Peptidergic Neuromodulation of the Cerebellum

ABSTRACT The cerebellum is involved in refining motor and cognitive-affective processes in diverse complex behaviors that engage neuromodulatory systems. However, how neuromodulation dynamically adapts cerebellar processing to the ever-changing demands of physiological state and behavioral context remains a critical

knowledge gap. Especially the mechanisms of peptidergic neuromodulation remain elusive because slow- acting signals were long thought to play a minor role in cerebellar function. However, recent large-scale gene expression studies revealed a wealth of neuropeptide receptor types in the mouse cerebellar cortex,

suggesting that they may have a profound impact on cerebellar processing. Among those receptors, we identified receptors for oxytocin, a highly conserved neuropeptide associated with diverse social behaviors. We, therefore, hypothesize that the cerebellum is part of the oxytocin-sensitive brain networks that facilitate

social behavior in specific physiological contexts. The goal of this proposal is to elucidate the fundamental cellular and circuit mechanisms by which oxytocin regulates cerebellar processing. The cerebellar cortex is composed of three layers and relatively few cell types. Synaptic input from sensory and higher-order brain

areas arrives via mossy fibers that are integrated in granule cells of the input layer. Granule cell axons then excite interneurons and the cerebellar cortical output neurons, the Purkinje cells. The excitability of granule cells critically depends on inhibition provided by Golgi interneurons. Our initial findings suggest that oxytocin

robustly excites Golgi interneurons, leading to an increased inhibitory tone in the input layer. We propose that this mechanism dynamically regulates granule cell excitability, the integration of mossy fiber input, and ultimately Purkinje cell output. To test these hypotheses, we first aim to determine the types and distribution of

oxytocin-binding receptors across the cerebellar cortex and investigate the effects of oxytocin on neuronal activity and synaptic transmission. We will then examine the circuit mechanisms that underlie the remarkably robust Golgi cell network excitation by oxytocin. Finally, we aim to better understand the effects of oxytocin on

cerebellar cortical oscillations and Purkinje cell output in awake behaving mice. Our study will establish the cerebellum as an oxytocin-sensitive brain region and form the basis for investigating how peptidergic neuromodulation reconfigures cerebellar output to control behavior, potentially bridging the gap between the

cognitive-affective and motor effects of oxytocin in affiliative behaviors. These findings might be relevant for numerous neurodevelopmental, psychiatric, and neurological disorders characterized by impairments in both the social communication and motor domains.