Purkinje Cell Discharge Research Articles

Excitation and Inhibition Delays within a Feedforward Inhibitory Pathway Modulate Cerebellar Purkinje Cell Output in Mice.

The cerebellar cortex computes sensorimotor information from many brain areas through a feedforward inhibitory (FFI) microcircuit between the input stage, the granule cell (GC) layer, and the output stage, the Purkinje cells (PCs). Although in other brain areas FFI underlies a precise excitation versus inhibition temporal correlation, recent findings in the cerebellum highlighted more complex behaviors at GC-molecular layer interneuron (MLI)-PC pathway. To dissect the temporal organization of this cerebellar FFI pathway, we combined ex vivo patch-clamp recordings of PCs in male mice with a viral-based strategy to express Channelrhodopsin2 in a subset of mossy fibers (MFs), the major excitatory inputs to GCs. We show that although light-mediated MF activation elicited pairs of excitatory and inhibitory postsynaptic currents in PCs, excitation (E) from GCs and inhibition (I) from MLIs reached PCs with a wide range of different temporal delays. However, when GCs were directly stimulated, a low variability in E/I delays was observed. Our results demonstrate that in many recordings MF stimulation recruited different groups of GCs that trigger E and/or I, and expanded PC temporal synaptic integration. Finally, using a computational model of the FFI pathway, we showed that this temporal expansion could strongly influence how PCs integrate GC inputs. Our findings show that specific E/I delays may help PCs encoding specific MF inputs.SIGNIFICANCE STATEMENT Sensorimotor information is conveyed to the cerebellar cortex by mossy fibers. Mossy fiber inputs activate granule cells that excite molecular interneurons and Purkinje cells, the sole output of the cerebellar cortex, leading to a sequence of synaptic excitation and inhibition in Purkinje cells, thus defining a feedforward inhibitory pathway. Using electrophysiological recordings, optogenetic stimulation, and mathematical modeling, we demonstrated that different groups of granule cells can elicit synaptic excitation and inhibition with various latencies onto Purkinje cells. This temporal variability controls how granule cells influence Purkinje cell discharge and may support temporal coding in the cerebellar cortex.

Cerebellar complex spikes multiplex complementary behavioral information.

Purkinje cell (PC) discharge, the only output of cerebellar cortex, involves 2 types of action potentials, high-frequency simple spikes (SSs) and low-frequency complex spikes (CSs). While there is consensus that SSs convey information needed to optimize movement kinematics, the function of CSs, determined by the PC’s climbing fiber input, remains controversial. While initially thought to be specialized in reporting information on motor error for the subsequent amendment of behavior, CSs seem to contribute to other aspects of motor behavior as well. When faced with the bewildering diversity of findings and views unraveled by highly specific tasks, one may wonder if there is just one true function with all the other attributions wrong? Or is the diversity of findings a reflection of distinct pools of PCs, each processing specific streams of information conveyed by climbing fibers? With these questions in mind, we recorded CSs from the monkey oculomotor vermis deploying a repetitive saccade task that entailed sizable motor errors as well as small amplitude saccades, correcting them. We demonstrate that, in addition to carrying error-related information, CSs carry information on the metrics of both primary and small corrective saccades in a time-specific manner, with changes in CS firing probability coupled with changes in CS duration. Furthermore, we also found CS activity that seemed to predict the upcoming events. Hence PCs receive a multiplexed climbing fiber input that merges complementary streams of information on the behavior, separable by the recipient PC because they are staggered in time.

Stellate cell computational modeling predicts signal filtering in the molecular layer circuit of cerebellum

The functional properties of cerebellar stellate cells and the way they regulate molecular layer activity are still unclear. We have measured stellate cells electroresponsiveness and their activation by parallel fiber bursts. Stellate cells showed intrinsic pacemaking, along with characteristic responses to depolarization and hyperpolarization, and showed a marked short-term facilitation during repetitive parallel fiber transmission. Spikes were emitted after a lag and only at high frequency, making stellate cells to operate as delay-high-pass filters. A detailed computational model summarizing these physiological properties allowed to explore different functional configurations of the parallel fiber—stellate cell—Purkinje cell circuit. Simulations showed that, following parallel fiber stimulation, Purkinje cells almost linearly increased their response with input frequency, but such an increase was inhibited by stellate cells, which leveled the Purkinje cell gain curve to its 4 Hz value. When reciprocal inhibitory connections between stellate cells were activated, the control of stellate cells over Purkinje cell discharge was maintained only at very high frequencies. These simulations thus predict a new role for stellate cells, which could endow the molecular layer with low-pass and band-pass filtering properties regulating Purkinje cell gain and, along with this, also burst delay and the burst-pause responses pattern.

Inhibition of GABAergic Transmission as a Model of Hyperactivation of Purkinje Cells in the Rat Cerebellum

Abstract—Pathological changes in the cerebellum are often associated with dysfunction of Purkinje cells, which is manifested in excessive spike activity. In our experiments, the increase in the frequency of spike activity of Purkinje cells was caused by the suppression of inhibitory transmission by the GABA receptor antagonist gabazin (hydrobromide 6-imino-3-(4-methoxyphenyl)-1(6H)-pyrazinobutanic acid) contrary to the classical model of neurodegeneration, in which hyperactivation of neurons is caused by the long-term action of high concentrations of excitatory agonists (glutamate or N-methyl-D-aspartate). In adult and young animals, gabazine caused a significant increase in the frequency of Purkinje cell discharges after 25 and 45 min of action, respectively. Thus, this model worked more effectively in adult animals than in young ones, which is due to the ontogenetic features of the formation of the cerebellar cortex. Moreover, the use of NS 309 (6,7-dichloro-1H-indole-2,3-diketone-3-oxime), a modulator of Ca2+-activated K+ channels of small conductance, in this model made it possible to compensate for the increase in the frequency of simple spikes induced by the gabazine in the discharge of Purkinje cells to the level of the control values in young and adult rats.

Impact of 4-aminopyridine on vestibulo-ocular reflex performance.

Vestibulo-ocular reflexes (VOR) are mediated by frequency-tuned pathways that separately transform the different dynamic and static aspects of head motion/position-related sensory signals into extraocular motor commands. Voltage-dependent potassium conductances such as those formed by Kv1.1 are important for the ability of VOR circuit elements to encode highly transient motion components. Here we describe the impact of the Kv1.1 channel blocker 4-aminopyridine (4-AP) on spontaneous and motion-evoked discharge of superior oblique motoneurons. Spike activity was recorded from the motor nerve in isolated preparations of Xenopus laevis tadpoles. Under static conditions, bath application of 1-10µM 4-AP increased the spontaneous firing rate and provoked repetitive bursts of spikes. During motion stimulation 4-AP also augmented and delayed the peak firing rate suggesting that this drug affects the magnitude and timing of vestibular-evoked eye movements. The exclusive Kv1.1 expression in thick vestibular afferent fibers in larval Xenopus at this developmental stage suggests that the altered extraocular motor output in the presence of 4-AP mainly derives from a firing rate increase of irregular firing vestibular afferents that propagates along the VOR circuitry. Clinically and pharmacologically, the observed 4-AP-mediated increase of peripheral vestibular input under resting and dynamic conditions can contribute to the observed therapeutic effects of 4-AP in downbeat and upbeat nystagmus as well as episodic ataxia type 2, by an indirect increase of cerebellar Purkinje cell discharge.

Short-Term Plasticity Combines with Excitation-Inhibition Balance to Expand Cerebellar Purkinje Cell Dynamic Range.

The balance between excitation (E) and inhibition (I) in neuronal networks controls the firing rate of principal cells through simple network organization, such as feedforward inhibitory circuits. Here, we demonstrate in male mice, that at the granule cell (GrC)-molecular layer interneuron (MLI)-Purkinje cell (PC) pathway of the cerebellar cortex, E/I balance is dynamically controlled by short-term dynamics during bursts of stimuli, shaping cerebellar output. Using a combination of electrophysiological recordings, optogenetic stimulation, and modeling, we describe the wide range of bidirectional changes in PC discharge triggered by GrC bursts, from robust excitation to complete inhibition. At high frequency (200 Hz), increasing the number of pulses in a burst (from 3 to 7) can switch a net inhibition of PC to a net excitation. Measurements of EPSCs and IPSCs during bursts and modeling showed that this feature can be explained by the interplay between short-term dynamics of the GrC-MLI-PC pathway and E/I balance impinging on PC. Our findings demonstrate that PC firing rate is highly sensitive to the duration of GrC bursts, which may define a temporal-to-rate code transformation in the cerebellar cortex.SIGNIFICANCE STATEMENT Sensorimotor information processing in the cerebellar cortex leads to the occurrence of a sequence of synaptic excitation and inhibition in Purkinje cells. Granule cells convey direct excitatory inputs and indirect inhibitory inputs to the Purkinje cells, through molecular layer interneurons, forming a feedforward inhibitory pathway. Using electrophysiological recordings, optogenetic stimulation, and mathematical modeling, we found that presynaptic short-term dynamics affect the balance between synaptic excitation and inhibition on Purkinje cells during high-frequency bursts and can reverse the sign of granule cell influence on Purkinje cell discharge when burst duration increases. We conclude that short-term dynamics may play an important role in transforming the duration of sensory inputs arriving on cerebellar granule cells into cerebellar cortical output firing rate.

Modulation of sensory prediction error in Purkinje cells during visual feedback manipulations

It is hypothesized that the cerebellum implements a forward internal model that transforms motor commands into predictions about upcoming movements. The predictions are compared with sensory feedback to generate sensory prediction errors critical to controlling movements. The simple spike firing of cerebellar Purkinje cells both lead and lag movement consistent with representations of motor predictions and sensory feedback. This study tests whether this leading and lagging modulation provides the prediction and sensory feedback necessary to compute sensory prediction errors. Two manipulations of the visual feedback are used in rhesus monkeys performing pseudo-random tracking. Consistent with a forward model, delaying the visual feedback demonstrates that the leading simple spike modulation with position error is time-locked to the hand movement. Reducing the feedback shows that the lagged modulation is directly driven by visual inputs. Therefore, Purkinje cell discharge carries both the motor predictions and sensory feedback required of a forward internal model.

Searching for an Internal Representation of Stimulus Kinematics in the Response of Ventral Paraflocculus Purkinje Cells.

Motor control theories propose that the central nervous system builds internal representations of the motion of both our body and external objects. These representations, called forward models, are essential for accurate motor control. For instance, to produce a precise reaching movement to catch a flying ball, the central nervous system must build predictions of the current and future states of both the arm and the ball. Accumulating evidence suggests that the cerebellar cortex contains a forward model of an individual's body movement. However, little evidence is yet available to suggest that it also contains a forward model of the movement of external objects. We investigated whether Purkinje cell simple spike responses in an oculomotor region of the cerebellar cortex called the ventral paraflocculus contained information related to the kinematics of behaviorally relevant visual stimuli. We used a visuomotor task that obliges animals to track moving targets while keeping their eyes fixated on a stationary target to separate signals related to visual tracking from signals related to eye movement. We found that ventral paraflocculus Purkinje cells do not contain information related to the kinematics of behaviorally relevant visual stimuli; they only contain information related to eye movements. Our data stand in contrast with data obtained from cerebellar Crus I, wherein Purkinje cell discharge contains information related to moving visual stimuli. Together, these findings suggest specialization in the cerebellar cortex, with some areas participating in the computation of our movement kinematics and others computing the kinematics of behaviorally relevant stimuli.

Long-Term Predictive and Feedback Encoding of Motor Signals in the Simple Spike Discharge of Purkinje Cells.

Most hypotheses of cerebellar function emphasize a role in real-time control of movements. However, the cerebellum’s use of current information to adjust future movements and its involvement in sequencing, working memory, and attention argues for predicting and maintaining information over extended time windows. The present study examines the time course of Purkinje cell discharge modulation in the monkey (Macaca mulatta) during manual, pseudo-random tracking. Analysis of the simple spike firing from 183 Purkinje cells during tracking reveals modulation up to 2 s before and after kinematics and position error. Modulation significance was assessed against trial shuffled firing, which decoupled simple spike activity from behavior and abolished long-range encoding while preserving data statistics. Position, velocity, and position errors have the most frequent and strongest long-range feedforward and feedback modulations, with less common, weaker long-term correlations for speed and radial error. Position, velocity, and position errors can be decoded from the population simple spike firing with considerable accuracy for even the longest predictive (-2000 to -1500 ms) and feedback (1500 to 2000 ms) epochs. Separate analysis of the simple spike firing in the initial hold period preceding tracking shows similar long-range feedforward encoding of the upcoming movement and in the final hold period feedback encoding of the just completed movement, respectively. Complex spike analysis reveals little long-term modulation with behavior. We conclude that Purkinje cell simple spike discharge includes short- and long-range representations of both upcoming and preceding behavior that could underlie cerebellar involvement in error correction, working memory, and sequencing.

P298 Effects of cerebellar transcranial direct-current stimulation on cerebellar sensory-induced LFPs and Purkinje cell activity in alert mice

Introduction During last years the putative effects of cerebellar transcranial direct-current stimulation (tDCS) has attracted the attention of basic and clinical neuroscientist. Nevertheless, the impact of exogenous electric fields on the different components of the cerebellar network is not already elucidated. Objectives The aim of this study was to characterize physiological mechanisms underlying short- and long-term effects associated to cerebellar tDCS in alert behaving mice. In particular, we explored the tDCS impact on the cerebellar response to sensory inputs (whisker stimulation) and the potential modulation of Purkinje Cell (PC) discharge rates. Materials & methods Mice were prepared for chronic recording of local field potentials (LFPs) and PC firing in the CrusI/II region of the cerebellum. Along the experimental sessions spontaneous and stimulus-induced (by electrical whisker pad stimulation) activity of PCs (identified by the presence of simple and complex spikes) were recorded before, during and after anodal and cathodal tDCS applied over the cerebellum. For that, we used ring-electrodes placed over the skull allowing simultaneous tDCS stimulation and glass micropipette insertion for LFPs and extracellular unitary recording. tDCS was performed at different current intensities for 5 s to test the immediate effects on sensory-related LFPs and PC activity, and during 20 min to show after-effects on sensory related LFPs. Results Regarding to the immediate short-term effects (5 s), anodal and cathodal cerebellar tDCS increased and decreased, respectively, the amplitude of N3 component of LFPs induced by simultaneous whisker stimulation. This component has been previously reported to reflect the synaptic activity between parallel fiber and the dendritic tree of PC. Interestingly, longer stimulation sessions (20 min) induced long-term effects that last for more than one hour. Coherently, the firing rate of identified PC was increased or decreased depending of the anodal or cathodal tDCS, respectively. PC response to whisker tactile stimulation was also modulated in the same manner. Conclusions Present results demonstrate tDCS’s capability for short- and long-term modulation of the cerebellar cortex, and specifically PCs firing activities.

The Neural Code for Motor Control in the Cerebellum and Oculomotor Brainstem.

A single extra spike makes a difference. Here, the size of the eye velocity in the initiation of smooth eye movements in the right panel depends on whether a cerebellar Purkinje cell discharges 3 (red), 4 (green), 5 (blue), or 6 (black) spikes in the 40-ms window indicated by the gray shading in the rasters on the left. Spike trains are rich in information that can be extracted to guide behaviors at millisecond time resolution or across longer time intervals. In sensory systems, the information usually is defined with respect to the stimulus. Especially in motor systems, however, it is equally critical to understand how spike trains predict behavior. Thus, our goal was to compare systematically spike trains in the oculomotor system with eye movement behavior on single movements. We analyzed the discharge of Purkinje cells in the floccular complex of the cerebellum, floccular target neurons in the brainstem, other vestibular neurons, and abducens neurons. We find that an extra spike in a brief analysis window predicts a substantial fraction of the trial-by-trial variation in the initiation of smooth pursuit eye movements. For Purkinje cells, a single extra spike in a 40 ms analysis window predicts, on average, 0.5 SDs of the variation in behavior. An optimal linear estimator predicts behavioral variation slightly better than do spike counts in brief windows. Simulations reveal that the ability of single spikes to predict a fraction of behavior also emerges from model spike trains that have the same statistics as the real spike trains, as long as they are driven by shared sensory inputs. We think that the shared sensory estimates in their inputs create correlations in neural spiking across time and across each population. As a result, one or a small number of spikes in a brief time interval can predict a substantial fraction of behavioral variation.

Modulated discharge of Purkinje and stellate cells persists after unilateral loss of vestibular primary afferent mossy fibers in mice

Cerebellar Purkinje cells are excited by two afferent pathways: climbing and mossy fibers. Climbing fibers evoke large "complex spikes" (CSs) that discharge at low frequencies. Mossy fibers synapse on granule cells whose parallel fibers excite Purkinje cells and may contribute to the genesis of "simple spikes" (SSs). Both afferent systems convey vestibular information to folia 9c-10. After making a unilateral labyrinthectomy (UL) in mice, we tested how the discharge of CSs and SSs was changed by the loss of primary vestibular afferent mossy fibers during sinusoidal roll tilt. We recorded from cells identified by juxtacellular neurobiotin labeling. The UL preferentially reduced vestibular modulation of CSs and SSs in folia 8-10 contralateral to the UL. The effects of a UL on Purkinje cell discharge were similar in folia 9c-10, to which vestibular primary afferents project, and in folia 8-9a, to which they do not project, suggesting that vestibular primary afferent mossy fibers were not responsible for the UL-induced alteration of SS discharge. UL also induced reduced vestibular modulation of stellate cell discharge contralateral to the UL. We attribute the decreased modulation to reduced vestibular modulation of climbing fibers. In summary, climbing fibers modulate CSs directly and SSs indirectly through activation of stellate cells. Whereas vestibular primary afferent mossy fibers cannot account for the modulated discharge of SSs or stellate cells, the nonspecific excitation of Purkinje cells by parallel fibers may set an operating point about which the discharges of SSs are sculpted by climbing fibers.

Motor dysfunction and cerebellar Purkinje cell firing impairment in Ebf2 null mice

Mice deficient for the transcription factor Ebf2 lose a subset of Purkinje cells during development and have a hypotrophic cerebellar cortex. Related motor symptoms and the function of Purkinje cells surviving in the adult have not been studied so far. Ebf2 null mice presented locomotor impairment and a deficiency of motor coordination and motor learning. Ebf2 null Purkinje cells of the anterior lobe, relative to wild-type controls, were patch-clamp recorded in acutely prepared slices. While immature Purkinje cells (10-20 postnatal days) of Ebf2 null mice showed no significant difference relative to wild-types, in the adult they featured a higher input resistance, increased anomalous rectification, decreased first spike latency, higher initial firing frequency, lower voltage threshold and reduced afterhyperpolarizations and post-burst hyperpolarizations. These parameters indicate a difference in the response to both hyperpolarizing and depolarizing stimuli, corresponding to an altered cerebellar cortical output signaling. In contrast, adult climbing fibers attained a normal monoinnervation pattern and the parallel fiber-Purkinje cell synapse showed evoked postsynaptic currents and paired-pulse facilitation functionally indistinguishable from wild-type PCs. These results suggest that the motor deficits exhibited by Ebf2 null mice could be due, at least in part, to an impairment of the firing properties of surviving Purkinje cells. These findings indicate that Ebf2 is important for the development and maintenance of normal Purkinje cell discharge properties.

Climbing fiber‐evoked Purkinje cell discharge reduces expression of GABAa receptor‐associated protein and decreases its interaction with GABAa receptors

Sustained neuronal activity induces synaptic remodeling, in part, by altering gene expression. We have used a major climbing fiber pathway onto cerebellar Purkinje cells to investigate the effects of sustained climbing fiber-evoked glutamatergic synaptic transmission on transcription, expression and phosphorylation of proteins related to the regulation of inhibitory GABA(A) receptor function. Binocular horizontal optokinetic stimulation was used to modulate climbing fiber signals to Purkinje cells in the flocculus and nodulus of rabbits and mice. Purkinje cells in the flocculus and nodulus ipsilateral to the eye stimulated in the Posterior→Anterior direction received increased climbing fiber activity. Purkinje cells in flocculus and nodulus ipsilateral to the eye stimulated in the Anterior→Posterior direction received decreased climbing fiber activity. We identified changes in levels of gene transcripts in floccular and nodular Purkinje cells with the technique of differential display RT-PCR. Increased climbing fiber input reduced transcript levels and expression of GABA receptor-associated protein (GABARAP). Using a protein 'pull down' technique, we showed that GABARAP interacts with serine phosphorylated GABA(A)γ2, gephyrin and β-tubulin. Serine de-phosphorylation of GABA(A)γ2 reduced association of GABARAP with GABA(A)γ2. Climbing fiber activity did not influence the expression of GABA(A)γ2. Rather, it decreased its serine phosphorylation. Climbing fiber discharge decreased both expression of GABARAP and serine phosphorylation of GABA(A)γ2. Consequently, climbing fiber activity may reduce the surface expression of GABA(A) receptors in Purkinje cells rendering Purkinje cells less susceptible to interneuronal GABAergic inhibition.

Human Muscle Spindles Act as Forward Sensory Models

Modern theories of motor control incorporate forward models that combine sensory information and motor commands to predict future sensory states. Such models circumvent unavoidable neural delays associated with on-line feedback control. Here we show that signals in human muscle spindle afferents during unconstrained wrist and finger movements predict future kinematic states of their parent muscle. Specifically, we show that the discharges of type Ia afferents are best correlated with the velocity of length changes in their parent muscles approximately 100-160 ms in the future and that their discharges vary depending on motor sequences in a way that cannot be explained by the state of their parent muscle alone. We therefore conclude that muscle spindles can act as "forward sensory models": they are affected both by the current state of their parent muscle and by efferent (fusimotor) control, and their discharges represent future kinematic states. If this conjecture is correct, then sensorimotor learning implies learning how to control not only the skeletal muscles but also the fusimotor system.

Effect of harmaline on the complex spike shape and depression time in cerebellar Purkinje cell discharge in rat postnatal ontogenesis

Functional relationship between waveform of complex spike (CS) and depression time of simple spike (SS) in discharge of cerebellar Purkinje cells was studied after their activation with afferent climbing fiber at different terms of postnatal ontogenesis in norm and after treatment with harmaline. The experiments were carried out on three age groups of Wistar rats: rat pups (2 weeks), the adult (4-6 months), and the old animals (22-26 months). It was established that the CS duration in norm was approximately equal in rat pups, adult, and old animals, whereas it markedly decreased from the young to the old animals during the SS depression in the Purkinje cell discharge. Frequency of small action potential (sAP) and their number in the Purkinje cell discharge were approximately equal in young rat pups and adult animals, while in old animals these parameters were higher, on average, by 30%. After administration of harmaline, all CS parameters in rat pups and old animals increased in parallel with the depression time elongation. In adult rats, harmaline did not produce statistically significant changes of the mean values of CS parameters, but an increase of the simple spike depression time was observed. The obtained results allow concluding that the CS waveform and the simple spike depression time in norm are functionally coupled and change with age. The effect of harmaline on the CS waveforms as well as on interrelation of the CS duration and the SS depression time in the Purkinje cell discharge was more pronounced at the early and the late stages of Wistar rat postnatal ontogenesis.

Dynamic correspondence between Purkinje cell discharge and forelimb muscle activity during reaching

There remain conflicting models of the cerebellar control of limb movement, ranging from the suggestion that the inhibitory output from Purkinje cells (PCs) is meant to suppress unwanted muscle activity, to the hypothesis that the cerebellar cortex embodies complex internal models of limb dynamics. To test these ideas, we undertook a quantitative comparison of PC simple spike dynamics to those of muscle activity. We recorded simultaneously from Purkinje cells in the paravermal anterior lobe and from muscles of the hand and arm in the behaving monkey during a simple, sequential button pressing task. The task-related discharge of each neuron was determined from peri-event histograms aligned to the onset of the behavior. Bursts of discharge were more than twice as common as pauses, but there was no difference in their timing relative to movement. From the same recordings, the similarity between discharge and muscle activity was evaluated by calculating the cross correlation between firing rate and rectified EMG. Surprisingly, given the inhibitory projection of PCs, most of the bursts of PC discharge were positively correlated with muscle activity. Although our results do not support a simple correspondence of pauses and bursts with limb acceleration and deceleration respectively, they are consistent with a more complex PC regulation of cerebellar nuclear activity from task-related, corticopontine drive.

Analysis of Floccular Purkinje (P-) Cell Discharge during 3D Pursuit

Analysis of Floccular Purkinje (P-) Cell Discharge during 3D Pursuit

Force field effects on cerebellar Purkinje cell discharge with implications for internal models

The cerebellum has been hypothesized to provide internal models for limb movement control. If the cerebellum is the site of an inverse dynamics model, then cerebellar neural activity should signal limb dynamics and be coupled to arm muscle activity. To address this, we recorded from 166 task-related Purkinje cells in two monkeys performing circular manual tracking under varying viscous and elastic loads. Hand forces and arm muscle activity increased with the load, and their spatial tuning differed markedly between the viscous and elastic fields. In contrast, the simple spike firing of 91.0% of the Purkinje cells was not significantly modulated by the force nor was their spatial tuning affected. For the 15 cells with a significant force effect, changes were small and isolated. These results do not support the hypothesis that Purkinje cells represent the output of an inverse dynamics model of the arm. Instead these neurons provide a kinematic representation of arm movements.

Cerebellar Cortical Molecular Layer Inhibition Is Organized in Parasagittal Zones

Molecular layer inhibitory interneurons generate on-beam and off-beam inhibition in the cerebellar cortex that is hypothesized to control the timing and/or spatial patterning of Purkinje cell discharge. On- and off-beam inhibition has been assumed to be spatially uniform and continuous within a folium. Using flavoprotein autofluorescence optical imaging in the mouse cerebellar cortex in vivo, this study demonstrates that the inhibition evoked by parallel fiber and peripheral stimulation results in parasagittal bands of decreases in fluorescence that correspond to zebrin II-positive bands. The parasagittal bands of decreased fluorescence are abolished by GABA(A) antagonists and reflect the activity of molecular layer interneurons on their targets. The same banding pattern was observed using Ca2+ imaging. The bands produce spatially specific decreases in the responses to peripheral input. Therefore, molecular layer inhibition is compartmentalized into zebrin II parasagittal domains that differentially modulate the spatial pattern of cerebellar cortical activity.