Quasiperiodic Rhythms of the Inferior Olive

Abstract

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...

Oculopalatal tremor following sequential medullary infarcts that did not cause hypertrophic olivary degeneration

“…The amplitude spectra shown in the lower three graphs are the distributions of X, Y and X root mean square angular velocity distributed over frequency (Hz). The spectra demonstrate a finely tuned oscillation at 2.4 Hz tremor exclusively stems from abnormal olivary hypersynchrony, but these data are compatible with the hypothesis that the olivocerebellar pathway normally functions to suppress abnormal or latent rhythmicity (e.g., myorhythmia) in brainstem networks [2,[17][18][19]. Recordings from unanesthetized monkeys and mice suggest that the normal olivocerebellar pathway is resistant to sustained oscillation, and the putative role of olivary oscillation in tremor is based on the questionablyrelevant harmaline model and has no direct experimental support [20].…”

Complex spike firing adapts to saliency of inputs and engages readiness to act

“…As a consequence, these Purkinje cells can set the stage for welltimed, context-dependent behavior, engaging a readiness to act, but without being indispensable for acute motor execution, nor being restricted to reward expectation. Together, in line with the periodic operations of neurons in the inferior olive (Negrello et al, 2019), our findings highlight how climbing fiber signaling in the olivocerebellar system may set the pace when coordinating non-motor with motor functions.…”

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

“…Thus, although anatomical and functional data support the microzonal organization, the activity patterns are best understood as produced dynamically depending on the behavioural context that is transmitted via cerebellar and extra‐cerebellar synaptic input (Negrello et al . ).…”

“…The overall firing rate of complex spikes was stable across conditions, with response peaks being compensated for by reduced inter‐trial firing (see also Negrello et al . ). The stronger the response peak, the less inter‐trial firing, leading to homeostasis of complex spike firing over longer time periods.…”

“…; Negrello et al . ). To date, the paradox between the persistence of complex spike firing and the behavioural relevance of individual complex spikes remains largely unresolved.…”