Control of Noradrenaline in Learned Behaviors

去甲肾上腺素是一种关键的神经调节剂，对大多数大脑区域都有广泛的影响。然而，尽管去甲肾上腺素对整个大脑有影响，但人们对去甲肾上腺素释放的条件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，传统上是在反射反应的背景下进行研究的，如打斗或逃跑行为，但缺乏明确的理论来解释其在认知过程中的作用。我的研究计划的长期目标是了解去甲肾上腺素在习得行为中的作用。我的物理工程和神经科学背景使我的实验室能够开拓和优化方法，在复杂的行为过程中研究去甲肾上腺素能电路。在这个提案中，我们将关注蓝斑在行为中的两个不同的功能：1)去甲肾上腺素促进行为执行；2)促进新任务策略的学习。我之前证明了蓝斑神经元活动的时间动力学特别支持听觉检测任务中的这些不同角色。在这项任务中，我发现短暂的去甲肾上腺素能活动发生在运动反应和强化之后，而沉默这一活动会损害任务的执行和学习。我现在对了解控制这种瞬时去甲肾上腺素能活动的远端和局部回路很感兴趣。我们将致力于两个主要目标：1.评估蓝斑抑制神经元如何在听觉检测任务中调节去甲肾上腺素能活动。2.在听觉检测任务中，确定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，我将扩展我在之前的培训中开发的方法。我的实验室将使用多学科研究策略，包括有针对性的电生理记录、双光子功能成像、神经活动的光遗传和化学遗传操纵，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活体技术，以实现对不同神经元群体的有效靶向、操作和记录。有了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角色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，从外科方法、行为设计到电路建设、电生理学和光学。学习这些互补的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.