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Disynaptic inhibitory cerebellar control over caudal medial accessory olive

Research group De Zeeuw
Publication year 2024
Published in eNeuro
Authors Willem S van Hoogstraten, Marit C C Lute, Zhiqiang Liu, Robin Broersen, Luca Mangili, Lieke Kros, Zhenyu Gao, Xiaolu Wang, Arn M J M van den Maagdenberg, Chris I De Zeeuw

The olivocerebellar system, which is critical for sensorimotor performance and learning, functions through modules with feedback loops. The main feedback to the inferior olive comes from the cerebellar nuclei (CN), which are predominantly GABAergic and contralateral. However, for the d subnucleus of the caudomedial accessory olive (cdMAO), a crucial region for oculomotor and upper-body movements, the source of GABAergic input has yet to be identified. Here, we demonstrate the existence of a disynaptic inhibitory projection from the medial CN (MCN) to the cdMAO via the superior colliculus (SC) by exploiting retrograde, anterograde and transsynaptic viral tracing at the light microscopic level as well as anterograde classical and viral tracing combined with immunocytochemistry at the electron microscopic level. Retrograde tracing in Gad2-Cre mice reveals that the cdMAO receives GABAergic input from the contralateral SC. Anterograde transsynaptic tracing uncovered that the SC neurons receiving input from the contralateral MCN provide predominantly inhibitory projections to contralateral cdMAO, ipsilateral to the MCN. Following ultrastructural analysis of the monosynaptic projection about half of the SC terminals within the contralateral cdMAO are GABAergic. The disynaptic GABAergic projection from the MCN to the ipsilateral cdMAO mirrors that of the monosynaptic excitatory projection from the MCN to the contralateral cdMAO. Thus, while completing the map of inhibitory inputs to the olivary subnuclei, we established that the MCN inhibits the cdMAO via the contralateral SC, highlighting a potential push-pull mechanism in directional gaze control that appears unique in terms of laterality and polarity among olivocerebellar modules.Significance Statement All dendritic spines of the inferior olive receive a combined inhibitory and excitatory input, which is critical for regulation of temporal control during sensorimotor coordination. Yet, some sources of GABAergic input to specific parts of the olive remain to be identified. While completing the map of inhibitory inputs, we establish here that part of the caudal medial accessory olive receives a GABAergic input from neurons in the contralateral superior colliculus that receive a direct input from the cerebellar nuclei. Interestingly, the laterality of this disynaptic projection is unique among olivocerebellar modules, highlighting a potential push-pull mechanism in directional gaze control.

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