The role of the locus coeruleus in mediating pupil-linked arousal

蓝斑在调节瞳孔相关唤醒中的作用

基本信息

批准号：
10063037
负责人：
Qi Wang
金额：
$ 39.63万
依托单位：
COLUMBIA UNIV NEW YORK MORNINGSIDE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10063037
关键词：
Address Animal Behavior Animal Disease Models Animals Anxiety Arousal Attention Attention deficit hyperactivity disorder Bayesian Modeling Behavior Behavioral Brain Brain Diseases Brain Stem Cell Nucleus Cervical Clinical Cognition Cognitive Correlation Studies Couples Data Detection Diagnosis Diagnostic Dimensions Discrimination Disease Electroencephalography Electrophysiology (science)Exhibits Frequencies Functional disorder Future Ganglionectomy Goals Head Human Image Individual Knowledge Lasers Link Location Mediating Mental Depression Mental disorders Modeling Mydriasis Outcome Pathologic Pathway interactions Perception Performance Phase Physiologic pulse Positioning Attribute Process Property Psyche structure Pupil Rattus Rodent Rodent Model Role Sensory Tactile Techniques Technology Testing Time Training Vibrissae Work cognitive task cost electrical microstimulation experimental study indexing innovation locus ceruleus structure luminance mind control neuropsychiatric disorder neuroregulation nonhuman primate noradrenergic novel optogenetics prevent relating to nervous system success tool translational impact

项目摘要

The role of the locus coeruleus in mediating pupil-linked arousal Non-luminance-mediated changes in pupil size have been widely used to index state of arousal in rodents, non-human primates, and humans. Individuals with neuropsychiatric disorders exhibit atypical task-evoked pupil dilation during cognitive tasks. However, the underlying mechanism which couples arousal and pupil size remains unclear. This limits the use of pupillometry in studies of state dependent neural computation and behavior in the healthy brain, and as a tool to infer the pathological dynamics of neuromodulatory processes in the diseased brain. It has long been postulated that the locus coeruleus (LC) mediates the tight correlation between arousal and non-luminance-mediated changes in pupil size during cognitive tasks. However, due to the small size and location of the LC, there is no direct experimental evidence to support this hypothesis. Using a combination of electrophysiology, optogenetic activation/silencing technology, pupillometry, and behavior tasks, we are uniquely positioned to test this hypothesis. In this project, we will 1) determine the modulatory effect of LC activation on pupil size, 2) elucidate the modulatory effect of LC activation on cognitive factors and behavioral performance of head-fixed rats performing tactile detection tasks, and 3) determine the extent to which the LC mediates the correction between changes in pupil size and arousal/behavior by optogenetically silencing the LC. Significance: Human and animal studies have shown that nonluminance-mediated changes in pupil size are tightly correlated with many factors varying along with the dimension of arousal. It has long been posited that task-evoked changes in pupil size during cognitive tasks are modulated by the LC. However, the precise link between LC activity, change in pupil size, arousal and behavioral performance remains little understood. The success of our aims will advance our understanding of how the LC modulates arousal and pupil size simultaneously, allowing us to precisely interpret pupillometry in many cognitive tasks and clinical settings. Innovation: We will use a novel combination of experimental techniques, including pupillometry, optogenetic perturbation, electrophysiology, and behavioral tasks, to address the role of the locus coeruleus in mediating the correlation between changes in pupil size and arousal/behavior. Moreover, we will develop a novel model to infer LC activation from pupillometry.

蓝斑在调节瞳孔相关唤醒中的作用非亮度介导的瞳孔大小变化已被广泛用于指示啮齿动物的唤醒状态，非人类灵长类动物和人类。患有神经精神疾病的个体表现出非典型的任务诱发认知任务期间瞳孔扩张。然而，耦合唤醒和瞳孔大小的潜在机制仍不清楚。这限制了瞳孔测量法在状态依赖神经计算研究中的使用和健康大脑中的行为，并作为推断神经调节过程病理动力学的工具患病的大脑。长期以来，人们一直假设蓝斑（LC）介导紧密相关性认知任务期间唤醒和非亮度介导的瞳孔大小变化之间的关系。然而，由于由于LC的尺寸和位置都很小，所以没有直接的实验证据支持这一假设。使用电生理学、光遗传学激活/沉默技术、瞳孔测量和行为的结合任务中，我们具有独特的优势来检验这一假设。在这个项目中，我们将 1) 确定调制 LC 激活对瞳孔大小的影响，2) 阐明 LC 激活对认知因素的调节作用和执行触觉检测任务的头部固定大鼠的行为表现，以及3）确定程度 LC 通过光遗传学介导瞳孔大小变化和唤醒/行为之间的校正使 LC 静音。意义：人类和动物研究表明，非亮度介导的变化瞳孔大小与许多随唤醒程度变化的因素密切相关。它有很长的有人假设认知任务期间任务诱发的瞳孔大小变化是由 LC 调节的。然而， LC 活动、瞳孔大小变化、觉醒和行为表现之间的精确联系仍然很少明白了。我们目标的成功将加深我们对 LC 如何调节觉醒和同时瞳孔大小，使我们能够在许多认知任务和临床中精确解释瞳孔测量设置。创新：我们将使用新颖的实验技术组合，包括瞳孔测量、光遗传学扰动、电生理学和行为任务，以解决蓝斑在调节瞳孔大小变化与唤醒/行为之间的相关性。此外，我们将开发一个从瞳孔测量推断 LC 激活的新模型。