Locus coeruelus-prefrontal interactions for flexible decision-making

项目摘要/摘要 更高级的大脑功能包括学习对世界的期望、更新这些期望的能力 适当地给予新的感觉信息，并使用这些不断更新的预期来指导 行为。神经电路如何实现这些灵活的信息处理动力学尚不清楚。我们 提出一个新颖的研究项目，该项目与大脑计划的目标一致，使用创新的 理解灵长类特定回路中活动模式的方法学综合方法 用于行为相关决策的大脑支持灵活更新。该电路包括两个主电路 具有与我们建议的研究相关的已知性质的组件。第一个组件是背外侧 前额叶皮质(DlPFC)，它包括编码正在进行的预期和感觉加工的神经元 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dlPFC中的工作记忆表征。然而，它并不是 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 决策。在我们以前关于灵活决策和LC-NE系统效果的工作的基础上 在神经信息处理方面，我们提出并验证了LC介导的dlPFC去甲肾上腺素释放的假说。 管理dlPFC神经种群如何灵活地将工作记忆中的学习期望与 传入的感官信息形成指导行为的决定。我们通过训练来检验这一假设 猴子参与了一项新的任务，它允许我们量化学习到的期望和新的感觉信息是如何 以灵活的、依赖于上下文的方式组合，以做出跳动的决定。然后，我们将阐明 基础电路机制，通过三个目标，每个目标都利用一套创新的方法。目标1是 测量单个神经元分辨率下的LC和dlPFC活动与灵活决策的关系。目标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，以检验LC-GT；dlPFC投射的时间特异性放电模式的因果作用 灵活的决策。AIM 3使用计算建模来关联LC-dlPFC电路属性(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。每个人 AIM本身就提供了对LC-dlPFC的相关、因果和计算贡献的新见解 巡回演绎灵活决策。综上所述，这些研究提供了一个新的、统一的观点，即LC是如何- PFC电路执行关键计算，灵活地将预期与证据相结合，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.