Project Summary Noradrenergic and cholinergic mechanisms underlying pupil-linked arousal modulation of thalamic sensory processing 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 locus coeruleus-norepinephrine (LC-NE) system and the cholinergic system. Abnormal activity in the LC-NE and 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, changes in pupil size under constant illumination have been widely used as a non-invasive read out of the activation of certain central arousal circuits, and thus are used to index pupil-linked arousal. Atypical pupil dynamics have been reported in the aforementioned neurological disorders. However, the mechanisms underlying modulation of information processing in the brain by pupil-linked arousal remain little known. The proposed project will test our central hypothesis: pupil-linked arousal modulates thalamic sensory processing and perceptual behavior through both adrenergic and cholinergic receptors. We focus on the thalamus in this project because most information about the external world reaches the cerebral cortex through the thalamus, and the thalamus plays a critical role in gating information to the cortex. Using a synthesis of electrophysiology, genetic manipulations, and behavioral paradigms, we will test this hypothesis in three Aims. Aim 1 will focus on characterization of the extent to which thalamic sensory processing and its contribution to perception depend on pupil-linked arousal. Aim 2 will examine the extent to which norepinephrine and acetylcholine (ACh) dynamics in the thalamus can be tracked by pupil size. Aim 3 will develop cutting-edge genetic tools based on CRISPR/Cas9 + guide RNA technology to selectively knock out each subtype of adrenergic and cholinergic receptor in the thalamus. Further, we will characterize the role of each subtype of NE/Ach receptor in mediating pupil-linked arousal modulation of sensory processing and perceptual behavior. This project will provide much-needed insight about how the LC-NE and cholinergic systems contribute to pupil-linked arousal modulation of thalamic processing of sensory information and perception. Such information is essential to better understand neurological disorders in which abnormal thalamic activity and pupil dynamics have been reported.