Purkinje cells translate subjective salience into readiness to act and choice performance

Bina, Lorenzo; Romano, Vincenzo; Hoogland, Tycho M.; Bosman, Laurens W. J.; Zeeuw, Chris I. De

doi:10.1016/j.celrep.2022.110362

Cited by 6 publications

(7 citation statements)

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“…The eyeblink reflex, for instance, is not just an isolated contraction of the eyelid muscles, but part of a defensive reflex involving the whole face, or maybe even the entire body [ 11 ]. These findings are in agreement with the notion of the cerebellum as a coordinating area for most, if not all, complex motor as well as non-motor functions [ 5 , 8 , 12 , 13 ].…”

Section: Introductionsupporting

confidence: 91%

“…Given the widespread projections, it is quite striking that most brainstem motor nuclei do not receive direct input from the cerebellum, or only sparse projections. This could be in line with modulatory and coordinating roles, rather than with direct motor control [ 12 ]. The study of these projections in diseases has just begun, but it is already clear that various diseases implicate variations in connectivity between the cerebellum and the rest of the brain.…”

Section: Discussionmentioning

confidence: 97%

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A Systematic Review of Direct Outputs from the Cerebellum to the Brainstem and Diencephalon in Mammals

2022

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The cerebellum is involved in many motor, autonomic and cognitive functions, and new tasks that have a cerebellar contribution are discovered on a regular basis. Simultaneously, our insight into the functional compartmentalization of the cerebellum has markedly improved. Additionally, studies on cerebellar output pathways have seen a renaissance due to the development of viral tracing techniques. To create an overview of the current state of our understanding of cerebellar efferents, we undertook a systematic review of all studies on monosynaptic projections from the cerebellum to the brainstem and the diencephalon in mammals. This revealed that important projections from the cerebellum, to the motor nuclei, cerebral cortex, and basal ganglia, are predominantly di- or polysynaptic, rather than monosynaptic. Strikingly, most target areas receive cerebellar input from all three cerebellar nuclei, showing a convergence of cerebellar information at the output level. Overall, there appeared to be a large level of agreement between studies on different species as well as on the use of different types of neural tracers, making the emerging picture of the cerebellar output areas a solid one. Finally, we discuss how this cerebellar output network is affected by a range of diseases and syndromes, with also non-cerebellar diseases having impact on cerebellar output areas.

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Section: Introductionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 97%

A Systematic Review of Direct Outputs from the Cerebellum to the Brainstem and Diencephalon in Mammals

2022

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“…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 combined inhibitory and excitatory input to dendritic spines in the IO facilitates its neurons to fine-tune the timing of its climbing fiber activity ( Loyola et al, 2023 ), allowing for precise control of online motor performance ( Welsh et al, 1995 ; Van Der Giessen et al, 2008 ; Hoogland et al, 2015 ) and long-term adjustments ( Gao et al, 2012 ; Kostadinov et al, 2019 ; Bina et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Disynaptic Inhibitory Cerebellar Control Over Caudal Medial Accessory Olive

van Hoogstraten,

Lute,

Liu

et al. 2024

eNeuro

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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 StatementAll 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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“…Activation of the climbing fiber terminals elicits both short-term and long-term effects ( De Zeeuw et al, 2011 ). In the short-term, it evokes powerful, all-or-none, depolarizations in Purkinje cells also known as complex spikes ( Thach, 1967 ); increases in complex spike activity within cerebellar microzones can facilitate reflex-like movements, such as fast reactive limb movements following a perturbation ( De Gruijl et al, 2014a ; Hoogland et al, 2015 ), but when occurring in more widespread ensembles they also mediate more demanding forms of motor behavior, such as skilled sequences of contractions of tongue muscles upon presentation of specific sensory cues ( Welsh et al, 1995 ; Bina et al, 2022 ; Romano et al, 2022 ). In the more long term, modulation of climbing fiber activity facilitates the induction of various forms of pre- and postsynaptic plasticity at most, if not all, parallel fiber synapses onto interneurons and Purkinje cells in the molecular layer of the cerebellar cortex ( Gao et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

“…In the more long term, modulation of climbing fiber activity facilitates the induction of various forms of pre- and postsynaptic plasticity at most, if not all, parallel fiber synapses onto interneurons and Purkinje cells in the molecular layer of the cerebellar cortex ( Gao et al, 2012 ). Due to the fact that these different subcellular effects occur in a synergistic fashion in that they ultimately converge into either a downbound or upbound impact on simple spike activity in the Purkinje cells ( De Zeeuw, 2021 ), climbing fibers are also prominently implicated in cerebellar learning ( Ito and Kano, 1982 ; Raymond and Lisberger, 1998 ; Safo and Regehr, 2008 ; ten Brinke et al, 2015 and ten Brinke et al, 2019 ; Gutierrez-Castellanos et al, 2017 ; Boele et al, 2018 ; Bina et al, 2022 ; Romano et al, 2018 ). For both the short-term and long-term effects in the cerebellar cortex the precise timing of the climbing fiber activation is crucial.…”

Section: Introductionmentioning

confidence: 99%

How inhibitory and excitatory inputs gate output of the inferior olive

Loyola

Hoogland

Hoedemaker

et al. 2023

eLife

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The inferior olive provides the climbing fibers to Purkinje cells in the cerebellar cortex, where they elicit all-or-none complex spikes and control major forms of plasticity. Given their important role in both short-term and long-term coordination of cerebellum-dependent behaviors, it is paramount to understand the factors that determine the output of olivary neurons. Here, we use mouse models to investigate how the inhibitory and excitatory inputs to the olivary neurons interact with each other, generating spiking patterns of olivary neurons that align with their intrinsic oscillations. Using dual color optogenetic stimulation and whole-cell recordings, we demonstrate how intervals between the inhibitory input from the cerebellar nuclei and excitatory input from the mesodiencephalic junction affect phase and gain of the olivary output at both the sub- and suprathreshold level. When the excitatory input is activated shortly (~50 ms) after the inhibitory input, the phase of the intrinsic oscillations becomes remarkably unstable and the excitatory input can hardly generate any olivary spike. Instead, when the excitatory input is activated one cycle (~150 ms) after the inhibitory input, the excitatory input can optimally drive olivary spiking, riding on top of the first cycle of the subthreshold oscillations that have been powerfully reset by the preceding inhibitory input. Simulations of a large-scale network model of the inferior olive highlight to what extent the synaptic interactions penetrate in the neuropil, generating quasi-oscillatory spiking patterns in large parts of the olivary subnuclei, the size of which also depends on the relative timing of the inhibitory and excitatory inputs.

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Purkinje cells translate subjective salience into readiness to act and choice performance

Abstract: In the originally published version of this article, Figure 5E contained a mistake in the explanation of the symbols, with the colored square erroneously labeled as "Fig. 6" as opposed to the correct "Fig.

Cited by 6 publications

References 0 publications

A Systematic Review of Direct Outputs from the Cerebellum to the Brainstem and Diencephalon in Mammals

A Systematic Review of Direct Outputs from the Cerebellum to the Brainstem and Diencephalon in Mammals

Disynaptic Inhibitory Cerebellar Control Over Caudal Medial Accessory Olive

How inhibitory and excitatory inputs gate output of the inferior olive

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