Excitatory nucleo-olivary pathway shapes cerebellar outputs for motor control

Abstract

The brain generates predictive motor commands to control the spatiotemporal precision of high-velocity movements. Yet, how the brain organizes automated internal feedback to coordinate the kinematics of such fast movements is unclear. Here we unveil a unique nucleo-olivary loop in the cerebellum and its involvement in coordinating high-velocity movements. Activating the excitatory nucleo-olivary pathway induces well-timed internal feedback complex spike signals in Purkinje cells to shape cerebellar outputs. Anatomical tracing reveals extensive axonal collaterals from the excitatory nucleo-olivary neurons to downstream motor regions, supporting integration of motor output and internal feedback signals within the cerebellum. This pathway directly drives saccades and head movements with a converging direction, while curtailing their amplitude and velocity via the powerful internal feedback mechanism. Our finding challenges the long-standing dogma that the cerebellum inhibits the inferior olivary pathway and provides a new circuit mechanism for the cerebellar control of high-velocity movements.

Disynaptic Inhibitory Cerebellar Control Over Caudal Medial Accessory Olive

“…Interestingly, although the direct MCN-cdMAO projection ( Wang et al, 2023 ) follows the modular closed circuit organization of the nucleo-olivary projections ( Ruigrok and Voogd, 1990 ), it comprises excitatory glutamatergic synapses, contrary to the usual GABAergic nucleo-olivary projections. This stresses the relevance of the currently described MCN-SC-IO pathway targeting the ipsilateral cdMAO, hereby complementing the direct excitatory projection from the MCN to the contralateral cdMAO ( Wang et al, 2023 ) with an, in effect, ipsilateral inhibition ( Fig. 6 A ).…”

“…Taken together, the SC neurons receiving input from the MCN appear to have a rather prominent and specific GABAergic projection to the cdMAO, not extending into the surrounding IO subnuclei (Fig. 3F) and thereby mirroring the direct excitatory projection from MCN to cdMAO that comes from the other side (Wang et al, 2023). In contrast, LCN cells target both the GABAergic pathway from SC to cdMAO and a parallel non-GABAergic, potentially excitatory, pathway from SC to cdMAO and ccMAO.…”

“…More specifically, in line with the recent dissection of the connections within the olivocerebellar system ( Fujita et al, 2020 ), this excitatory projection ends up in the subnucleus d of the cMAO (cdMAO). The reason for this exception to the norm of inhibitory CN-IO projections could be that the cdMAO is involved in control of directional saccade and upper body movements ( Wang et al, 2023 ), which may require feedback signals of opposite polarity. Given that all dendrites of all olivary neurons are studded with GABAergic terminals ( De Zeeuw et al, 1989 , 1990a , b ; Ruigrok et al, 1990 ) and that all olivary subnuclei receive a GABAergic input ( Nelson et al, 1989 ), the finding of the excitatory MCN projection to the cdMAO raises the question what the source is of GABAergic input to the cdMAO.…”

“…The main feedback pathway concerns the projection from CN to IO, which is predominantly GABAergic and contralateral (de Zeeuw et al, 1988;Fredette and Mugnaini, 1991;De Zeeuw et al, 1993;De Zeeuw et al, 1994a). However, a recent study has uncovered that the projection from the medial cerebellar nucleus (MCN) to the contralateral caudal Medial Accessory Olive (cMAO) is predominantly excitatory rather than inhibitory (Wang et al, 2023), which is an exception to the longstanding view that the CN can only inhibit the IO. More specifically, in line with the recent dissection of the connections within the olivocerebellar system (Fujita et al, 2020), this excitatory projection ends up in the subnucleus d of the cMAO (cdMAO).…”

Identification and organization of a postural anti-gravity module in the cerebellar vermis

“…The cerebellum is well-known to be organized in cortico-nuclear-olivo loop modules, each encompassing a subregion of the inferior olive (IO), which projects to a translobular parasagittal band of PCs via the climbing fibers (CFs), and to a subregion of the deep cerebellar nuclei (DCN) supposed to be interconnected in closed loops (Groenewegen and Voogd 1977; Groenewegen, Voogd, and Freedman 1979; Sugihara and Shinoda 2007; Sugihara 2011; Ruigrok 2011). How the DCN outputs relate functionally to this modular organization has been the subject of attention (Fujita, Kodama, and Du Lac 2020; Heiney, Wojaczynski, and Medina 2021; Wang et al 2023). Recently, specific regions of the brain that are related to several generic posture-motor functions were shown to receive projections from genetically identified subdivisions of the medial nucleus, which are also innervated by PCs of the vermis and the hemispheres (Fujita, Kodama, and Du Lac 2020).…”