Spatiotemporal dynamics of locus coeruleus circuits during learned behavior

学习行为期间蓝斑环路的时空动态

基本信息

批准号：
10380042
负责人：
MRIGANKA SUR
金额：
$ 41.49万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
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/10380042
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

项目摘要

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.

小脑干核位基因座（LC）是神经调节剂的主要来源大脑中的去甲肾上腺素（NE）。 LC从整个整个大脑区域和项目中收到投入前脑，脑干，小脑和脊髓。 LC神经元在调节基线唤醒的情况下释放NE，并在各种感觉运动和行为函数的背景下进行。但是，尽管有大脑广泛的效果，LC-NE神经元被定位激活的条件和NE作用的模式在行为期间，人们理解的。一种流行的理论表明，NE采取行动来控制产出的增长电路，从而通过增强或减弱对刺激的反应来调节任务性能。然而，另一种理论表明，皮质输出区域中的NE释放起来重置网络活动，从而实现了任务 - 切换或学习新规则。这些理论都没有充分解释观察到的许多作用学习和行为的LC-NE系统。我们提出了一个新的LC功能的假设，即时空动力学和模块化电路可以在行为执行和强化中为LC解离角色在学习的行为中。在这里，我们建议使用创新来检查该假设的多个特征结合特定神经元种群的光学标记记录，高级2光子成像的方法已鉴定的神经元和轴突，LC神经元和亚群的光学遗传操作以及计算定义神经元对任务变量编码的方法。在AIM 1中，我们将记录和操纵活动在小鼠中执行具有乐器任务的小鼠中的LC神经元，在其中检测到听觉音调可变强度，执行响应并接收正或负强化。使用目标记录从LC-NE神经元以及新发现的LC-GABA神经元中，我们将研究以下假设。 LC-NE和LC-GABA神经元的子集编码任务执行信号或增强信号。使用此信息，我们将使用细胞类型特定的光遗传学激活或抑制LC-NE或LC-GABA神经元在测量对行为的影响的同时，特定的任务时期。在AIM 2中，我们将评估解剖模块 LC对运动皮层或前额叶皮层（PFC）的投影，并检查了与神经元神经元的假设执行或增强响应优先针对运动皮层或PFC。随后，我们会的调节投射到这些目标的LC神经元的活动，并衡量对执行和学习。在AIM 3中，我们将研究以下假设：运动皮层中NE释放的差分整合 PFC分别促进了任务执行和学习。我们将监视电动机中NE释放的快速动力学使用遗传编码的NE传感器使用皮层和PFC，并测量对沉默NE行为的影响使用LC-NE轴突的光遗传沉默在这些皮质靶标中的活性。这些数据将提供必不可少的有关LC在认知中作用的计算知情理论的信息，并提供机械基础了解LC-NE功能障碍在一系列神经精神疾病中的作用。