EFFECTS OF LOCUS COERULEUS ACTIVATION: SELECTIVE OPTOGENETIC STIMULATION AND fMRI

蓝斑激活的影响：选择性光遗传学刺激和功能磁共振成像

• 批准号: 8434378
• 负责人: Gary S. Aston-Jones
• 金额: $ 22.13万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-30 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8434378
• 关键词: Address; Affect; Afferent Neurons; Alzheimer' s Disease; Attention; Basic Science; Behavioral; Brain; Cell Nucleus; Chemosensitization; Cognitive; Cognitive deficits; Data; Degenerative Disorder; Development; Disease; Etiology; Event; Foundations; Functional Imaging; Functional Magnetic Resonance Imaging; Functional disorder; Future; Goals; Human; Image; Individual; Magnetic Resonance Imaging; Measurement; Measures; Mental disorders; Methods; Metric; Monitor; Moods; Neurodegenerative Disorders; Neurons; Norepinephrine; Parkinson Disease; Pattern; Pharmacotherapy; Process; Psyche structure; Rattus; Research; Rest; Role; Sensory; Signal Transduction; Sleep Disorders; Source; Structure; System; Testing; Therapeutic; Time; Treatment outcome; blood oxygenation level dependent response; flexibility; human disease; human subject; imaging modality; in vivo; innovation; locus ceruleus structure; neuroregulation; norepinephrine system; optogenetics; photoactivation; programs; relating to nervous system; research study; response; somatosensory; transmission process

DESCRIPTION (provided by applicant): The goal of this project is to establish an empirical foundation for measuring locus coeruleus (LC)- norepinephrine (NE) system effects in target networks using functional magnetic resonance imaging (fMRI). LC has been implicated in a variety of mental and degenerative disorders and therefore is an important target for pharmacotherapy. LC-NE neurons have widespread modulatory influences on brain function to regulate attention and modify the gain of sensory neurons, for example. However, it has been difficult to measure such global influences due to limitations in the ability to selectively activae LC-NE neurons while monitoring CNS network activity. It also is unclear how fMRI metrics characterize network effects of phasic and tonic patterns of LC activity that relate to different states of attention. This project seeks to surmount these limitations using innovative optogenetic methods to induce different patterns of activity specifically in LC-NE neurons during ultra high-field functional imaging in vivo. Our preliminary data demonstrate that we can photoactivate LC-NE neurons selectively with optogenetics, and simultaneously observe strong BOLD responses throughout the rat brain. Aim 1 is to fully develop an approach that will measure and distinguish effects of tonic vs phasic LC activation on large scale brain networks with fMRI. Aim 2 is to use fMRI to measure alterations in somatosensory neuronal responses to hindpaw stimulation induced by selective LC- NE activation. These studies will provide the first reliable and valid approaches for evaluating basic science and therapeutic questions about LC function with non-invasive imaging. PUBLIC HEALTH RELEVANCE: The ability to non-invasively measure effects of locus coeruleus (LC) activity on its global target networks using magnetic resonance imaging would advance our understanding of the role(s) for this important brain system in a host of mental functions and dysfunctions, and facilitate rationale development of new pharmacotherapies. This project uses selective optogenetic activation of LC-norepinephrine neurons and ultra high-field functional MRI (fMRI) to provide the first controlled estimates of LC effects on global network function, including during sensory stimulation. The results will establish the extent to which specific patterns of LC activity, resembling those implicated in attention and behavioral flexibility, affect brain networks in ways that can be observed in human subjects using fMRI.

描述（由申请人提供）：该项目的目标是建立使用功能磁共振成像（fMRI）测量目标网络中蓝斑（LC）-去甲肾上腺素（NE）系统效应的经验基础。 LC 与多种精神疾病和退行性疾病有关，因此是药物治疗的重要靶点。 LC-NE 神经元对大脑功能具有广泛的调节影响，例如调节注意力和改变感觉神经元的增益。然而，由于在监测 CNS 网络活动时选择性激活 LC-NE 神经元的能力有限，因此很难测量这种全局影响。目前还不清楚 fMRI 指标如何表征与不同注意力状态相关的 LC 活动的阶段性和紧张性模式的网络效应。该项目旨在利用创新的光遗传学方法克服这些限制，在体内超高场功能成像过程中诱导 LC-NE 神经元特异的不同活动模式。我们的初步数据表明，我们可以通过光遗传学选择性地光激活 LC-NE 神经元，并同时观察整个大鼠大脑的强烈 BOLD 反应。目标 1 是充分开发一种方法，通过 fMRI 测量和区分强直性与阶段性 LC 激活对大规模脑网络的影响。目标 2 是使用功能磁共振成像来测量选择性 LC-NE 激活诱导的后爪刺激的体感神经元反应的变化。这些研究将为通过非侵入性成像评估有关 LC 功能的基础科学和治疗问题提供第一个可靠且有效的方法。 公共健康相关性：使用磁共振成像非侵入性测量蓝斑 (LC) 活动对其全球目标网络的影响的能力将增进我们对这一重要大脑系统在许多心理功能和功能中的作用的理解。功能障碍，并促进新药物疗法的合理开发。该项目使用 LC-去甲肾上腺素神经元的选择性光遗传学激活和超高场功能 MRI (fMRI)，首次提供 LC 对全局网络功能（包括感觉刺激期间）影响的受控估计。结果将确定 LC 活动的特定模式（类似于那些与注意力和行为灵活性有关的模式）对大脑网络的影响程度，这些影响方式可以使用功能磁共振成像在人类受试者中观察到。