Dynamic modulation of activity in cerebellar nuclei neurons during pavlovian eyeblink conditioning in mice

Brinke, Michiel M. ten; Heiney, Shane A.; Wang, Xiaolu; Onori, Martina Proietti; Boele, Henk−Jan; Bakermans, Jacob J. W.; Medina, Javier F.; Gao, Zhenyu; Zeeuw, Chris I. De

doi:10.7554/elife.28132

Cited by 109 publications

(176 citation statements)

References 92 publications

(181 reference statements)

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“…The inferior olive is the sole source of the climbing fibers, the activity of which dictates complex spike firing by cerebellar Purkinje cells (for review, see (20)). Climbing fiber activity is essential for motor coordination, as it contributes to both initiation and learning of movements (8, 10, 21–26), and it may also be involved in sensory processing and regulating more cognitive tasks (27–30). Understanding the systemic consequences of inferior olivary spiking is therefore of great importance.…”

Section: Introductionmentioning

confidence: 99%

Quasiperiodic Rhythms of the Inferior Olive

Negrello

Warnaar

Romano

et al. 2018

Preprint

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Inferior olivary activity causes both short-term and long-term changes in cerebellar output underlying motor performance and motor learning. Many of its neurons engage in coherent subthreshold oscillations and are extensively coupled via gap junctions. Studies in reduced preparations suggest that these properties promote rhythmic, synchronized output. However, how these properties interact with synaptic inputs controlling inferior olivary output in intact, awake behaving animals is poorly understood. Here we combine electrophysiological recordings in awake mice with a novel and realistic tissue-scale computational model of the inferior olive to study the relative impact of intrinsic and extrinsic mechanisms governing its activity. Our data and model suggest that if subthreshold oscillations are present in the awake state, the period of these oscillations will be transient and variable. Accordingly, by using different temporal patterns of sensory stimulation, we found that complex spike rhythmicity was readily evoked but limited to short intervals of no more than a few hundred milliseconds and that the periodicity of this rhythmic activity was not fixed but dynamically related to the synaptic input to the inferior olive as well as to motor output. In contrast, in the long-term the average olivary spiking activity was not affected by the strength and duration of the sensory stimulation, while the level of gap junctional coupling determined the stiffness of the rhythmic activity in the olivary network during its dynamic response to sensory modulation. Thus, interactions between intrinsic properties and extrinsic inputs can explain the variations of spiking activity of olivary neurons, providing a conceptual framework for the creation of both the short-term and long-term changes in cerebellar output. AUTHOR SUMMARY Activity of the inferior olive, transmitted via climbing fibers to the cerebellum, regulates initiation and amplitude of movements, signals unexpected sensory feedback, and directs cerebellar learning. It is characterized by widespread subthreshold oscillations and synchronization promoted by strong electrotonic coupling. In brain slices, subthreshold oscillations gate which inputs can be transmitted by inferior olivary neurons and which will not - dependent on the phase of the oscillation. In our study, we tested whether the subthreshold oscillations had a measurable impact on temporal patterning of climbing fiber activity in intact, awake mice. We did so by recording neural activity of the postsynaptic Purkinje cells, in which complex spike firing faithfully represents climbing fiber activity. For short intervals (<300 ms), we found that many Purkinje cells indeed showed spontaneously rhythmic complex spike activity. However, our experiments designed to evoke resonant responses indicated that complex spikes are not predominantly predicated on stimulus history. Our realistic network model of the inferior olive explains the experimental observations via continuous phase modulations of the subthre...

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Section: Introductionmentioning

confidence: 99%

Quasiperiodic Rhythms of the Inferior Olive

Negrello

Warnaar

Romano

et al. 2018

Preprint

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“…From this perspective, spike coding from thalamus to motor cortex is depending on recovery from synaptic depression during a pause in high-frequency CN spiking. Such pauses are found during several behavioral paradigms (Ohmae et al 2013;Ten Brinke et al 2017). For instance, during natural running on a treadmill the CN firing rate rises above 100 Hz during the lift of the paw and decreases sharply during the 100 ms before paw movement (Sarnaik and Raman 2018).…”

Section: Discussionmentioning

confidence: 97%

Cerebello-Thalamic Spike Transfer via Temporal Coding and Cortical Adaptation

Schäfer

Gao

Zeeuw

et al. 2020

Preprint

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Orchestrating the ensemble of muscle contractions necessary for coordinated movements requires the interaction of cerebellar, thalamic and cerebral structures, but the mechanisms underlying the integration of information remain largely unknown. Here we investigated how excitatory inputs from cerebellar nuclei (CN) and primary motor cortex layer VI (M1 L6) neurons may regulate together the activity of neurons in the mouse ventrolateral (VL) thalamus. Using dual-optogenetic stimulation and whole-cell recordings in vitro we were able to specifically activate the CN and M1 pathways and study their differential impact. We found that VL spiking probability is effectively determined by a pause in CN stimuli, whereas VL membrane potential can be modulated subthreshold by M1 L6 input. Upon mild depolarization of the VL membrane potential, repetitive CN stimulation evokes at best single action potential firing, whereas more negative membrane potentials increase VL spiking probability. Moreover, whereas high-frequency cerebellar activity attenuates thalamic spiking, pauses in cerebellar activity re-activate thalamic spiking. In contrast, facilitating inputs from cerebral cortex modulate thalamo-cortical spike transfer via fluctuations in the membrane potential. The fine-tuning by cerebellar and cerebral activity allows the motor thalamus to operate as a low-pass filter for cerebellar activity, generating sparse but precisely timed outputs for the cerebral cortex.

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“…It is well-established that the cerebellum plays a key role in motor control and coordination (Stoodley and Schmahmann, 2010). More recent studies have suggested that it can also encode expectation for sensory outcomes (Brinke et al, 2017;Sawtell, 2017;Wagner et al, 2017) as well as that its activity is necessary to maintain cortical preparatory activity in motor planning (Gao et al, 2018). Thus, given our above observations on the pre-motor decision-dependent dPCs of the cerebellum and ARTR, we hypothesize that they may represent preparatory neuroactivity for motor response, similar to what has been reported in the cortex (Churchland et al, 2012;Gao et al, 2018;Li et al, 2016).…”

Section: Preparatory Neuroactivity In Cerebellum and Artr Predict Decmentioning

confidence: 99%

Cerebellar neurodynamics during motor planning predict decision timing and outcome on single-trial level

Lin

Helmreich

Schlumm

et al. 2019

Preprint

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The neuronal basis of goal-directed behavior requires interaction of multiple separated brain regions. How subcortical regions and their interactions with brain-wide activity are involved in action selection is less understood. We have investigated this question by developing an assay based on whole-brain volumetric calcium imaging using light-field microscopy combined with an operant-conditioning task in larval zebrafish. We find global and recurring dynamics of brain states to exhibit pre-motor bifurcations towards mutually exclusive decision outcomes which arises from a spatially distributed network. Within this network the cerebellum shows a particularly strong pre-motor activity, predictive of both the timing and outcome of behavior up to ~10 seconds before movement initiation. Furthermore, on the single-trial level, decision directions can be inferred from the difference neuroactivity between the ipsilateral and contralateral hemispheres, while the decision time can be quantitatively predicted by the rate of bihemispheric population ramping activity. Our results point towards a cognitive role of the cerebellum and its importance in motor planning. KEYWORDSCerebellum, decision making, action selection, motor planning, whole-brain calcium imaging, population ramping activity, zebrafish Recurring brain state dynamics capture representation of heat and show bifurcation for different behavioral outcomesVolumetric reconstruction of the LFM data (see also Movie S1), followed by neuronal signal extraction using our established data processing pipeline (Prevedel et al., 2014), allowed us to obtain neuronal activity traces from ~5000 of the most active neurons across the entire brain. Figure 2 shows the data for an example

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Dynamic modulation of activity in cerebellar nuclei neurons during pavlovian eyeblink conditioning in mice

Cited by 109 publications

References 92 publications

Quasiperiodic Rhythms of the Inferior Olive

Quasiperiodic Rhythms of the Inferior Olive

Cerebello-Thalamic Spike Transfer via Temporal Coding and Cortical Adaptation

Cerebellar neurodynamics during motor planning predict decision timing and outcome on single-trial level

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