Bidirectional Modulation of Beam Traversal Performance by Acetylcholine in the Cerebellar Nuclei

Abstract

The cerebellum plays a key role in coordinating balance and movement control. Most studies of cerebellar function focus on the role of cerebellar glutamatergic inputs; thus, the roles of neuromodulatory inputs remain unexplored. We sought to determine whether the cholinergic projections from the Pedunculopontine tegmental nucleus (PPN) to the interpositus nuclei of the cerebellum are involved in modulating performance of a beam traversal task in rats. We manipulated cholinergic signaling in the cerebellum using chemogenetic and pharmacological methods. Experiments were conducted in male rats, except for studies specifically targeting PPN cholinergic neurons, which included rats of both sexes. Chemogenetic inhibition of either a mixed population of projections from the PPN to interpositus nuclei or specific inhibition of cholinergic PPN projections improved balance and foot placement on the beam traversal task. This effect is likely mediated by nicotinic receptors, as infusion of the nicotinic receptor antagonist mecamylamine improved balance and foot placement accuracy. In contrast, enhancing cholinergic signaling using the cholinesterase inhibitor physostigmine reduced accuracy of foot placement. Surprisingly, infusion of muscarinic receptor antagonists mimicked the effect of cholinesterase inhibition leading to impaired motor performance. We investigated the cellular effects of cholinergic receptor activation using adult rat cerebellar slices. Interpositus nuclear neurons exhibited decreased intrinsic excitability and reduced responsivity to synaptic inputs in the presence of a cholinergic agonist. Together, our findings indicate that low levels of acetylcholine in the cerebellar interpositus are optimal for performance on the beam traversal task, while enhancing cholinergic signaling decreases interpositus excitability and impairs task performance.