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:9114241
- 负责人:
- 金额:$ 24.9万
- 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:2015-09-23 至 2018-06-30
- 项目状态:已结题
- 来源:
- 关键词:Anxiety DisordersAreaAttention deficit hyperactivity disorderAwardBasal GangliaBehaviorBehavioralBrainBrain regionCognitiveCuesDataDecision MakingDementiaDevelopmentElectrophysiology (science)FoundationsFunctional disorderFutureGoalsGrantHealthImpaired cognitionKnowledgeLaboratoriesLearningLeftMediatingMental disordersMentorsMonitorMood DisordersMotorNatureNeuronsNorepinephrineObservational StudyPerformancePhasePhysiologyPopulationPrimatesProcessProton PumpPublicationsRattusReaction TimeRegulationResearchRodentRodent ModelRoleSensorySignal TransductionSiteStimulusStudy modelsSystemTechniquesTestingTrainingTranslationsUncertaintyWorkbehavioral outcomebehavioral responsecareercognitive functioncognitive neurosciencecognitive taskimprovedin vivoinnovationlocus ceruleus structuremathematical modelnerve supplyneural patterningneurophysiologynoradrenergicoptogeneticsprematureprogramsrelating to nervous systemresearch studyresponseselective expressiontheories
项目摘要
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.
描述(由申请人提供):许多精神疾病的决策都会出错。大量证据支持蓝斑去甲肾上腺素 (LC-NE) 在决策处理调节中的作用。 LC-NE 功能障碍也是多种决策受损疾病的一个关键特征,包括情绪障碍、注意力缺陷多动障碍和痴呆。阿斯顿-琼斯实验室和其他实验室的工作表明,LC-NE 神经元在决策任务(例如两个替代强制选择任务 (2AFC))期间会做出阶段性反应。阶段性 LC-NE 活动紧密且始终先于行为结果,被认为是决策完成的信号。 NE 的释放增加了皮质目标的增益,该目标被认为充当时间过滤器,用于整合任务相关信息并促进决策执行。这些证据大部分来自观察研究和数学建模,并导致了强大的理论框架的发展 - LC-NE 函数的自适应增益假设。然而,缺乏对 LC 的选择性操作来测试 NE 在皮质功能和行为表现的适应性增益中的精确功能,从而显着削弱了这一重要框架。通过监测和控制系统来了解 LC-NE 功能的确切性质,将完善和扩展这一假设,并将揭示有关 NE 调节对皮质处理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,我建议对决策处理中去甲肾上腺素能自适应增益的概念框架进行实证测试。我将在 2AFC 任务期间表征并选择性地操纵 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 和前运动皮层 (M2) 之间的网络功能。 M2 与运动和认知大脑区域紧密相连,并接受来自 LC 的强烈 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,我将接受执行 2AFC 的大鼠的行为电生理学记录培训。通过使用 LC 和 M2 中的同步多站点记录,我将识别这两个区域之间的内源时间关系,并确认这些区域的神经活动如何与最佳行为表现相关。此次培训将由 Gary Aston-Jones 博士进行,他是 LC-NE 生理学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纵 LC-NE 神经元的技术。在独立 R00 期间,我将在 2AFC 期间使用这些技术以光遗传学方式激活 LC,以确定 LC-NE 在信号决策完成和启动决策执行中的因果作用。我还将研究 LC-NE 的选择性操作如何改变与行为执行相关的运动前神经活动。我的初步数据表明,LC 的光遗传学激活可以驱动皮质中传入感觉信息的自适应增益,并且 NE 信号传导对于 2AFC 任务中的最佳性能至关重要。此外,在 R00 中,我将相互测试任务诱发的与决策完成相关的 LC-NE 放电的光遗传学抑制是否会破坏前运动皮层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出版物提供数据,并为多个竞争性 R01 应用提供初步证据,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。
项目成果
期刊论文数量(0)
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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:
$ 24.9万 - 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:
9031940 - 财政年份:2015
- 资助金额:
$ 24.9万 - 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:
$ 24.9万 - 项目类别:
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