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Key points Purkinje cells in the cerebellum integrate input from sensory organs with that from premotor centres.Purkinje cells use a variety of sensory inputs relaying information from the environment to modify motor control.Here we investigated to what extent the climbing fibre inputs to Purkinje cells signal mono‐ or multi‐sensory information, and to what extent this signalling is subject to recent history of activity.We show that individual climbing fibres convey multiple types of sensory information, together providing a rich mosaic projection pattern of sensory signals across the cerebellar cortex.Moreover, firing probability of climbing fibres following sensory stimulation depends strongly on the recent history of activity, showing a tendency to homeostatic dampening. Abstract 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 and 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, with climbing fibres showing some degree of input‐specificity. 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 depends strongly 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 multi‐sensory stimulation around a relatively low set‐point, highlighting an integrative coding scheme of complex spike firing under homeostatic control., Key points Purkinje cells in the cerebellum integrate input from sensory organs with that from premotor centres.Purkinje cells use a variety of sensory inputs relaying information from the environment to modify motor control.Here we investigated to what extent the climbing fibre inputs to Purkinje cells signal mono‐ or multi‐sensory information, and to what extent this signalling is subject to recent history of activity.We show that individual climbing fibres convey multiple types of sensory information, together providing a rich mosaic projection pattern of sensory signals across the cerebellar cortex.Moreover, firing probability of climbing fibres following sensory stimulation depends strongly on the recent history of activity, showing a tendency to homeostatic dampening.

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 behavioral responses. Neuronal and behavioral changes did not occur in two cell-specific mouse models with impaired long-term potentiation at their 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., eLife digest Rodents use their whiskers to explore the world around them. When the whiskers touch an object, it triggers involuntary movements of the whiskers called whisker reflexes. Experiencing the same sensory stimulus multiple times enables rodents to fine-tune these reflexes, e.g., by making their movements larger or smaller. This type of learning is often referred to as motor learning. A part of the brain called cerebellum controls motor learning. It contains some of the largest neurons in the nervous system, the Purkinje cells. Each Purkinje cell receives input from thousands of extensions of small neurons, known as parallel fibers. It is thought that decreasing the strength of the connections between parallel fibers and Purkinje cells can help mammals learn new movements. This is the case in a type of learning called Pavlovian conditioning. It takes its name from the Russian scientist, Pavlov, who showed that dogs can learn to salivate in response to a bell signaling food. Pavlovian conditioning enables animals to optimize their responses to sensory stimuli. But Romano et al. now show that increasing the strength of connections between parallel fibers and Purkinje cells can also support learning. To trigger reflexive whisker movements, a machine blew puffs of air onto the whiskers of awake mice. After repeated exposure to the air puffs, the mice increased the size of their whisker reflexes. At the same time, their Purkinje cells became more active and the connections between Purkinje cells and parallel fibers grew stronger. Artificially increasing Purkinje cell activity triggered the same changes in whisker reflexes as the air puffs themselves. Textbooks still report that only weakening of connections within the cerebellum enables animals to learn and modify movements. The data obtained by Romano al. thus paint a new picture of how the cerebellum works in the context of whisker learning. They show that strengthening these connections can also support movement-related learning.

The massive computational capacity of the cerebellar cortex is conveyed by Purkinje cells onto cerebellar and vestibular nuclei neurons through their GABAergic, inhibitory output. This implies that pauses in Purkinje cell simple spike activity are potentially instrumental in cerebellar information processing, but their occurrence and extent are still heavily debated. The cerebellar cortex, although often treated as such, is not homogeneous. Cerebellar modules with distinct anatomical connectivity and gene expression have been described, and Purkinje cells in these modules also differ in firing rate of simple and complex spikes. In this study we systematically correlate, in awake mice, the pausing in simple spike activity of Purkinje cells recorded throughout the entire cerebellum, with their location in terms of lobule, transverse zone, and zebrin-identified cerebellar module. A subset of Purkinje cells displayed long (>500-ms) pauses, but we found that their occurrence correlated with tissue damage and lower temperature. In contrast to long pauses, short pauses (

Due to the uniform cyto-architecture of the cerebellar cortex, its overall physiological characteristics have traditionally been considered to be homogeneous. In this study, we show in awake mice at rest that spiking activity of Purkinje cells, the sole output cells of the cerebellar cortex, differs between cerebellar modules and correlates with their expression of the glycolytic enzyme aldolase C or zebrin. Simple spike and complex spike frequencies were significantly higher in Purkinje cells located in zebrin-negative than zebrin-positive modules. The difference in simple spike frequency persisted when the synaptic input to, but not intrinsic activity of, Purkinje cells was manipulated. Blocking TRPC3, the effector channel of a cascade of proteins that have zebrin-like distribution patterns, attenuated the simple spike frequency difference. Our results indicate that zebrin-discriminated cerebellar modules operate at different frequencies, which depend on activation of TRPC3, and that this property is relevant for all cerebellar functions. DOI: http://dx.doi.org/10.7554/eLife.02536.001, eLife digest The cerebellum, located at the back of the brain underneath the cerebral hemispheres, is best known for its role in the control of movement. Despite its small size, the cerebellum contains more than half of the brain's neurons. These are organized in a repeating pattern in which cells called Purkinje cells receive inputs from two types of fibers: climbing fibers, which ascend into the cerebellum from the brainstem; and parallel fibers, which run perpendicular to the climbing fibers. This gives rise to a characteristic ‘crystalline’ structure. As a result of this uniform circuitry, it was widely believed was that all Purkinje cells throughout the cerebellum would function the same way. However, the presence of distinct patterns of gene expression in different regions suggests that this is not the case. Molecules called zebrins, for example, are found in some Purkinje cells but not others, and this gives rise to a pattern of zebrin-positive and zebrin-negative stripes. A number of other molecules have similar distributions, suggesting that these differences in molecular machinery could underlie differences in cellular physiology. Zhou, Lin et al. have now provided one of the first direct demonstrations of such physiological differences by showing that zebrin-positive cells generate action potentials at lower frequencies than zebrin-negative cells. This pattern is seen throughout the cerebellum, and is evident even when the positive and negative cells are neighbors, which indicates that these differences do not simply reflect differences in the locations of the cells or differences in the inputs they receive from parallel fibers. Additional experiments revealed that the distinct firing rates are likely not generated by zebrin itself, but rather by proteins that are expressed alongside zebrin, most notably those that work through an ion channel called TRPC3. By showing that cells arranged in the same type of circuit can nevertheless have distinct firing rates, the work of Zhou, Lin et al. has revealed an additional level of complexity in the physiology of the cerebellum. In addition to improving our understanding of how the brain controls movement, these findings might also be of interest to researchers studying the increasing number of neurological and psychiatric disorders in which cerebellar dysfunction has been implicated. DOI: http://dx.doi.org/10.7554/eLife.02536.002

The rodent whisker system is widely used as a model system for investigating sensorimotor integration, neural mechanisms of complex cognitive tasks, neural development, and robotics. The whisker pathways to the barrel cortex have received considerable attention. However, many subcortical structures are paramount to the whisker system. They contribute to important processes, like filtering out salient features, integration with other senses, and adaptation of the whisker system to the general behavioral state of the animal. We present here an overview of the brain regions and their connections involved in the whisker system. We do not only describe the anatomy and functional roles of the cerebral cortex, but also those of subcortical structures like the striatum, superior colliculus, cerebellum, pontomedullary reticular formation, zona incerta, and anterior pretectal nucleus as well as those of level setting systems like the cholinergic, histaminergic, serotonergic, and noradrenergic pathways. We conclude by discussing how these brain regions may affect each other and how they together may control the precise timing of whisker movements and coordinate whisker perception.