Noradrenergic and cholinergic mechanisms underlying pupil-linked arousal modulation of thalamic sensory processing

丘脑感觉处理的瞳孔相关唤醒调节的去甲肾上腺素能和胆碱能机制

基本信息

批准号：
10298400
负责人：
Qi Wang
金额：
$ 40.77万
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：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10298400
关键词：
Ablation Acetylcholine Adrenergic Receptor Affect Afferent Neurons Arousal Attention Attention deficit hyperactivity disorder Behavior Behavioral Behavioral Paradigm Biosensor Brain Brain Diseases Brain Stem Brain region CRISPR/Cas technology Cerebral cortex Cholinergic Receptors Clinical Code Cognition Complex Detection Development Diagnosis Disease Electrophysiology (science)Genetic Goals Guide RNA Head Health Individual Knock-out Knowledge Lighting Link Measures Mediating Mental Depression Mental disorders Molecular Mus Neurons Norepinephrine Outcome Parkinson Disease Perception Performance Play Property Psyche structure Psychometrics Pupil Reporting Role Schizophrenia Sensory Short-Term Memory Signal Transduction Stimulus System Tactile Technology Testing Thalamic structure Vibrissae Work adeno-associated viral vector awake barrel cortex base behavioral impairment cholinergic common symptom cost experimental study genetic manipulation improved indexing information processing insight knowledge base locus ceruleus structure nervous system disorder neuropsychiatric disorder neuroregulation noradrenergic norepinephrine system novel receptor relating to nervous system response sensor tool translational impact

项目摘要

Project Summary Noradrenergic and cholinergic mechanisms underlying pupil-linked arousal modulation of thalamic sensory processing Behavioral state, including attention and arousal, exerts heavy influences on neural representation, perception, cognition, and behavioral performance and is regulated by several neuromodulatory systems, including the locus coeruleus-norepinephrine (LC-NE) system and the cholinergic system. Abnormal activity in the LC-NE and cholinergic systems has been implicated in major clinical disorders that affect millions of people, including schizophrenia, Parkinson’s disease (PD), and depression. Non-luminance mediated changes in pupil size have been known to co-vary with mental processing underlying behavior for decades. Recent work highlighted that pupil dynamics were able to track rapid fluctuation of cortical arousal state. Therefore, changes in pupil size under constant illumination have been widely used as a non-invasive read out of the activation of certain central arousal circuits, and thus are used to index pupil-linked arousal. Atypical pupil dynamics have been reported in the aforementioned neurological disorders. However, the mechanisms underlying modulation of information processing in the brain by pupil-linked arousal remain little known. The proposed project will test our central hypothesis: pupil-linked arousal modulates thalamic sensory processing and perceptual behavior through both adrenergic and cholinergic receptors. We focus on the thalamus in this project because most information about the external world reaches the cerebral cortex through the thalamus, and the thalamus plays a critical role in gating information to the cortex. Using a synthesis of electrophysiology, genetic manipulations, and behavioral paradigms, we will test this hypothesis in three Aims. Aim 1 will focus on characterization of the extent to which thalamic sensory processing and its contribution to perception depend on pupil-linked arousal. Aim 2 will examine the extent to which norepinephrine and acetylcholine (ACh) dynamics in the thalamus can be tracked by pupil size. Aim 3 will develop cutting-edge genetic tools based on CRISPR/Cas9 + guide RNA technology to selectively knock out each subtype of adrenergic and cholinergic receptor in the thalamus. Further, we will characterize the role of each subtype of NE/Ach receptor in mediating pupil-linked arousal modulation of sensory processing and perceptual behavior. This project will provide much-needed insight about how the LC-NE and cholinergic systems contribute to pupil-linked arousal modulation of thalamic processing of sensory information and perception. Such information is essential to better understand neurological disorders in which abnormal thalamic activity and pupil dynamics have been reported.

项目概要丘脑瞳孔相关唤醒调节的去甲肾上腺素能和胆碱能机制感觉处理行为状态，包括注意力和唤醒，对神经表征、感知、认知和行为表现，并受到多种神经调节系统的调节，包括蓝斑去甲肾上腺素 (LC-NE) 系统和 LC-NE 胆碱能系统异常活动。胆碱能系统与影响数百万人的重大临床疾病有关，包括精神分裂症、帕金森病 (PD) 和抑郁症会导致非亮度介导的瞳孔大小变化。几十年来，人们已经知道它与心理处理的潜在行为共同变化，最近的研究强调了这一点。瞳孔动态能够跟踪皮层唤醒状态的快速波动，因此瞳孔大小的变化。在恒定照明下已被广泛用作某些激活的非侵入式读出中枢唤醒回路，因此被用来索引与瞳孔相关的唤醒动态。然而，在提到的神经系统疾病中报道了调节的机制。与瞳孔相关的唤醒在大脑中进行的信息处理仍然鲜为人知。拟议的项目将进行测试。我们的中心假设：瞳孔相关的唤醒调节丘脑的感觉处理和知觉行为通过肾上腺素能和胆碱能受体，我们在这个项目中重点关注丘脑，因为大多数。外界的信息通过丘脑到达大脑皮层，丘脑发挥作用通过综合电生理学、基因操作、和行为范式，我们将在三个目标中测试这一假设，目标 1 将重点关注特征的描述。丘脑感觉处理及其对知觉的贡献在多大程度上依赖于与瞳孔相关的唤醒。目标 2 将检查丘脑中去甲肾上腺素和乙酰胆碱 (ACh) 的动态变化程度 Aim 3 将开发基于 CRISPR/Cas9 + 引导 RNA 的尖端遗传工具。选择性敲除丘脑中肾上腺素能和胆碱能受体每种亚型的技术。此外，我们将描述 NE/Ach 受体每种亚型在介导瞳孔相关唤醒中的作用该项目将提供急需的洞察力。关于 LC-NE 和胆碱能系统如何促进瞳孔相关的唤醒调节丘脑处理感觉信息和感知对于更好地理解至关重要。据报道，丘脑活动和瞳孔动态异常的神经系统疾病。