Pablo M. Blazquez

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.

A network representation of response probability in the striatum.

The striatum of the basal ganglia is considered a key structure in the learning circuitry of the brain. To analyze neural signals that underlie striatal plasticity, we recorded from an identifiable class of striatal interneurons as macaque monkeys underwent training in a range of conditioning and non-associative learning paradigms, and recorded eyeblink electromyographs as the measure of behavioral response. We found that the responses of these striatal interneurons were modifiable under all training conditions and that their population responses were tightly correlated with the probability that a given stimulus would evoke a behavioral response. Such a network signal, proportional to current response probability, could be crucial to the learning and decision functions of the basal ganglia.

The vestibulo-ocular reflex as a model system for motor learning: what is the role of the cerebellum?

Motor systems are under a continuous adaptive process to maintain behavior throughout developmental changes and disease, a process called motor learning. Simple behaviors with easily measurable inputs and outputs are best suited to understand the neuronal signals that contribute to the required motor learning. Considering simple behaviors, the vestibulo-ocular reflex (VOR) allows quantification of its input and motor output and its neural circuitry is among the best documented. The main candidates for plastic change are the cerebellum and its target neurons in the brainstem. This review focuses on recent data regarding the involvement of the cerebellum in VOR motor learning. Learning can be divided into that acutely acquired over a period of hours and that chronically acquired over longer periods. Both acute and chronic learning have three phases named acquisition, consolidation, and retention. The cerebellar role in retention is disputed, but there is a consensus on the need of an intact cerebellum for acquisition. Data from neuronal recording, lesion studies and transgenic mouse experiments is complex but suggests that the signal representation in the cerebellum contains aspects of both motor output and sensory input. The cerebellum apparently uses different mechanisms for acute and chronic learning as well as for increases and decreases in VOR gain. Recent studies also suggest that the signal content in the cerebellum changes following learning and that the mechanisms used for chronic adaptation involve not only changes in a head velocity component but also in the efference copy of an eye movement command signal reaching Purkinje cells. This data leads to a new conceptual framework having implications for developing theories on the role of the cerebellum in motor learning and in the search for plastic elements within the VOR circuitry. For chronic learning we hypothesize that changes in the head velocity information traveling through the circuitry occur in parallel with changes in the integrator pathway and the efference copy pathway. We further propose that these changes are necessary to maintain the broadband characteristics of the learned behavior.

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.

Memory retention of vestibuloocular reflex motor learning in squirrel monkeys.

The vestibuloocular reflex (VOR) motor learning can be induced chronically by wearing lenses for several weeks to months, or acutely by visual-vestibular mismatch for several hours. Cerebellar long term depression (LTD) has been proposed as a causal mechanism for acute learning. We demonstrate differences in retention of acutely and chronically acquired VOR gains in squirrel monkeys and discuss neuronal correlates and possible roles of cerebellar LTD. Our data is compatible with the idea that cerebellar LTD might be a mechanism responsible for acute VOR adaptation.

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.

Kinematic analyses of classically-conditioned eyelid movements in the cat suggest a brain stem site for motor learning

Upper eyelid movements were conditioned in the alert cat to the presentation of either tones or short, weak air puffs applied to the ipsi- or contralateral cornea followed by an unconditioned stimulus consisting of a long, strong air puff applied to the ipsilateral cornea. Eyelid movements were measured with the search-coil technique. Electromyographs of the orbicularis oculi muscle were also recorded. Quantitative analysis of the latencies and topographic profiles of eyelid conditioned responses suggests that the primary site for their initiation is the brain stem reflex circuit involved, depending on the sensory modality of and on the side where the conditioning stimulus was applied. However, the kinematic of the conditioned response indicates that other neural structures are involved in its acquisition and consolidation.

Probabilistic identification of cerebellar cortical neurones across species.

Despite our fine-grain anatomical knowledge of the cerebellar cortex, electrophysiological studies of circuit information processing over the last fifty years have been hampered by the difficulty of reliably assigning signals to identified cell types. We approached this problem by assessing the spontaneous activity signatures of identified cerebellar cortical neurones. A range of statistics describing firing frequency and irregularity were then used, individually and in combination, to build Gaussian Process Classifiers (GPC) leading to a probabilistic classification of each neurone type and the computation of equi-probable decision boundaries between cell classes. Firing frequency statistics were useful for separating Purkinje cells from granular layer units, whilst firing irregularity measures proved most useful for distinguishing cells within granular layer cell classes. Considered as single statistics, we achieved classification accuracies of 72.5% and 92.7% for granular layer and molecular layer units respectively. Combining statistics to form twin-variate GPC models substantially improved classification accuracies with the combination of mean spike frequency and log-interval entropy offering classification accuracies of 92.7% and 99.2% for our molecular and granular layer models, respectively. A cross-species comparison was performed, using data drawn from anaesthetised mice and decerebrate cats, where our models offered 80% and 100% classification accuracy. We then used our models to assess non-identified data from awake monkeys and rabbits in order to highlight subsets of neurones with the greatest degree of similarity to identified cell classes. In this way, our GPC-based approach for tentatively identifying neurones from their spontaneous activity signatures, in the absence of an established ground-truth, nonetheless affords the experimenter a statistically robust means of grouping cells with properties matching known cell classes. Our approach therefore may have broad application to a variety of future cerebellar cortical investigations, particularly in awake animals where opportunities for definitive cell identification are limited.

Diversity of vestibular nuclei neurons targeted by cerebellar nodulus inhibition

•  Electrical stimulation of the cerebellar nodulus and ventral uvula decreases the time constant of the horizontal vestibulo‐ocular reflex during yaw rotation. •  Unlike the flocculus and ventral paraflocculus which target a particular cell group, nodulus/ventral uvula inhibition targets a large diversity of cell types in the vestibular nuclei. •  Twenty per cent of nodulus/ventral uvula‐target neurons were sensitive to both vestibular stimuli and eye movements, whereas the majority was only sensitive to vestibular stimuli. •  Most nodulus/ventral uvula‐target cells responded to both rotation and translation and only approximately half discriminated translational and gravitational accelerations. •  Projections of the nodulus/ventral uvula to both eye movement‐and non‐eye movement‐sensitive vestibular nuclei neurons suggest a role in both eye movement generation and vestibulo‐spinal or thalamo‐cortical systems.