Cerebellar Motor Learning: When Is Cortical Plasticity Not Enough?

Classical Marr-Albus theories of cerebellar learning employ only cortical sites of plasticity. However, tests of these theories using adaptive calibration of the vestibulo–ocular reflex (VOR) have indicated plasticity in both cerebellar cortex and the brainstem. To resolve this long-standing conflict, we attempted to identify the computational role of the brainstem site, by using an adaptive filter version of the cerebellar microcircuit to model VOR calibration for changes in the oculomotor plant. With only cortical plasticity, introducing a realistic delay in the retinal-slip error signal of 100 ms prevented learning at frequencies higher than 2.5 Hz, although the VOR itself is accurate up to at least 25 Hz. However, the introduction of an additional brainstem site of plasticity, driven by the correlation between cerebellar and vestibular inputs, overcame the 2.5 Hz limitation and allowed learning of accurate high-frequency gains. This “cortex-first” learning mechanism is consistent with a wide variety of evidence concerning the role of the flocculus in VOR calibration, and complements rather than replaces the previously proposed “brainstem-first” mechanism that operates when ocular tracking mechanisms are effective. These results (i) describe a process whereby information originally learnt in one area of the brain (cerebellar cortex) can be transferred and expressed in another (brainstem), and (ii) indicate for the first time why a brainstem site of plasticity is actually required by Marr-Albus type models when high-frequency gains must be learned in the presence of error delay

Visuomotor Cerebellum in Human and Nonhuman Primates

In this paper, we will review the anatomical components of the visuomotor cerebellum in human and, where possible, in non-human primates and discuss their function in relation to those of extracerebellar visuomotor regions with which they are connected. The floccular lobe, the dorsal paraflocculus, the oculomotor vermis, the uvula–nodulus, and the ansiform lobule are more or less independent components of the visuomotor cerebellum that are involved in different corticocerebellar and/or brain stem olivocerebellar loops. The floccular lobe and the oculomotor vermis share different mossy fiber inputs from the brain stem; the dorsal paraflocculus and the ansiform lobule receive corticopontine mossy fibers from postrolandic visual areas and the frontal eye fields, respectively. Of the visuomotor functions of the cerebellum, the vestibulo-ocular reflex is controlled by the floccular lobe; saccadic eye movements are controlled by the oculomotor vermis and ansiform lobule, while control of smooth pursuit involves all these cerebellar visuomotor regions. Functional imaging studies in humans further emphasize cerebellar involvement in visual reflexive eye movements and are discussed

A Reevaluation of the Vestibulo-Ocular Reflex: New Ideas of its Purpose, Properties, Neural Substrate, and Disorders

Conventional views of the Vestibulo-Ocular Reflex (VOR) have emphasized testing with caloric stimuli and by passively rotating patients at low frequencies in a chair. The properties of the VOR tested under these conditions differ from the performance of this reflex during the natural function for which it evolved-locomotion. Only the VOR (and not visually mediated eye movements) can cope with the high-frequency angular and linear perturbations of the head that occur during locomotion; this is achieved by generating eye movements at short latency (less than 16 msec). Interpretation of vestibular testing is enhanced by the realization that, although the di- and trisynaptic components of the VOR are essential for this short-latency response, the overall accuracy and plasticity of the VOR depend upon a distributed, parallel network of neurons involving the vestibular nuclei. Neurons in this network variously encode inputs from the labyrinthine semicircular canals and otoliths, as well as from the visual and somatosensory systems. The central vestibular pathways branch to contact vestibular cortex (for perception) and the spinal cord (for control of posture). Thus, the vestibular nuclei basically coordinate the stabilization of gaze and posture, and contribute to the perception of verticality and self-motion. Consequently, brainstem disorders that disrupt the VOR cause not just only nystagmus, but also instability of posture (eg, increased fore-aft sway in patients with downbeat nystagmus) and disturbance of spatial orientation (eg, tilt of the subjective visual vertical in Wallenberg's syndrome)

Plasticity in eye movement control

The cerebellum plays an important role in the recalibration and adaptive adjustment of movements, as well as learning new motor skills and motor related associations. In this thesis, we investigated the mechanisms underlying cerebellar motor learning. To obtain a better understanding, in how the cerebellum processes and stores information, we used specific perturbations that affected the information processing of the cerebellum. Signal transduction pathways were affected that were considered important for cerebellar motor learning by using genetic tools (transgenic mice) and the application of antibodies. Alterations in cerebellar motor learning were studied by monitoring the oculomotor system of these transgenic and treated mice

Functional diversity of motoneurons in the oculomotor system

Extraocular muscles contain two types of muscle fibers according to their innervation pattern: singly innervated muscle fibers (SIFs), similar to most skeletal muscle fibers, and multiply innervated muscle fibers (MIFs). Morphological studies have revealed that SIF and MIF motoneurons are segregated anatomically and receive different proportions of certain afferents, suggesting that while SIF motoneurons would participate in the whole repertoire of eye movements, MIF motoneurons would contribute only to slow eye movements and fixations. We have tested that proposal by performing single-unit recordings, in alert behaving cats, of electrophysiologically identified MIF and SIF motoneurons in the abducens nucleus. Our results show that both types of motoneuron discharge in relation to eye position and velocity, displaying a tonic–phasic firing pattern for different types of eye movement (saccades, vestibulo-ocular reflex, vergence) and gaze-holding. However, MIF motoneurons presented an overall reduced firing rate compared with SIF motoneurons, and had significantly lower recruitment threshold and also lower eye position and velocity sensitivities. Accordingly, MIF motoneurons could control mainly gaze in the off-direction, when less force is needed, whereas SIF motoneurons would contribute to increase muscle tension progressively toward the on-direction as more force is required. Anatomically, MIF and SIF motoneurons distributed intermingled within the abducens nucleus, with MIF motoneurons being smaller and having a lesser somatic synaptic coverage. Our data demonstrate the functional participation of both MIF and SIF motoneurons in fixations and slow and phasic eye movements, although their discharge properties indicate a functional segregation.Ministerio de Ciencia, Innovación y Universidades – Fondo Europeo de Desarrollo Regional (BFU2015-64515-P)Junta de Andalucía (BIO-297

Aerospace medicine and biology. A continuing bibliography (supplement 231)

This bibliography lists 284 reports, articles, and other documents introduced into the NASA scientific and technical information system in March 1982

Analysis and Simulation of Cerebellar Circuitry

The cerebellum, a fist-sized structure of the brain, plays a crucial part in the execution and coordination of motor control tasks and cognitive activities. It is also remarkably able to adapt itself to new tasks and circumstances whenever errors in motor output are made. Over the years, valuable insight on cerebellar functionality has been gained through the application of concepts traditionally associated with control theory. In this thesis, neural spike train data recorded from cerebellar neurons at rest under in vivo conditions were examined. The goal is to give an initial characterization of the spike firing properties of such neurons, using statistical point process theory. The findings indicate that the distributions of inter-spike intervals are skewed, and often could be approximated with either a gamma distribution or a lognormal distribution. Furthermore, it is found that several spike trains could be reasonably treated as renewal processes, while others require more complex description of their inter-spike interval dependency. Secondly, a Matlab model was developed to simulate a structure of cerebellar contribution to motor control of the vestibulo-ocular reflex. The cerebellar output is feedforwarded to a linear model of the oculomotor plant. A comparison between head velocity and eye velocity serving as a teaching signal to the cerebellum enables it to alter its functionality to better compensate for head movements. A simulation of a cerebellar circuitry output reveals that feedforwarding of the cerebellar output to the oculomotor plant through learning is able to improve the control performance, and offers a plausible explanation for motor control of the vestibulo-ocular reflex

Roles Of Inhibitory Interneurons In Cerebellar Cortical Processing For Oculomotor Control

The cerebellar cortex is usually offered up as the prime example of a well-worked out circuit; indeed, its basic neuronal composition and organization has been known for over one hundred years. Yet mysteries still abound about the computations that are performed within its layers, and how these computations contribute to sensation and behavior. This project was an effort to look inside the cerebellar cortical circuit during behavior to see if I could shed some light on the computations being performed. The dissertation is divided into three main sections. In the first, I present the results of preliminary work performed by myself and my colleagues to advance the aims of the project. This included writing software to train squirrel monkeys and control a variety of vestibulo-oculomotor tasks, characterizing the oculomotor behavioral repertoire of the squirrel monkey in comparison to that of the rhesus macaque, and developing two techniques for examining the roles of interneurons in cerebellar processing. In the second, I present the results of a study of one such interneuron, the Golgi cell, which is the main type of inhibitory interneuron that regulates information flow at the input stage of the cerebellar cortex. I recorded Golgi cells in the ventral paraflocculus: VPFL), a region of the cerebellum known to be involved in oculomotor behavior, while squirrel monkeys performed visual, vestibular, and eye movement tasks, and found that the VPFL Golgi cells only carry information from the eye movement pathways. Further, I found that this eye movement information is highly specific, with individual Golgi cells having relatively narrow directional tuning during saccades and pursuit, and only responding within a range of eye positions. This suggests that Golgi cells, through their powerful inhibition of the main path from the input stage to subsequent levels of processing, may serve as spatio-temporal filters of the information arriving at the cerebellar cortex. I delve deeper into this problem in the third section of the dissertation, where I present results from my recordings of mossy fibers and Purkinje cells, the main input and sole output elements, respectively, of the cerebellar cortex. I recorded these elements while the monkeys performed the same tasks as with the Golgi cells, sometimes while simultaneously recording Golgi cells, and examined how their responses compared with the responses of Golgi cells. I found that mossy fibers as a population are more narrowly tuned than Golgi cells, though many individual Golgi cells share a similar tuning width as the mossy fibers, and have different temporal response properties. When individual mossy fibers were recorded near, or simultaneously with, a Golgi cell, the mossy fiber and Golgi cell responses were usually antiphasic. This suggests that the net effect of mossy fiber activity on Golgi cells is inhibitory. When I examined Purkinje cell responses with respect to mossy fibers and Golgi cells, I found that the Purkinje cells generally had broader tuning and more complex, multimodal responses than Golgi cells, consistent with a greater convergence of inputs to Purkinje cells. Finally, when I examined the potential role of Purkinje cell inhibitory inputs coming from molecular layer interneurons by blocking GABA-A receptors while recording Purkinje cells, I found that this inhibition may serve to suppress bursts that are present in the eye movement-related mossy fibers that provide a dominant input to the VPFL. At the end of that chapter I attempt to synthesize these results with the results on the Golgi cells, and in the concluding chapter I suggest additional experiments to further explore the roles of cerebellar cortical interneurons in sensorimotor processing

Implications of Potassium Channel Heterogeneity for Model Vestibulo-Ocular Reflex Response Fidelity

The Vestibulo-Ocular Reflex (VOR) produces compensatory eye movements in response to head and body rotations movements, over a wide range of frequencies and in a variety of dimensions. The individual components of the VOR are separated into parallel pathways, each dealing with rotations or movements in individual planes or axes. The Horizontal VOR (hVOR) compensates for eye movements in the Horizontal plane, and comprises a linear and non-linear pathway. The linear pathway of the hVOR provides fast and accurate compensation for rotations, the response being produced through 3-neuron arc, producing a direct translation of detected head velocity to compensatory eye velocity. However, single neurons involved in the middle stage of this 3-neuron arc cannot account for the wide frequency over which the reflex compensates, and the response is produced through the population response of the Medial Vestibular Nucleus (MVN) neurons involved. Population Heterogeneity likely plays a role in the production of high fidelity population response, especially for high frequency rotations. Here we present evidence that, in populations of bio-physical compartmental models of the MVN neurons involved, Heterogeneity across the population, in the form of diverse spontaneous firing rates, improves the response fidelity of the population over Homogeneous populations. Further, we show that the specific intrinsic membrane properties that give rise to this Heterogeneity may be the diversity of certain slow voltage activated Potassium conductances of the neurons. We show that Heterogeneous populations perform significantly better than Homogeneous populations, for a wide range of input amplitudes and frequencies, producing a much higher fidelity response. We propose that variance of Potassium conductances provides a plausible biological means by which Heterogeneity arises, and that the Heterogeneity plays an important functional role in MVN neuron population responses. We discuss our findings in relation to the specific mechanism of Desynchronisation through which the benfits of Heterogeneity may arise, and place those findings in the context of previous work on Heterogeneity both in general neural processing, and the VOR in particular. Interesting findings regarding the emergence of phase leads are also discussed, as well as suggestions for future work, looking further at Heterogeneity of MVN neuron populations