Tatyana A. Yakusheva

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.

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 brains 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/°/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/°/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/°. 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.

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 brains 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.

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°/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° ± 1° SE for FN neurons and 15.3° ± 2.2° 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.

Normalized entropy applied to the analysis of interindividual and gender-related differences in the cardiovascular effects of stress.

Abstract. Nonlinear dynamic methods are considered to be a potential tool for studying the complex behavior of the cardiovascular system. In the present study, interindividual and gender-related differences in cardiovascular (CV) responses to various stress stimuli were studied using conventional CV variables such as heart rate (HR) and blood pressure (BP), as well as a recently introduced criterion of system complexity, normalized entropy (E/H, where E is entropy and H is system energy). A group of healthy students (n=270) of both genders (17–20xa0years of age) were subjected to noise exposure, mental arithmetic, arithmetic against noise and examination stress. Results showed that CV reactivity depended upon the kind of stress imposed and the gender of the subject. HR and BP stress-induced responses did not differ between men and women. However, men had higher absolute BP levels at baseline and during exposure to stressors. Stress-induced pressor responses lasted longer in men than in women. Changes in the complexity degree of CV signals, as assessed by E/H, were more pronounced and prolonged than those of HR and BP. Unlike the latter, E/H changed significantly in all stress situations for each subject tested and could be divided into two types of stress-induced response. These results allow one to conclude that E/H can better quantitate individual differences in CV stress reactivity in comparison with HR and BP. These findings suggest that stress-induced changes in CV functioning are more varied than can be revealed by applying conventional CV measures.

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.

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.

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.