Spatiotemporal dynamics of locus coeruleus circuits during learned behavior

学习行为期间蓝斑环路的时空动态

• 批准号: 10199219
• 负责人: MRIGANKA SUR
• 金额: $ 43.14万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10199219
• 关键词: Address; Anatomy; Animals; Anxiety; Arousal; Auditory; Axon; Behavior; Behavior Control; Behavioral; Behavioral Paradigm; Brain; Brain Stem; Brain region; Cell Nucleus; Cerebellum; Cognition; Computer Analysis; Data; Electrophysiology (science); Exhibits; Functional disorder; Head; Image; Immunohistochemistry; Kinetics; Knowledge; Learning; Measures; Monitor; Motor; Motor Cortex; Mus; Negative Reinforcements; Neuromodulator; Neurons; Norepinephrine; Opsin; Optics; Output; Phase; Population; Positive Reinforcements; Prefrontal Cortex; Process; Prosencephalon; Psychological reinforcement; Punishment; Rewards; Role; Sensory; Signal Transduction; Source; Spinal Cord; Stimulus; Task Performances; Techniques; Testing; Tissues; Training; Uncertainty; Viral; base; behavior measurement; cell type; gamma-Aminobutyric Acid; genetic manipulation; inhibitory neuron; innovation; insight; learned behavior; locus ceruleus structure; neuropsychiatric disorder; neuroregulation; norepinephrine system; novel; optogenetics; response; segregation; sensor; spatiotemporal; theories; two-photon

The locus coeruleus (LC), a small brainstem nucleus, is the primary source of the neuromodulator norepinephrine (NE) in the brain. LC receives input from widespread brain regions and projects throughout the forebrain, brainstem, cerebellum, and spinal cord. LC neurons release NE tonically to regulate baseline arousal, and phasically in the context of a variety of sensory-motor and behavioral functions. However, despite its brain- wide effects, the conditions under which LC-NE neurons are phasically activated and the modes of NE action during behavior are poorly understood. One prevailing theory suggests that NE acts to control the gain of output circuits, thereby modulating task performance by enhancing or dampening responses to stimuli. However, another theory suggests that NE release in cortical output regions acts to reset network activity, enabling task- switching or learning of new rules. Neither of these theories adequately explains the many observed roles of the LC-NE system in learning and behavior. We propose a new hypothesis of LC function, that spatiotemporal dynamics and modular circuits enable dissociated roles for the LC in behavioral execution and reinforcement during learned behaviors. Here, we propose to examine multiple features of this hypothesis using innovative approaches combining optically-tagged recordings of specific neuronal populations, advanced 2-photon imaging of identified neurons and axons, optogenetic manipulation of LC neurons and subpopulations, and computational approaches to define encoding of task variables by neurons. In Aim 1, we will record and manipulate the activity of LC neurons in mice performing an instrumentally conditioned task in which they detect auditory tones of variable intensity, execute a response, and receive positive or negative reinforcement. Using targeted recordings from LC-NE neurons as well as newly discovered LC-GABA neurons, we will examine the hypothesis that subsets of LC-NE and LC-GABA neurons encode task execution signals or reinforcement signals. Using this information, we will use cell-type specific optogenetics to activate or inhibit LC-NE or LC-GABA neurons during specific task epochs while measuring the effects on behavior. In Aim 2, we will assess anatomical modularity of LC projections to motor cortex or the prefrontal cortex (PFC), and examine the hypothesis that neurons with execution or reinforcement responses project preferentially to motor cortex or PFC. Subsequently, we will modulate the activity of LC neurons projecting to these targets and measure the effects on execution and learning. In Aim 3, we will examine the hypothesis that differential integration of NE release in motor cortex and PFC facilitates task execution and learning, respectively. We will monitor the fast kinetics of NE release in motor cortex and PFC using a genetically encoded NE sensor, and measure the impact on behavior of silencing NE activity in these cortical targets using optogenetic silencing of LC-NE axons. These data will provide essential information for a computationally informed theory of the role of LC in cognition, and provide a mechanistic basis for understanding the role of LC-NE dysfunction in a range of neuropsychiatric disorders.

蓝斑 (LC) 是一个小的脑干核，是神经调节剂的主要来源 大脑中的去甲肾上腺素（NE）。 LC 接收来自整个大脑区域和项目的输入 前脑、脑干、小脑和脊髓。 LC 神经元紧张地释放 NE 来调节基线唤醒， 并在各种感觉运动和行为功能的背景下分阶段进行。然而，尽管它的大脑 广泛的影响、LC-NE 神经元被阶段性激活的条件以及 NE 作用的模式 行为期间的了解很少。一种流行的理论表明 NE 的作用是控制输出增益 电路，从而通过增强或抑制对刺激的反应来调节任务表现。然而， 另一种理论认为，皮质输出区的 NE 释放可以重置网络活动，从而实现任务- 转换或学习新规则。这些理论都没有充分解释许多观察到的作用 学习和行为中的LC-NE系统。我们提出了 LC 函数的一个新假设，即时空 动态和模块化电路使 LC 在行为执行和强化中发挥分离的作用 在习得行为期间。在这里，我们建议使用创新的方法来检查该假设的多个特征 结合特定神经元群的光学标记记录、先进的 2 光子成像的方法 已识别的神经元和轴突的识别、LC 神经元和亚群的光遗传学操作以及计算 定义神经元任务变量编码的方法。在目标 1 中，我们将记录并操纵活动 小鼠中的 LC 神经元执行仪器调节任务，其中它们检测听觉音调 不同的强度，执行响应，并接受积极或消极的强化。使用有针对性的录音 从 LC-NE 神经元以及新发现的 LC-GABA 神经元，我们将检验以下假设： LC-NE 和 LC-GABA 神经元的子集编码任务执行信号或强化信号。使用这个 信息，我们将使用细胞类型特异性光遗传学来激活或抑制 LC-NE 或 LC-GABA 神经元 特定任务时期，同时测量对行为的影响。在目标 2 中，我们将评估 LC 投射到运动皮层或前额叶皮层 (PFC)，并检验神经元的假设 执行或强化反应优先投射到运动皮层或 PFC。随后，我们将 调节投射到这些目标的 LC 神经元的活动并测量对执行和 学习。在目标 3 中，我们将检验以下假设：运动皮层和运动皮层中 NE 释放的差异整合 PFC 分别促进任务执行和学习。我们将监测运动中 NE 释放的快速动力学 使用基因编码的 NE 传感器检测皮层和 PFC，并测量沉默 NE 对行为的影响 使用 LC-NE 轴突的光遗传学沉默来检测这些皮质目标的活动。这些数据将提供必要的 为 LC 在认知中的作用的计算信息理论提供信息，并提供机制基础 了解 LC-NE 功能障碍在一系列神经精神疾病中的作用。