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.
Highlights
Two functional aspects of the cerebellum, that have been emphasized in turn but proved hard to reconcile, are the pronounced oscillatory dynamics (Llinas, 1988) and the role in sensorimotor learning (Marr, 1969; Albus, 1971; Ito, 1972)
Single-unit responses to low frequency tactile stimulation (0.5 Hz) generated spike bursts and pauses modifying the basal discharge (Figure 1C) that were likely to reflect the neuronal response to excitatory and inhibitory synaptic inputs impinging onto deep cerebellar nuclei (DCN) neurons (Rowland and Jaeger, 2005, 2008)
Unique in the cerebellum among the other long-lasting changes observed in vivo (Roggeri et al, 2008; Gao et al, 2012; D’Angelo, 2014; D’Angelo et al, 2016a; Ramakrishnan et al, 2016), the DCN Spike-Related Potentiation (SR-P)/SR-S distributions were correlated to the stimulus-induced oscillation frequency of DCN units through Lorentzian functions peaking in the theta-frequency range, disclosing the complex nature of the underlying plasticity mechanisms
Summary
Two functional aspects of the cerebellum, that have been emphasized in turn but proved hard to reconcile, are the pronounced oscillatory dynamics (Llinas, 1988) and the role in sensorimotor learning (Marr, 1969; Albus, 1971; Ito, 1972). Multiple forms of plasticity have been reported in DCN synapses in vitro (Morishita and Sastry, 1996; Ouardouz and Sastry, 2000; Zhang et al, 2004; Zhang and Linden, 2006; Pugh and Raman, 2009) (reviewed in Hansel et al, 2001; Gao et al, 2012; D’Angelo, 2014; Mapelli et al, 2015; D’Angelo et al, 2016b) and have been proposed to play a critical role in animal associative behaviors by computational models (Medina and Mauk, 1999; Casellato et al, 2015; Antonietti et al, 2016; D’Angelo et al, 2016a). These connections form the basis for reverberating loops that have been predicted to sustain rebound excitation and oscillatory cycles (Llinas and Muhlethaler, 1988; Kistler and De Zeeuw, 2003; Marshall and Lang, 2004; Hoebeek et al, 2010; Witter et al, 2013)
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