The Role of Locus Coeruleus in Decision Execution and Adaptive Gain

蓝斑在决策执行和自适应增益中的作用

基本信息

  • 批准号:
    9031940
  • 负责人:
  • 金额:
    $ 3.57万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-03-23 至 2016-06-30
  • 项目状态:
    已结题

项目摘要

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
主要研究者/项目负责人(最后,第一,中间):Vazey,Elena,M。 项目总结/摘要 在许多精神疾病中,决策都会出错。有大量证据表明, 蓝斑去甲肾上腺素(LC-NE)在决策加工中的调节作用。LC-NE功能障碍也是 具有决策障碍的几种情况的特征,包括情绪障碍、注意力缺陷 多动症和痴呆。阿斯顿-琼斯实验室和其他人的工作表明,LC-NE神经元 在决策任务中,如两个备选强迫选择任务(2AFC)。相性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 释放增加了皮层目标的增益,这被假定为充当整合任务相关的时间滤波器 信息和促进决策执行。大部分证据来自观测 研究和数学建模,并导致了强大的理论框架-- LC-NE功能的自适应增益假设。然而,选择性操作LC以测试精确功能 NE在皮质功能和行为表现的适应性增益中的作用明显缺乏, 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,将完善和扩展这一假设,并将揭示重要的新知识 NE调节对皮层处理以及认知功能和功能障碍的影响。 在此K99/R 00应用程序的指导和独立阶段,我建议进行经验测试 决策处理中去甲肾上腺素能适应性增益的概念框架。我将描述和 在2AFC任务中选择性地操纵LC-NE神经元的活动,以确定它们在决策中的作用。 执行力和最佳性能。蓝斑强烈投射到许多涉及的额叶皮层区域 in decision决策processing处理.我将专门描述LC-NE和前运动皮层之间的网络功能 (M2)。M2与运动和认知脑区紧密相连,并接受强NE神经支配 从LC。由于M2与运动规划和动作选择/启动有关,因此它是一个理想的区域。 其测试去甲肾上腺素能介导的对决策执行的适应性增益。在K99部分的奖励 我将接受大鼠进行2AFC的行为电生理学记录的培训。通过同时使用 在LC和M2的多站点记录,我将确定这两者之间的内源性时间关系 区域,并确认这些区域的神经活动如何与最佳行为表现相关。这 培训将与加里阿斯顿-琼斯博士一起进行,他是LC-NE生理学和功能方面的著名专家, 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选择性地 操纵LC-NE神经元。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在信号决定完成中的因果作用 并启动决策执行。我还将研究如何选择性操纵LC-NE改变运动前 与行为执行相关的神经活动。我的初步数据表明,LC的光遗传学激活可以 在皮层中为传入的感觉信息驱动适应性增益,NE信号传导对于最佳的 在2AFC任务中的表现。同样在R 00中,我将再次测试任务的光遗传学抑制是否 与决策完成相关的诱发LC-NE放电可以破坏与任务相关的神经活动, 前运动皮层和准确的行为表现。这些实验将提供广泛的 认知神经科学和行为神经生理学的培训, 研究计划整合强大的技术与强大的理论框架,以提高翻译 从这些发现和未来的研究潜力。这项工作还将为高质量的出版物提供数据 以及研究去甲肾上腺素能调节的多个竞争性R 01应用的初步证据。 决策和其他认知功能的皮质网络。 项目描述第6页

项目成果

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Elena Vazey其他文献

Elena Vazey的其他文献

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{{ truncateString('Elena Vazey', 18)}}的其他基金

The Role of Locus Coeruleus in Decision Execution and Adaptive Gain
蓝斑在决策执行和自适应增益中的作用
  • 批准号:
    9147634
  • 财政年份:
    2015
  • 资助金额:
    $ 3.57万
  • 项目类别:
The Role of Locus Coeruleus in Decision Execution and Adaptive Gain
蓝斑在决策执行和自适应增益中的作用
  • 批准号:
    9114241
  • 财政年份:
    2015
  • 资助金额:
    $ 3.57万
  • 项目类别:
The Role of Locus Coeruleus in Decision Execution and Adaptive Gain
蓝斑在决策执行和自适应增益中的作用
  • 批准号:
    8767205
  • 财政年份:
    2014
  • 资助金额:
    $ 3.57万
  • 项目类别:

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