CLIMBING FIBER INSTRUCTIVE SIGNALS FOR LOCOMOTOR LEARNING

The cerebellum plays a critical role in learning and adapting movements, which is essential for interacting with continuously changing environments. For simple tasks like eyeblink classical conditioning, climbing fibers originating in the inferior olive and projecting to the cerebellum provide necessary and sufficient instructive signals for learning (Silva et al., 2024). For complex whole-body behaviors like locomotion, however, the role of climbing fibers is not known. Locomotor learning can be studied on a split-belt treadmill, where the speed under each side of the body can be controlled independently. We recently demonstrated that in mice, as in humans, split-belt adaptation is cerebellum-dependent and reflects learned changes in interlimb symmetry (Darmohray et al., 2019), but the nature of the neural instructive signals driving this form of learning is still unclear.

Here, we use genetic circuit dissection, closed-loop optogenetics and electrophysiology to investigate whether and how climbing fibers provide instructive signals for locomotor learning. We show that: 1) Climbing fibers are necessary for rapid, learned changes in interlimb temporal symmetry during split-belt adaptation. 2) Unilateral optogenetic climbing fiber perturbations, precisely time-locked to specific phases of the locomotor cycle, can abolish or enhance split-belt adaptation, depending on the phase of the locomotor cycle in which they occur. 3) Even in the absence of imposed asymmetries, the same optogenetic manipulations are sufficient to drive bidirectional, learned changes in interlimb symmetry.

These results reveal powerful climbing fiber control of interlimb coordination and its adaptation to external perturbations, opening the door to potential neurotherapeutics for gait asymmetries.