Locus coeruelus-prefrontal interactions for flexible decision-making

项目总结/摘要 大脑的高级功能包括学习对世界的期望，更新这些期望， 适当地当给予新的感官信息，并使用这些不断更新的期望，以指导 行为神经回路如何实现这些灵活的信息处理动力学尚不清楚。我们 提出一个新的研究项目，与大脑倡议的目标一致，使用创新， 方法学上的综合方法，以了解活动模式在一个特定的电路在灵长类动物 大脑支持用于行为相关决策的灵活更新。该电路包括两个主要的 具有与我们拟议研究相关的已知特性的组分。第一部分是背外侧 前额叶皮层（dlPFC），其中包括编码预期和感觉的持续处理的神经元 工作记忆中的证据第二种成分是蓝斑（LC）-去甲肾上腺素（NE） 神经调节系统，它可以影响工作记忆表征的dlPFC。但不 已知dlPFC中工作记忆表征的LC-NE调制是否以及如何有助于灵活的 决策的在我们以前关于LC-NE系统的灵活决策和影响的工作的基础上 在神经信息处理方面，我们提出并验证了LC介导的去甲肾上腺素释放的假说， 支配着dlPFC神经群如何灵活地联合收割机工作记忆中的学习期望与 输入感官信息，形成指导行为的决定。我们通过训练来检验这个假设 猴子正在执行一项新颖的任务，该任务使我们能够量化习得的期望和新的感官信息的方式 以灵活的、依赖于上下文的方式组合以做出扫视决定。然后我们阐明 基础电路机制，通过三个目标，每一个都利用一套创新的方法。目标1： 测量单神经元分辨率下的LC和dlPFC活动与灵活决策的关系。目的2 使用多种技术，包括用于时间特异性的电微刺激和用于 通路特异性，以测试LC->dlPFC投射的时间特异性放电模式对 灵活的决策。目标3使用计算建模将LC-dlPFC电路特性（包括 NE介导的神经元增益变化）到支持灵活决策的计算原理。每个 目的单独提供了新的见解相关，因果关系和计算的贡献，LC-dlPFC 灵活的决策。总之，这些研究提供了一个新的，统一的看法，如何LC- PFC电路执行关键计算，灵活地将联合收割机期望与证据结合起来，为决策提供信息。

PROJECT SUMMARY/ABSTRACT Higher brain functions include the ability to learn expectations about the world, update those expectations appropriately when given new sensory information, and use those continually updating expectations to guide behavior. How neural circuits implement these flexible information-processing dynamics is not known. We propose a novel research project that, consistent with the goals of the BRAIN initiative, uses innovative, methodologically integrated approaches to understand how activity pattens in a specific circuit in the primate brain support flexible updating used for behaviorally relevant decisions. The circuit includes two main components with known properties relevant to our proposed studies. The first component is the dorsolateral prefrontal cortex (dlPFC), which includes neurons that encode ongoing processing of expectations and sensory evidence in working memory. The second component is the locus coeruleus (LC)-norepinephrine (NE) neuromodulatory system, which can affect working-memory representations in the dlPFC. However, it is not known whether and how LC-NE modulations of working-memory representations in dlPFC contribute to flexible decision-making. Building on our previous work on flexible decision-making and effects of the LC-NE system on neural information processing, we propose and test the hypothesis that LC-mediated NE release in dlPFC governs how dlPFC neural populations flexibly combine learned expectations held in working memory with incoming sensory information to form decisions that guide behavior. We test this hypothesis by training monkeys on a novel task that allows us to quantify how learned expectations and new sensory information are combined in a flexible, context-dependent manner to make saccadic decisions. We then elucidate the underlying circuit mechanisms, via three Aims that each leverage an innovative set of approaches. Aim 1 is to measure how LC and dlPFC activity at a single-neuron resolution relates to flexible decision-making. Aim 2 uses multiple techniques, including electrical microstimulation for temporal specificity and chemogenetics for pathway specificity, to test for causal roles of temporally specific firing patterns of LC->dlPFC projections on flexible decision-making. Aim 3 uses computational modeling to relate LC-dlPFC circuit properties (including NE-mediated changes in neuronal gain) to computational principles that support flexible decision-making. Each Aim alone provides new insights into correlative, causal, and computational contributions of the LC-dlPFC circuit to flexible decision-making. Taken together, these studies provide a novel, unified view of how the LC- PFC circuit performs critical computations that flexibly combine expectations with evidence to inform decisions.