Electrophysiological properties of mesodiencephalic junction neurons projecting to the inferior olive

Abstract

The neocortex has the largest volume, whereas the cerebellum houses the most neurons of the mammalian brain, underscoring paramount functions for interactions between them. Neocortical projections to the cerebellum involve both the mossy fibre and climbing fibre systems; mossy fibres find their origin predominantly in the pons, whereas the climbing fibres are relayed via subnuclei of the inferior olive (IO) that receive cortical input via the mesodiencephalic junction (MDJ). Given that climbing fibres regulate cerebellar plasticity in a timing-dependent manner, the MDJ-IO pathway probably contributes to both sensorimotor and cognitive learning. However, the physiological properties of IO-projecting MDJ neurons remain largely unknown. Here, we made targeted whole-cell recordings in brain slices of the mouse MDJ, separating IO- from non-IO-projecting neurons following retrograde tracing. We show that IO-projecting neurons are, unlike non-IO-projecting neurons, highly spontaneously active and capable of high-frequency bursts of ≤350 Hz during current injections. Optogenetic stimulation shows that excitatory neocortical inputs to IO-projecting MDJ neurons can be integrated directly with excitatory inputs from the cerebellar nuclei. Moreover, unlike non-IO-projecting neurons, IO-projecting MDJ neurons depolarize and repolarize quickly, and hyperpolarizing inputs consistently trigger rebound action potentials upon stimulus offset. This hyperpolarization is probably induced predominantly by inhibitory inputs from the ventral tegmental area and periaqueductal grey, which provide prominent bilateral inputs to MDJ neurons, as revealed by viral tracing in Gad2-Cre mice. Our results highlight how neocortical inputs to the MDJ can be transformed into diverse IO firing patterns and thereby contribute to the required specifics of cerebellar learning. KEY POINTS: The mesodiencephalic junction is an important brainstem region connecting the cerebral cortex with the cerebellum through its projection to the inferior olive, the sole source of the climbing fibres that drive cerebellar learning. We find that mesodiencephalic junction neurons projecting to the inferior olive represent a population of physiologically distinct neurons, capable of high firing frequencies and rebound activity following hyperpolarization. We reveal that mesodiencephalic junction neurons receive prominent excitatory inputs from neocortex and cerebellar nuclei, whereas their main inhibitory inputs are derived from the ventral tegmental area and periaqueductal grey. These findings shed light on how the activity of neurons in the mesodiencephalic junction can be regulated and how these neurons might influence activity in the inferior olive, and thereby cerebellar learning.

The authors' abstract, as published at the source. The Journal of Physiology, 2026 · DOI ↗