Control of Noradrenaline in Learned Behaviors

去甲肾上腺素是一种重要的神经调质，对大多数大脑区域产生广泛的影响。然而，尽管它的大脑范围的影响，去甲肾上腺素释放的条件下，以及它如何影响行为的不同方面仍然知之甚少。蓝斑神经元是前脑去甲肾上腺素释放的主要来源，传统上一直在反射反应的背景下进行研究，如战斗或逃跑行为，但缺乏明确的理论来解释其在认知过程中的功能。我的研究计划的长期目标是了解去甲肾上腺素在学习行为中的作用。我在物理工程和神经科学方面的背景使我的实验室能够开拓和优化研究复杂行为中去甲肾上腺素能回路的方法。在这个提议中，我们将重点关注蓝斑在行为中的两个不同功能：1）去甲肾上腺素使行为执行和2）促进新任务策略的学习。我以前表明，蓝斑神经元活动的时间动力学特别支持这些不同的角色在听觉检测任务。在这项任务中，我表明，短暂的去甲肾上腺素能活动发生在运动反应的时间和以下的强化，并沉默这种活动损害任务的执行和学习。我现在有兴趣了解控制这种短暂的去甲肾上腺素能活动的远端和局部回路。我们的工作主要集中在两个方面：1.评估蓝斑抑制神经元在听觉检测任务中如何调节去甲肾上腺素能活动。2.确定在听觉检测任务中自上而下的皮质输入对去甲肾上腺素能反应的贡献。为了实现我的研究目标，我将扩展我在以前的培训中开发的方法。我的实验室将使用多学科的研究策略，包括有针对性的电生理记录，双光子功能成像，神经元活动的光遗传学和化学遗传学操纵，以及计算分析，以定义学习和注意力的神经元编码。我实验室的高素质人员将在转基因小鼠模型中使用这些体内技术，以有效地靶向、操纵和记录不同的神经元群体。通过这种先进的神经科学方法，我的研究计划旨在为LC-NA在学习行为中尚未解决的作用产生一个详细的理论框架。最后，通过这个项目加入我的实验室的人将发展一系列技能，从手术方法，行为设计到电路构建，电生理学和光学。学习这些补充技能将使高素质的人员成为下一代多学科科学家。

Noradrenaline is a critical neuromodulator that exerts widespread influence over most brain regions. However, despite its brain-wide effects, the conditions under which noradrenaline is released and how it affects different facets of behavior are still poorly understood. Neurons in the locus coeruleus, which are the predominant source of forebrain noradrenaline release, have been traditionally studied in the context of reflexive responses, such as the fight or flight behavior, but an explicit theory for its function in cognitive processes is lacking. The long-term objective of my research program is to understand the function of noradrenaline in learned behaviors. My background in Physics Engineering and Neuroscience situates my lab to pioneer and optimize methods to study noradrenergic circuits during sophisticated behaviors. In this proposal, we will focus on two distinct functions for the locus coeruleus in behavior: 1) noradrenaline enables behavioral execution and 2) facilitates learning of new task strategies. I previously shown that the temporal dynamics of locus coeruleus neuronal activity specifically supports these differential roles in an auditory detection task. During this task, I showed that transient noradrenergic activity occurs at the time of motor response and following a reinforcement, and silencing this activity impairs task execution and learning. I am now interested in understanding the distal and local circuits controlling this transient noradrenergic activity. We will focus our efforts on two main objectives: 1.Evaluate how locus coeruleus inhibitory neurons regulate noradrenergic activity during an auditory detection task. 2.Determine the contribution of top-down cortical inputs to noradrenergic responses during an auditory detection task. To achieve my research goals, I will expand the approach I have developed during my previous training. My lab will use a multidisciplinary research strategy, including targeted electrophysiological recordings, two-photon functional imaging, optogenetic and chemogenetic manipulations of neuronal activity, as well as computational analyses, to define neuronal encoding of learning and attention. Highly qualified personnel in my lab will use these in vivo techniques in transgenic mouse models to allow efficient targeting, manipulating, and recording of different neuronal populations. With this advanced neuroscience approach, my research program aims at generating a detailed theoretical framework for the yet unresolved role of LC-NA in learned behavior. Finally, the people joining my lab through this program will develop a range of skills from surgical methods, and behavioral design to circuit building, electrophysiology and optics. Learning these complementary skills will enable highly qualified personnel to become the next generation of multidisciplinary scientists.