用。我还将调查选择性操作LC-NE如何改变与行为执行相关的运动前神经活动。我的初步数据显示，LC的光基因激活可以驱动大脑皮层传入感觉信息的适应性增益，NE信号对于2AFC任务中的最佳表现至关重要。此外，在R00中，我还将相互测试与决策完成相关的任务诱发LC-NE放电的光遗传抑制是否会扰乱运动前皮质中与任务相关的神经活动，以及准确的行为表现。拟议的实验将提供认知神经科学和行为神经生理学方面的广泛培训，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，以提高这些发现和未来研究的翻译潜力。这项工作还将为高质量的出版物提供数据，并为研究去甲肾上腺素在决策和其他认知功能中的皮质网络调节的多个竞争性R01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.