EXPLORING THE DRIVERS OF NORADRENERGIC RELEASE IN ASSOCIATIVE, CEREBELLAR-DEPENDENT LEARNING

Abstract

Delay eyeblink conditioning (EBC) is a well-established paradigm used to study associative, cerebellar-dependent learning. Behavioral states, such as locomotion, have been shown to profoundly modulate performance in EBC. Additionally, the neuromodulator norepinephrine (NE) plays an important role in modulating the acquisition of learning in EBC and is also known to be released during behavioral states and sensory novelty. To this date, no research has examined the simultaneous role of sensory-novelty and locomotion in driving enhanced learning during EBC. Using CS pre-exposure (latent inhibition (LI) paradigm) to knockdown sensory novelty and learning, I sought to rescue these effects by subjecting mice to undergo forcedlocomotion during subsequent EBC training sessions. Fixed locomotor speed in head-fixed mice drove enhanced learning, earlier onset and increases in learned responses, during EBC. However, forced-locomotion was not sufficient to rescue the effects of LI. Fiberphotometry experiments in head-fixed freely-locomoting mice during EBC directly measured GCaMP fluorescence (GCaMPf) in locus coeruleus (LC) axon terminals in the deep cerebellar nuclei, serving as a proxy for NE release in the cerebellum. Indeed, increases in GCaMPf were larger and more frequent during earlier in CS-US and CS-only sessions of EBC. Levels of locomotion and locomotive speed across sessions also increased. GCaMPf signal amplitude during the conditioned response window was negatively correlated with locomotion across sessions and significantly correlated during sessions in which the animal began to develop a CR. Taken together, these results suggest that locomotion and sensory novelty differentially modulate information processing in LC target of deep cerebellar nuclei and associative motor learning.