Shining New Light on an Old Concept: Optogenetic Investigations of the Brain Circuits Underlying Pupil-Linked Arousal

Changes in central arousal state shape cortical computations underlying perception, thought, and action. Variations in arousal are accompanied by fluctuations in pupil size. In turn, pupil dynamics are often used as a marker of noradrenaline release from neurons of the locus coeruleus. However, also other aminergic brain regions contribute to the regulation of arousal states. Yet, little is known about their relationship to noradrenergic activity and pupil dynamics. Here, I will present data from our recent studies that where we combined genetic tools to simultaneously target noradrenergic neurons of the locus coeruleus and serotonergic neurons of the dorsal raphe nucleus or dopaminergic neurons of the ventral tegmental area. Using optogenetic tools to manipulate and read out these systems in awake mice we unravel their functional links. Serotonergic and noradrenergic systems co-fluctuated, and serotonergic dorsal raphe neurons affected pupil size partly via noradrenergic populations in the locus coeruleus. Yet, part of the serotonergic control of pupil dynamics was independent of the locus coeruleus. In contrast, dopaminergic neurons of the VTA showed an inverse correlation with pupil dilation and activity of noradrenergic neurons of the LC. Our findings challenge common assumptions about the neuromodulatory control of pupil dynamics and illuminate the interplay between distinct neurochemical systems within the arousal network of the brainstem.