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The investigation of the dynamics of Purkinje cell (PC) activity is crucial to unravel the role of the cerebellum in motor control, learning and cognitive processes. Within the cerebellar cortex (CC), these neurons receive all the incoming sensory and motor information, transform it and generate the entire cerebellar output. The relatively homogenous and repetitive structure of the CC, common to all vertebrate species, suggests a single computation mechanism shared across all PCs. While PC models have been developed since the 70's, a comprehensive review of contemporary models is currently lacking. Here, we provide an overview of PC models, ranging from the ones focused on single cell intracellular PC dynamics, through complex models which include synaptic and extrasynaptic inputs. We review how PC models can reproduce physiological activity of the neuron, including firing patterns, current and multistable dynamics, plateau potentials, calcium signaling, intrinsic and synaptic plasticity and input/output computations. We consider models focusing both on somatic and on dendritic computations. Our review provides a critical performance analysis of PC models with respect to known physiological data. We expect our synthesis to be useful in guiding future development of computational models that capture real-life PC dynamics in the context of cerebellar computations.

SignificanceAlthough it is undisputed that striatal dopamine plays a prominent role in motivated behavior and learning, the precise information conveyed by dopamine signals as such is under active debate. For a long time, the idea dominated that dopamine encodes a reward prediction error and that this signal is broadcast uniformly throughout the brain. However, here, we capture dopamine dynamics across many striatal regions and demonstrate that dopamine release is, regionally, extremely heterogeneous and that a reward prediction error-like signal is predominantly found in the relatively small limbic domain of the striatum. Another striking organizing principle is that stimulus valence directs dopamine concentration homogeneously across all regions (i.e., appetitive stimuli increase dopamine and aversive stimuli decrease dopamine).

Habits are automatic, inflexible behaviors that develop slowly with repeated performance. Striatal dopamine signaling instantiates this habit-formation process, presumably region specifically and via ventral-to-dorsal and medial-to-lateral signal shifts. Here, we quantify dopamine release in regions implicated in these presumed shifts (ventromedial striatum [VMS], dorsomedial striatum [DMS], and dorsolateral striatum [DLS]) in rats performing an action-sequence task and characterize habit development throughout a 10-week training. Surprisingly, all regions exhibited stable dopamine dynamics throughout habit development. VMS and DLS signals did not differ between habitual and non-habitual animals, but DMS dopamine release increased during action-sequence initiation and decreased during action-sequence completion in habitual rats, whereas non-habitual rats showed opposite effects. Consistently, optogenetic stimulation of DMS dopamine release accelerated habit formation. Thus, we demonstrate that dopamine signals do not shift regionally during habit formation and that dopamine in DMS, but not VMS or DLS, determines habit bias, attributing "habit functions" to a region previously associated exclusively with non-habitual behavior.

SignificanceAlthough it is undisputed that striatal dopamine plays a prominent role in motivated behavior and learning, the precise information conveyed by dopamine signals as such is under active debate. For a long time, the idea dominated that dopamine encodes a reward prediction error and that this signal is broadcast uniformly throughout the brain. However, here, we capture dopamine dynamics across many striatal regions and demonstrate that dopamine release is, regionally, extremely heterogeneous and that a reward prediction error-like signal is predominantly found in the relatively small limbic domain of the striatum. Another striking organizing principle is that stimulus valence directs dopamine concentration homogeneously across all regions (i.e., appetitive stimuli increase dopamine and aversive stimuli decrease dopamine).

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, the interaction of these properties with torrential synaptic inputs in awake behaving animals is not well understood. Here we combine electrophysiological recordings in awake mice with a 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 temporal framework for the creation of both the short-term and long-term changes in cerebellar output.

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 asked 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 strongly depends 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

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.