The role of the locus coeruleus in mediating pupil-linked arousal

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The role of the locus coeruleus in mediating pupil-linked arousal Non-luminance-mediated changes in pupil size have been widely used to index state of arousal in rodents, non-human primates, and humans. Individuals with neuropsychiatric disorders exhibit atypical task-evoked pupil dilation during cognitive tasks. However, the underlying mechanism which couples arousal and pupil size remains unclear. This limits the use of pupillometry in studies of state dependent neural computation and behavior in the healthy brain, and as a tool to infer the pathological dynamics of neuromodulatory processes in the diseased brain. It has long been postulated that the locus coeruleus (LC) mediates the tight correlation between arousal and non-luminance-mediated changes in pupil size during cognitive tasks. However, due to the small size and location of the LC, there is no direct experimental evidence to support this hypothesis. Using a combination of electrophysiology, optogenetic activation/silencing technology, pupillometry, and behavior tasks, we are uniquely positioned to test this hypothesis. In this project, we will 1) determine the modulatory effect of LC activation on pupil size, 2) elucidate the modulatory effect of LC activation on cognitive factors and behavioral performance of head-fixed rats performing tactile detection tasks, and 3) determine the extent to which the LC mediates the correction between changes in pupil size and arousal/behavior by optogenetically silencing the LC. Significance: Human and animal studies have shown that nonluminance-mediated changes in pupil size are tightly correlated with many factors varying along with the dimension of arousal. It has long been posited that task-evoked changes in pupil size during cognitive tasks are modulated by the LC. However, the precise link between LC activity, change in pupil size, arousal and behavioral performance remains little understood. The success of our aims will advance our understanding of how the LC modulates arousal and pupil size simultaneously, allowing us to precisely interpret pupillometry in many cognitive tasks and clinical settings. Innovation: We will use a novel combination of experimental techniques, including pupillometry, optogenetic perturbation, electrophysiology, and behavioral tasks, to address the role of the locus coeruleus in mediating the correlation between changes in pupil size and arousal/behavior. Moreover, we will develop a novel model to infer LC activation from pupillometry.