Negrello, M. | Search bioRxiv

bioRxiv2018

Aperiodic Rhythms of the Inferior Olive

Inferior olivary activity causes both short-term and long-term changes in cerebellar output underlying motor adaptation and motor learning, respectively. 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 oscillations are present in the awake state, but that the period of subthreshold oscillations is variable, resulting in semi-periodic activity, which result in the high unpredictability of sensory-triggered complex spikes occurring in windows of opportunity lasting a few tens of milliseconds. To test the resonant properties of complex spike firing we used different temporal patterns of sensory stimulation in awake mice. Resonance was found to be limited to short intervals no more than a few hundred milliseconds, which could be explained by our network model to be a result of synaptic input to the inferior olive. The model also shows how gap junctional coupling stiffens the olivary network response to sensory modulation of complex spike rhythmicity. Interactions between intrinsic properties and extrinsic inputs can explain short-lasting semi- periodic variations of the spiking rhythms of olivary neurons even though their long-term average firing rate is stable, providing a conceptual framework for the creation of both the short-term and long-term changes in cerebellar output.\n\nAUTHOR SUMMARYActivity 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 set a temporal framework determining 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 any 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 clearly indicated that complex spikes are not predicated on stimulus history. Our realistic network model of the inferior olive explains the experimental findings via continuous phase modulations of the subthreshold oscillations. We conclude that inferior olivary activity is emerging from an aperiodic rhythm, stabilized by electrotonic coupling, and dependent on the behavioral context transmitted via synaptic input.

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bioRxiv2018

Neurons of the inferior olive respond to broad classes of sensory input while subject to homeostatic control

Cerebellar Purkinje cells integrate sensory information with motor efference copies to adapt movements to behavioural and environmental requirements. They produce complex spikes that are triggered by the activity of climbing fibres originating in neurons of the inferior olive. These complex spikes can shape the onset, amplitude and direction of movements as well as the adaptation of such movements to sensory feedback. Clusters of nearby inferior olive neurons project to parasagittally aligned stripes of Purkinje cells, referred to as "microzones". It is currently unclear to what extent individual Purkinje cells within a single microzone integrate climbing fibre inputs from multiple sources of different sensory origins, and to what extent sensory-evoked climbing fibre responses depend on the strength and recent history of activation. Here we imaged complex spike responses in cerebellar lobule crus 1 to various types of sensory stimulation in awake mice. We find that different sensory modalities and receptive fields have a mild, but consistent, tendency to converge on individual Purkinje cells. Purkinje cells encoding the same stimulus show increased events with coherent complex spike firing and tend to lie close together. Moreover, whereas complex spike firing is only mildly affected by variations in stimulus strength, it strongly depends on the recent history of climbing fibre activity. Our data point towards a mechanism in the olivo-cerebellar system that regulates complex spike firing during mono- or multisensory stimulation around a relatively low set-point, highlighting an integrative coding scheme of complex spike firing under homeostatic control.

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bioRxiv2018

Adaptation of Whisker Movements Requires Cerebellar Potentiation

Cerebellar plasticity underlies motor learning. However, how the cerebellum operates to enable learned changes in motor output is largely unknown. We developed a sensory-driven adaptation protocol for reflexive whisker protraction and recorded Purkinje cell activity from crus 1 and 2 of awake mice. Before training, simple spikes of individual Purkinje cells correlated during reflexive protraction with the whisker position without lead or lag. After training, simple spikes and whisker protractions were both enhanced with the spiking activity now leading the behavioral response. Neuronal and behavior changes did not occur in two cell-specific mouse models with impaired long-term potentiation at parallel fiber to Purkinje cell synapses. Consistent with cerebellar plasticity rules, increased simple spike activity was prominent in cells with low complex spike response probability. Thus, potentiation at parallel fiber to Purkinje cell synapses may contribute to reflex adaptation and enable expression of cerebellar learning through increases in simple spike activity.\n\nImpact statementRomano et al. show that expression of cerebellar whisker learning can be mediated by increases in simple spike activity, depending on LTP induction at parallel fiber to Purkinje cell synapses.

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