How inhibitory and excitatory inputs gate output of the inferior olive
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Inferior olivary neurons drive complex spiking activity in Purkinje neurons of the cerebellar cortex, ultimately playing critical roles in controlling motor coordination and plasticity. Using transgenic mice or optogenetic techniques to independently control a major excitatory and inhibitory pathway to the inferior olive, the authors show that the probability and phase of olivary neuron output depend critically on the relative timing of excitation and inhibitory inputs. Network models predict that appropriately timed excitatory and inhibitory input patterns efficiently synchronize larger clusters of inferior olivary neurons, raising the possibility that input timing can gate the output of the motor commands. These valuable findings have the potential to impact the field's understanding of sensorimotor processing, but the strength of evidence is currently incomplete.
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Abstract
The inferior olive provides the climbing fibers to Purkinje cells in the cerebellar cortex, where they elicit all-or-none complex spikes and control major forms of plasticity. Given their important role in both short-term and long-term coordination of cerebellum-dependent behaviors, it is paramount to understand the factors that determine the output of olivary neurons. Here, we use mouse models to investigate how the inhibitory and excitatory inputs to the olivary neurons interact with each other, generating spiking patterns of olivary neurons that align with their intrinsic oscillations. Using dual color optogenetic stimulation and whole-cell recordings, we demonstrate how intervals between the inhibitory input from the cerebellar nuclei and excitatory input from the mesodiencephalic junction affect phase and gain of the olivary output at both the sub- and suprathreshold level. When the excitatory input is activated shortly (~50 ms) after the inhibitory input, the phase of the intrinsic oscillations becomes remarkably unstable and the excitatory input can hardly generate any olivary spike. Instead, when the excitatory input is activated one cycle (~150 ms) after the inhibitory input, the excitatory input can optimally drive olivary spiking, riding on top of the first cycle of the subthreshold oscillations that have been powerfully reset by the preceding inhibitory input. Simulations of a large-scale network model of the inferior olive highlight to what extent the synaptic interactions penetrate in the neuropil, generating quasi-oscillatory spiking patterns in large parts of the olivary subnuclei, the size of which also depends on the relative timing of the inhibitory and excitatory inputs.
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eLife assessment
Inferior olivary neurons drive complex spiking activity in Purkinje neurons of the cerebellar cortex, ultimately playing critical roles in controlling motor coordination and plasticity. Using transgenic mice or optogenetic techniques to independently control a major excitatory and inhibitory pathway to the inferior olive, the authors show that the probability and phase of olivary neuron output depend critically on the relative timing of excitation and inhibitory inputs. Network models predict that appropriately timed excitatory and inhibitory input patterns efficiently synchronize larger clusters of inferior olivary neurons, raising the possibility that input timing can gate the output of the motor commands. These valuable findings have the potential to impact the field's understanding of sensorimotor processing, but …
eLife assessment
Inferior olivary neurons drive complex spiking activity in Purkinje neurons of the cerebellar cortex, ultimately playing critical roles in controlling motor coordination and plasticity. Using transgenic mice or optogenetic techniques to independently control a major excitatory and inhibitory pathway to the inferior olive, the authors show that the probability and phase of olivary neuron output depend critically on the relative timing of excitation and inhibitory inputs. Network models predict that appropriately timed excitatory and inhibitory input patterns efficiently synchronize larger clusters of inferior olivary neurons, raising the possibility that input timing can gate the output of the motor commands. These valuable findings have the potential to impact the field's understanding of sensorimotor processing, but the strength of evidence is currently incomplete.
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Reviewer #1 (Public Review):
The network of neurons of the inferior olive has long been suggested as a timing machine that controls the precise timing of movements, correcting movement and participating in the prediction of movement time. These timing capabilities have been attributed to the unique feature of the neurons to generate subthreshold voltage oscillations that can be used as a timing machine. In this study, the effect of the inhibitory and excitatory synaptic inputs on the oscillatory behavior was examined, demonstrating their different effects as well as the effects of combing the two inputs.
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Reviewer #2 (Public Review):
Neurons of the inferior olive exhibit strong subthreshold oscillations, and drive complex spiking through climbing fiber synapses onto Purkinje cells in the cerebellar cortex. This activity plays an essential role in coordinating motor control and the induction of cerebellar plasticity. In this study, the authors make use of optogenetic and electrophysiological approaches to examine the interplay between intrinsic oscillations and two important excitatory and inhibitory input populations to the inferior olive. The authors show that excitation is enhanced when it occurs in the rebound phase of the preceding inhibition. Using a computer model, the authors also show that enhanced excitation can effectively recruit larger populations of neurons, presumably through gap junctional coupling. The strengths of the …
Reviewer #2 (Public Review):
Neurons of the inferior olive exhibit strong subthreshold oscillations, and drive complex spiking through climbing fiber synapses onto Purkinje cells in the cerebellar cortex. This activity plays an essential role in coordinating motor control and the induction of cerebellar plasticity. In this study, the authors make use of optogenetic and electrophysiological approaches to examine the interplay between intrinsic oscillations and two important excitatory and inhibitory input populations to the inferior olive. The authors show that excitation is enhanced when it occurs in the rebound phase of the preceding inhibition. Using a computer model, the authors also show that enhanced excitation can effectively recruit larger populations of neurons, presumably through gap junctional coupling. The strengths of the study include the authors' ability to independently control both excitatory and inhibitory pathways, as well as the rigorous and systematic examination of input timing and amplitude and their effects on spike output. There were some weaknesses; high variability in cell resting potentials raised questions about how cell health impacted the findings, and there needed to be better documentation of recording conditions and parameters. There also needed to be a more extensive discussion about the nature of input timing and frequency under behaviorally relevant conditions. Given these relatively minor issues, the study provides new insight and depth into synaptic integration in the inferior olive and adds to our understanding of how input timing is translated into climbing fiber signals.
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Reviewer #3 (Public Review):
This is an interesting paper but not entirely surprising. Given the known voltage dependency of intrinsic oscillations of IO neurons, the fact that a hyperpolarizing input from a GABAergic synapse or a depolarization from an excitatory input can phase shift an oscillation depending on the timing is not surprising. It could be predicted from what is already known about the underlying conductances of the oscillations in these cells. The authors, however, do provide some quantification for both the inputs and the effects they have on the oscillations. Whether or not this quantification can be extrapolated to in vivo conditions, however, remains to be seen. There are multiple technical issues that the authors need to address.
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