Neuromodulator recruitment during listening and learning in mice and humans.

Abstract

Auditory learning is facilitated by adaptive plasticity in auditory cortex circuits that supports more efficient, reliable, and accurate representation of behaviorally relevant acoustic features. Plasticity in the adult auditory cortex is critically enabled by acetylcholine release from neurons in the basal forebrain. Because of its role in regulating cortical plasticity, the basal forebrain is a promising target for therapies aiming at reshaping sensory encoding. However, our understanding of this structure has been hampered by the technical difficulties of performing targeted recordings of a deep brain area. The overarching goal of this dissertation is to further investigate the role of the cholinergic basal forebrain in sensory learning, and to explore neuromodulatory recruitment during perceptual training. We leveraged the optical tools available in mice to perform genetically targeted fiber imaging from cholinergic cells of the basal forebrain. First, we recorded activity in the horizontal diagonal band of Broca (HDB) and globus pallidus/substantia innominata (GP/SI) throughout an extended auditory learning paradigm. Our results revealed diverse responses to sensory cues and behavioral reinforcers, and they demonstrated the existence of functional specialization within the basal forebrain. Next, we addressed how cholinergic activity participates in auditory fear learning when a long gap separates the auditory cue from the reinforcer. In freely moving mice, imaging of activity in the caudal tail of the basal forebrain revealed a selective potentiation of the cholinergic response to the conditioned tone and the emergence of sustained cholinergic activity bridging the gap. Finally, we used pupillometry as a proxy for neuromodulatory activity and task engagement in human subjects to assess the potential of using an interactive audiomotor game as a platform for non-invasive neurorehabilitation. We measured pupil fluctuations in subjects playing a custom game before and after extended home-based practice, and we explored how training shaped pupil dynamics. We reported robust and long-lasting dilations indicating that the game promoted sustained periods of high engagement. Together, the results presented herein advance our fundamental understanding of the cholinergic basal forebrain and establish a groundwork for the development of non-invasive therapies that leverage pupil fluctuations to identify moments of heightened auditory brain plasticity.