Translation information processing is regulated by protein kinase C-dependent mechanism in Purkinje cells in murine posterior vermis.

The cerebellar posterior vermis generates an estimation of our motion (translation) and orientation (tilt) in space using cues originating from semicircular canals and otolith organs. Theoretical work has laid out the basic computations necessary for this signal transformation, but details on the cellular loci and mechanisms responsible are lacking. Using a multicomponent modeling approach, we show that canal and otolith information are spatially and temporally matched in mouse posterior vermis Purkinje cells and that Purkinje cell responses combine translation and tilt information. Purkinje cell-specific inhibition of protein kinase C decreased and phase-shifted the translation component of Purkinje cell responses, but did not affect the tilt component. Our findings suggest that translation and tilt signals reach Purkinje cells via separate information pathways and that protein kinase C-dependent mechanisms regulate translation information processing in cerebellar cortex output neurons.

The Macaque Cerebellar Flocculus Outputs a Forward Model of Eye Movement.

The central nervous system (CNS) achieves fine motor control by generating predictions of the consequences of the motor command, often called forward models of the movement. These predictions are used centrally to detect not-self generated sensations, to modify ongoing movements, and to induce motor learning. However, finding a neuronal correlate of forward models has proven difficult. In the oculomotor system, we can identify neuronal correlates of forward models vs. neuronal correlates of motor commands by examining neuronal responses during smooth pursuit at eccentric eye positions. During pursuit, torsional eye movement information is not present in the motor command, but it is generated by the mechanic of the orbit. Importantly, the directionality and approximate magnitude of torsional eye movement follow the half angle rule. We use this rule to investigate the role of the cerebellar flocculus complex (FL, flocculus and ventral paraflocculus) in the generation of forward models of the eye. We found that mossy fibers (input elements to the FL) did not change their response to pursuit with eccentricity. Thus, they do not carry torsional eye movement information. However, vertical Purkinje cells (PCs; output elements of the FL) showed a preference for counter-clockwise (CCW) eye velocity [corresponding to extorsion (outward rotation) of the ipsilateral eye]. We hypothesize that FL computes an estimate of torsional eye movement since torsion is present in PCs but not in mossy fibers. Overall, our results add to those of other laboratories in supporting the existence in the CNS of a predictive signal constructed from motor command information.

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.

GABA-A Inhibition Shapes the Spatial and Temporal Response Properties of Purkinje Cells in the Macaque Cerebellum.

Data from in vitro and anesthetized preparations indicate that inhibition plays a major role in cerebellar cortex function. We investigated the role of GABA-A inhibition in the macaque cerebellar ventral-paraflocculus while animals performed oculomotor behaviors that are known to engage the circuit. We recorded Purkinje cell responses to these behaviors with and without application of gabazine, a GABA-A receptor antagonist, near the recorded neuron. Gabazine increased the neuronal responsiveness to saccades in all directions and the neuronal gain to VOR cancellation and pursuit, most significantly the eye and head velocity sensitivity. L-glutamate application indicated that these changes were not the consequence of increases in baseline firing rate. Importantly, gabazine did not affect behavior or efference copy, suggesting that only local computations were disrupted. Our data, collected while the cerebellum performs behaviorally relevant computations, indicate that inhibition is a potent regulatory mechanism for the control of input-output gain and spatial tuning in the cerebellar cortex.

Spatiotemporal properties of optic flow and vestibular tuning in the cerebellar nodulus and uvula.

Convergence of visual motion and vestibular information is essential for accurate spatial navigation. Such multisensory integration has been shown in cortex, e.g., the dorsal medial superior temporal (MSTd) and ventral intraparietal (VIP) areas, but not in the parieto-insular vestibular cortex (PIVC). Whether similar convergence occurs subcortically remains unknown. Many Purkinje cells in vermal lobules 10 (nodulus) and 9 (uvula) of the macaque cerebellum are tuned to vestibular translation stimuli, yet little is known about their visual motion responsiveness. Here we show the existence of translational optic flow-tuned Purkinje cells, found exclusively in the anterior part of the nodulus and ventral uvula, near the midline. Vestibular responses of Purkinje cells showed a remarkable similarity to those in MSTd (but not PIVC or VIP) neurons, in terms of both response latency and relative contributions of velocity, acceleration, and position components. In contrast, the spatiotemporal properties of optic flow responses differed from those in MSTd, and matched the vestibular properties of these neurons. Compared with MSTd, optic flow responses of Purkinje cells showed smaller velocity contributions and larger visual motion acceleration responses. The remarkable similarity between the nodulus/uvula and MSTd vestibular translation responsiveness suggests a functional coupling between the two areas for vestibular processing of self-motion information.

Relationship between complex and simple spike activity in macaque caudal vermis during three-dimensional vestibular stimulation.

Lobules 10 and 9 in the caudal posterior vermis [also known as nodulus and uvula (NU)] are thought important for spatial orientation and balance. Here, we characterize complex spike (CS) and simple spike (SS) activity in response to three-dimensional vestibular stimulation. The strongest modulation was seen during translation (CS: 12.8 +/- 1.5, SS: 287.0 +/- 23.2 spikes/s/G, 0.5 Hz). Preferred directions tended to cluster along the cardinal axes (lateral, fore-aft, vertical) for CSs and along the semicircular canal axes for SSs. Most notably, the preferred directions for CS/SS pairs arising from the same Purkinje cells were rarely aligned. During 0.5 Hz pitch/roll tilt, only about a third of CSs had significant modulation. Thus, most CSs correlated best with inertial rather than net linear acceleration. By comparison, all SSs were selective for translation and ignored changes in spatial orientation relative to gravity. Like SSs, tilt modulation of CSs increased at lower frequencies. CSs and SSs had similar response dynamics, responding to linear velocity during translation and angular position during tilt. The most salient finding is that CSs did not always modulate out-of-phase with SSs. The CS/SS phase difference varied broadly among Purkinje cells, yet for each cell it was precisely matched for the otolith-driven and canal-driven components of the response. These findings illustrate a spatiotemporal mismatch between CS/SS pairs and provide the first comprehensive description of the macaque NU, an important step toward understanding how CSs and SSs interact during complex movements and spatial disorientation.

Direction discrimination thresholds of vestibular and cerebellar nuclei neurons.

To understand the roles of the vestibular system in perceptual detection and discrimination of self-motion, it is critical to account for response variability in computing the sensitivity of vestibular neurons. Here we study responses of neurons with no eye movement sensitivity in the vestibular (VN) and rostral fastigial nuclei (FN) using high-frequency (2 Hz) oscillatory translational motion stimuli. The axis of translation (i.e., heading) varied slowly (1 degrees /s) in the horizontal plane as the animal was translated back and forth. Signal detection theory was used to compute the threshold sensitivity of VN/FN neurons for discriminating small variations in heading around all possible directions of translation. Across the population, minimum heading discrimination thresholds averaged 16.6 degrees +/- 1 degrees SE for FN neurons and 15.3 degrees +/- 2.2 degrees SE for VN neurons, severalfold larger than perceptual thresholds for heading discrimination. In line with previous studies and theoretical predictions, maximum discriminability was observed for directions where firing rate changed steeply as a function of heading, which occurs at headings approximately perpendicular to the maximum response direction. Forward/backward heading thresholds tended to be lower than lateral motion thresholds, and the ratio of lateral over forward heading thresholds averaged 2.2 +/- 6.1 (geometric mean +/- SD) for FN neurons and 1.1 +/- 4.4 for VN neurons. Our findings suggest that substantial pooling and/or selective decoding of vestibular signals from the vestibular and deep cerebellar nuclei may be important components of further processing. Such a characterization of neural sensitivity is critical for understanding how early stages of vestibular processing limit behavioral performance.

Computation of egomotion in the macaque cerebellar vermis.

The nodulus and uvula (lobules X and IX of the vermis) receive mossy fibers from both vestibular afferents and vestibular nuclei neurons and are thought to play a role in spatial orientation. Their properties relate to a sensory ambiguity of the vestibular periphery: otolith afferents respond identically to translational (inertial) accelerations and changes in orientation relative to gravity. Based on theoretical and behavioral evidence, this sensory ambiguity is resolved using rotational cues from the semicircular canals. Recordings from the cerebellar cortex have identified a neural correlate of the brain's ability to resolve this ambiguity in the simple spike activities of nodulus/uvula Purkinje cells. This computation, which likely involves the cerebellar circuitry and its reciprocal connections with the vestibular nuclei, results from a remarkable convergence of spatially- and temporally-aligned otolith-driven and semicircular canal-driven signals. Such convergence requires a spatio-temporal transformation of head-centered canal-driven signals into an estimate of head reorientation relative to gravity. This signal must then be subtracted from the otolith-driven estimate of net acceleration to compute inertial motion. At present, Purkinje cells in the nodulus/uvula appear to encode the output of this computation. However, how the required spatio-temporal matching takes place within the cerebellar circuitry and what role complex spikes play in spatial orientation and disorientation remains unknown. In addition, the role of visual cues in driving and/or modifying simple and complex spike activity, a process potentially critical for long-term adaptation, constitutes another important direction for future studies.

How vestibular neurons solve the tilt/translation ambiguity. Comparison of brainstem, cerebellum, and thalamus.

The peripheral vestibular system is faced by a sensory ambiguity, where primary otolith afferents respond identically to translational (inertial) accelerations and changes in head orientation relative to gravity. Under certain conditions, this sensory ambiguity can be resolved using extra-otolith cues, including semicircular canal signals. Here we review and summarize how neurons in the vestibular nuclei, rostral fastigial nuclei, cerebellar nodulus/uvula, and thalamus respond during combinations of tilt and translation. We focus primarily on cerebellar cortex responses, as nodulus/uvula Purkinje cells reliably encode translation rather than net gravito-inertial acceleration. In contrast, neurons in the vestibular and rostral fastigial nuclei, as well as the ventral lateral and ventral posterior nuclei of the thalamus represent a continuum, with some encoding translation and some net gravito-inertial acceleration. This review also outlines how Purkinje cells use semicircular canal signals to solve the ambiguity problem and how this solution fails at low frequencies. We conclude by attempting to bridge the gap between the proposed roles of nodulus/uvula in tilt/translation discrimination and velocity storage.

Frequency-selective coding of translation and tilt in macaque cerebellar nodulus and uvula.

Spatial orientation depends critically on the brain's ability to segregate linear acceleration signals arising from otolith afferents into estimates of self-motion and orientation relative to gravity. In the absence of visual information, this ability is known to deteriorate at low frequencies. The cerebellar nodulus/uvula (NU) has been shown to participate in this computation, although its exact role remains unclear. Here, we show that NU simple spike (SS) responses also exhibit a frequency dependent selectivity to self-motion (translation) and spatial orientation (tilt). At 0.5 Hz, Purkinje cells encode three-dimensional translation and only weakly modulate during pitch and roll tilt (0.4 +/- 0.05 spikes/s/degrees/s). But this ability to selectively signal translation over tilt is compromised at lower frequencies, such that at 0.05 Hz tilt response gains average 2.0 +/- 0.3 spikes/s/degrees/s. We show that such frequency-dependent properties are attributable to an incomplete cancellation of otolith-driven SS responses during tilt by a canal-driven signal coding angular position with a sensitivity of 3.9 +/- 0.3 spikes/s/degrees. This incomplete cancellation is brought about because otolith-driven SS responses are also partially integrated, thus encoding combinations of linear velocity and acceleration. These results are consistent with the notion that NU SS modulation represents an internal neural representation of similar frequency dependencies seen in behavior.

Response clustering in transient stochastic synchronization and desynchronization of coupled neuronal bursters.

We studied the transient dynamics of synchronized coupled neuronal bursters subjected to repeatedly applied stimuli, using a hybrid neuroelectronic system of paddlefish electroreceptors. We show experimentally that the system characteristically undergoes poststimulus transients, in which the relative phases of the oscillators may be grouped in several clusters, traversing alternate phase trajectories. These signature transient dynamics can be detected and characterized quantitatively using specific statistical measures based on a stochastic approach to transient oscillator responses.

Noise-induced transition to bursting in responses of paddlefish electroreceptor afferents.

The response properties of ampullary electroreceptors of paddlefish, Polyodon spathula, were studied in vivo, as single-unit afferent responses to external electrical stimulation with varied intensities of several types of noise waveforms, all Gaussian and zero-mean. They included broadband white noise, Ornstein-Uhlenbeck noise, low- or high-frequency band-limited noise, or natural noise recorded from swarms of Daphnia zooplankton prey, or from individual prey. Normally the afferents fire spontaneously in a tonic manner, which is actually quasiperiodic due to embedded oscillators. 1) Weak noise stimuli increased the variability of afferent firing, but it remained tonic. 2) In contrast, stimulation with less-weak broadband noise led to a qualitative change of the firing patterns, to parabolic bursting, even though the mean firing rate was scarcely affected. 3) The transition to afferent bursting was marked by the development of two well-separated timescales: the fast frequency of spiking inside bursts at

Purkinje cells in posterior cerebellar vermis encode motion in an inertial reference frame.

The ability to orient and navigate through the terrestrial environment represents a computational challenge common to all vertebrates. It arises because motion sensors in the inner ear, the otolith organs, and the semicircular canals transduce self-motion in an egocentric reference frame. As a result, vestibular afferent information reaching the brain is inappropriate for coding our own motion and orientation relative to the outside world. Here we show that cerebellar cortical neuron activity in vermal lobules 9 and 10 reflects the critical computations of transforming head-centered vestibular afferent information into earth-referenced self-motion and spatial orientation signals. Unlike vestibular and deep cerebellar nuclei neurons, where a mixture of responses was observed, Purkinje cells represent a homogeneous population that encodes inertial motion. They carry the earth-horizontal component of a spatially transformed and temporally integrated rotation signal from the semicircular canals, which is critical for computing head attitude, thus isolating inertial linear accelerations during navigation.

Behavioral stochastic resonance: how the noise from a Daphnia swarm enhances individual prey capture by juvenile paddlefish.

Zooplankton emit weak electric fields into the surrounding water that originate from their own muscular activities associated with swimming and feeding. Juvenile paddlefish prey upon single zooplankton by detecting and tracking these weak electric signatures. The passive electric sense in this fish is provided by an elaborate array of electroreceptors, Ampullae of Lorenzini, spread over the surface of an elongated rostrum. We have previously shown that the fish use stochastic resonance to enhance prey capture near the detection threshold of their sensory system. However, stochastic resonance requires an external source of electrical noise in order to function. A swarm of plankton, for example Daphnia, can provide the required noise. We hypothesize that juvenile paddlefish can detect and attack single Daphnia as outliers in the vicinity of the swarm by using noise from the swarm itself. From the power spectral density of the noise plus the weak signal from a single Daphnia, we calculate the signal-to-noise ratio, Fisher information and discriminability at the surface of the paddlefish's rostrum. The results predict a specific attack pattern for the paddlefish that appears to be experimentally testable.