EFFECTS OF LOCUS COERULEUS ACTIVATION: SELECTIVE OPTOGENETIC STIMULATION AND fMRI

描述（由申请人提供）：本项目的目标是利用功能磁共振成像（fMRI）测量靶网络中的蓝斑(LC)-去甲肾上腺素（NE）系统效应，建立经验基础。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。例如，LC-NE神经元对大脑功能具有广泛的调节作用，可以调节注意力和改变感觉神经元的增益。然而，由于监测中枢神经系统网络活动时选择性激活LC-NE神经元的能力有限，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活动的相位和张力模式的网络效应。该项目旨在克服这些限制，使用创新的光遗传学方法，在体内超高场功能成像期间诱导LC-NE神经元的不同活动模式。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，同时在整个大鼠脑中观察到强烈的BOLD反应。目的1是充分开发一种方法，以fMRI测量和区分大尺度脑网络上强直和相位LC激活的影响。目的2是使用功能磁共振成像来测量选择性LC- NE激活引起的后爪刺激引起的体感觉神经元反应的变化。这些研究将为无创成像评估LC功能的基础科学和治疗问题提供第一个可靠和有效的方法。

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.