Long-Lasting Response Changes in Deep Cerebellar Nuclei in vivo Correlate With Low-Frequency Oscillations

Abstract

The deep cerebellar nuclei (DCN) have been suggested to play a critical role in sensorimotor learning and some forms of long-term synaptic plasticity observed in vitro have been proposed as a possible substrate. However, till now it was not clear whether and how DCN neuron responses manifest long-lasting changes in vivo. Here, we have characterized DCN unit responses to tactile stimulation of the facial area in anesthetized mice and evaluated the changes induced by theta-sensory stimulation (TSS), a 4 Hz stimulation pattern that is known to induce plasticity in the cerebellar cortex in vivo. DCN units responded to tactile stimulation generating bursts and pauses, which reflected combinations of excitatory inputs most likely relayed by mossy fiber collaterals, inhibitory inputs relayed by Purkinje cells, and intrinsic rebound firing. Interestingly, initial bursts and pauses were often followed by stimulus-induced oscillations in the peri-stimulus time histograms (PSTH). TSS induced long-lasting changes in DCN unit responses. Spike-related potentiation and suppression (SR-P and SR-S), either in units initiating the response with bursts or pauses, were correlated with stimulus-induced oscillations. Fitting with resonant functions suggested the existence of peaks in the theta-band (burst SR-P at 9 Hz, pause SR-S at 5 Hz). Optogenetic stimulation of the cerebellar cortex altered stimulus-induced oscillations suggesting that Purkinje cells play a critical role in the circuits controlling DCN oscillations and plasticity. This observation complements those reported before on the granular and molecular layers supporting the generation of multiple distributed plasticities in the cerebellum following naturally patterned sensory entrainment. The unique dependency of DCN plasticity on circuit oscillations discloses a potential relationship between cerebellar learning and activity patterns generated in the cerebellar network.

The Optogenetic Revolution in Cerebellar Investigations

“…The authors comment that these apparent contradictory results can arise from the fact that parvalbumin is also expressed in molecular layer interneurons, and that the net effect on DCN is therefore difficult to infer. This is in agreement with a recent report using a pan-neuronal promoter for ChR2 expression in the cerebellar molecular layer while recording from the DCN, showing the mixed effect of light activation likely depending on the prevalent effect of direct activation of PCs or inhibition through molecular layer interneurons [159]. Krook-Magnuson and colleagues further exploited optogenetic specificity by replicating their key findings in a mouse line expressing ChR2 selectively in PCs.…”

Response Dynamics in an Olivocerebellar Spiking Neural Network With Non-linear Neuron Properties

“…The main observation in this study is that neuron models with realistic non-linear properties EGLIF (Geminiani et al, 2018b, 2019), once embedded into networks with realistic geometry and connectivity (Casali et al, 2019), have a significant impact on ensemble response dynamics compared to simpler models (LIF). The effectiveness of EGLIF emerged as a pattern of burst-pause and pause-burst responses in PC and DCNp neurons reproducing observations in vivo (Herzfeld et al, 2015; Moscato et al, 2019) and was most evident when the microcomplex received the CF stimuli. Since we used stimulus patterns emulating those occurring in the eye-blink reflex, it is anticipated that single neuron properties will reverberate on sensorimotor control in closed-loop.…”

“…The burst-pause was the consequence of intrinsic PC non-linear electroresponsive dynamics engaged by patterned synaptic inputs from PFs, MLIs, and IO (Jirenhed et al, 2013). Always in EGLIF-SNN simulations, DCNp neurons showed pause-burst responses deriving from intrinsic DCNp neuron electroresponsiveness engaged by synaptic inputs from PCs, MF and CF collaterals (Herzfeld et al, 2015; Moscato et al, 2019). Indeed, these spiking patterns proved to have a crucial impact on response speed and time precision (Figure 8) providing a potential advantage for cerebellum-driven tasks, in which the cerebellum acts as a millisecond-precise controller (Bareš et al, 2019; Heck et al, 2013).…”

Stellate cell computational modelling predicts signal filtering in the molecular layer circuit of cerebellum

“…It is thus probable that SC pacing reflected intrinsic electroresponsive properties since, in our recordings, GABAergic inputs were blocked pharmacologically. When stimulated with positive or negative currents, SCs showed burst-pause or pause-burst responses resembling those of other cerebellar neurons, comprising PCs (De Zeeuw et al, 2011;, Golgi cells (Forti et al, 2006;Solinas et al, 2007b, a) and deep nuclear cells (Dykstra et al, 2016;Moscato et al, 2019).…”