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.