DOPAMINERGIC NEURONS OF THE VENTRAL TEGMENTAL AREA ARE NEGATIVELY COUPLED TO PUPIL-LINKED AROUSAL

Neuromodulators are crucially involved in the regulation of brain states and cognitive functions. One prominent example is the modulation of arousal, a brain state characterized by heightened sensory responsiveness and perception. Arousal, which is also accompanied by autonomic and endocrine activation, is tightly coupled to fluctuations in pupil size, making pupil diameter a non-invasive proxy of arousal. Traditionally, pupil-linked arousal was thought to be exclusively controlled by the activity of noradrenergic neurons in the locus coeruleus, but more recent studies also demonstrated contributions of cholinergic, serotonergic, and orexinergic neurons. Thus, additional neuromodulators also contribute to pupil dynamics and can, vice versa, be approximated by pupil diameter.
However, surprisingly little is known about the relationship between pupil-linked arousal and the dopaminergic system. This is particularly interesting as dopamine is not only structurally similar to noradrenaline, but is also involved in several processes associated with changes in pupil diameter, such as motivation, movement initiation, and reward expectation. To address this gap, we employed molecularly defined expression of calcium indicators and fiber photometry to systematically examine the relationship between dopaminergic neurons in the ventral tegmental area, pupil diameter, and locomotion. Our analysis revealed a modest, yet robust, negative correlation between pupil-linked arousal and the activity of VTA-DA neurons. This finding closes the remaining gap between pupil dynamics and neuromodulatory activity, and stands in contrast to the positive correlations observed for all other neuromodulatory systems that were previously related to pupil-linked arousal.