Abstract
Cholinergic contribution to pupil-linked arousal
Behavioral state, including attention and arousal, exerts heavy influences on neural representation, perception,
cognition, and behavioral performance and is regulated by several neuromodulatory systems, including the
cholinergic systems and the locus coeruleus-norepinephrine (LC-NE) system. Abnormal activity in the
cholinergic systems has been implicated in major clinical disorders that affect millions of people, including
schizophrenia, Parkinson’s disease (PD), and depression. Non-luminance mediated changes in pupil size have
been known to co-vary with mental processing underlying behavior for decades. Recent work highlighted that
pupil dynamics were able to track rapid fluctuation of cortical arousal state. Therefore, change in pupil size
under constant illumination has been widely used as a non-invasive readout of the activation of certain central
arousal circuits related to pupil size, and thus is used to index pupil-linked arousal. Atypical pupil dynamics
have been reported in the aforementioned neurological disorders. However, the neural circuits that mediate
pupil-linked arousal remain unclear. The proposed project will test our central hypothesis: the cholinergic
systems mediate pupil-linked arousal, in addition to the LC-NE system. Using a synthesis of optogenetic
stimulation, genetic manipulation, and calcium imaging, we will test this hypothesis in two Aims. Aim 1 will
determine the causal link between activation of the cholinergic systems and pupil size. Aim 2 will examine the
extent to which cholinergic activity can be tracked by pupil size. This project will provide much-needed insight
about the extent to which the cholinergic systems contribute to pupil-linked arousal. Such information is
essential to rigorous and accurate interpretation of results from numerous studies using pupillometry, which is
increasingly popularly used in cognitive neuroscience and psychiatry.