EFFECTS OF LOCUS COERULEUS ACTIVATION: SELECTIVE OPTOGENETIC STIMULATION AND fMRI

描述（由申请人提供）：本项目的目标是建立一个经验基础，测量蓝斑（LC）-去甲肾上腺素（NE）系统的影响，在目标网络中使用功能性磁共振成像（fMRI）。LC与多种精神和退行性疾病有关，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作用，例如调节注意力和修改感觉神经元的增益。然而，由于在监测CNS网络活动的同时选择性激活LC-NE神经元的能力的限制，难以测量这种全局影响。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。该项目旨在使用创新的光遗传学方法克服这些限制，以在体内超高场功能成像期间诱导LC-NE神经元中特异性的不同活动模式。我们的初步数据表明，我们可以选择性地用光遗传学光激活LC-NE神经元，同时观察到整个大鼠大脑的强烈BOLD反应。目的1是充分开发一种方法，将测量和区分的影响，强直与相位LC激活大规模脑网络与功能磁共振成像。目的二是利用功能磁共振成像（fMRI）技术研究选择性激活LC- NE引起的体感神经元对后爪刺激反应的改变。这些研究将提供第一个可靠和有效的方法来评估基础科学和治疗问题的LC功能与非侵入性成像。

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.