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. 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 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.