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一个经验基础，以使用功能磁共振成像（fMRI）（fMRI）来测量目标网络中的去甲肾上腺素（NE）系统效应。 LC与各种精神和退化性疾病有关，因此是药物治疗的重要靶标。 LC-NE神经元对大脑功能具有广泛的调节影响，以调节注意力并改变感觉神经元的增益。但是，由于在监测CNS网络活动的同时选择性Activae LC-NE神经元的能力限制，因此很难衡量这种全球影响。尚不清楚fMRI指标如何表征与不同关注状态相关的LC活动的阶段和滋补模式的网络效应。该项目旨在使用创新的光遗传学方法来克服这些局限性，以在体内超高场功能成像期间在LC-NE神经元中诱导不同的活动模式。我们的初步数据表明，我们可以将LC-NE神经元与光遗传学有选择性地进行光活化，同时观察到整个大鼠大脑中的强大大胆反应。目的1是充分开发一种方法，该方法将测量和区分使用fMRI大规模大脑网络的补品与阶段LC激活的影响。 AIM 2是使用fMRI来测量选择性LC-NE激活引起的对后爪刺激的体感神经元反应的改变。这些研究将提供第一种可靠且有效的方法，用于评估具有非侵入性成像的有关LC功能的基础科学和治疗问题。 公共卫生相关性：使用磁共振成像对基因座（LC）活性对其全球目标网络的影响的能力将提高我们对这一重要大脑系统在许多心理功能和功能障碍中的作用的理解，并促进新药物治疗的依据。该项目使用LC-氯肾上腺素神经元和超高场功能性MRI（fMRI）的选择性光遗传学激活，以提供对LC对全球网络功能的第一个受控估计值，包括在感觉刺激期间。结果将确定LC活性的特定模式在多大程度上类似于与注意力和行为灵活性有关的模式，以使用fMRI在人类受试者中观察到的方式影响大脑网络。