Deep cerebellar neurons mirror the spinal cord’s gain to implement an inverse controller

Smooth and coordinated motion requires precisely timed muscle activation patterns, which due to biophysical limitations, must be predictive and executed in a feed-forward manner. In a previous study, we tested Kawato’s original proposition, that the cerebellum implements an inverse controller, by mapping a multizonal microcomplex’s (MZMC) biophysics to a joint’s inverse transfer function and showing that inferior olivary neuron may use their intrinsic oscillations to mirror a joint’s oscillatory dynamics. Here, to continue to validate our mapping, we propose that climbing fiber input into the deep cerebellar nucleus (DCN) triggers rebounds, primed by Purkinje cell inhibition, implementing gain on IO’s signal to mirror the spinal cord reflex’s gain thereby achieving inverse control. We used biophysical modeling to show that Purkinje cell inhibition and climbing fiber excitation interact in a multiplicative fashion to set DCN’s rebound strength; where the former primes the cell for rebound by deinactivating its T-type Ca2⁺ channels and the latter triggers the channels by rapidly depolarizing the cell. We combined this result with our control theory mapping to predict how experimentally injecting current into DCN will affect overall motor output performance, and found that injecting current will proportionally scale the output and unmask the joint’s natural response as observed by motor output ringing at the joint’s natural frequency. Experimental verification of this prediction will lend support to a MZMC as a joint’s inverse controller and the role we assigned underlying biophysical principles that enable it.     

On the cerebellum and motor learning

A critical review of the role of the cerebellum in motor learning is presented. Specifically, the hypothesis that the climbing fibers that issue from the inferior olive serve to modify the responsiveness of cerebellar Purkinje cells is evaluated. It is concluded that there is no convincing evidence, at this time, to support the view that a long-term modification of Purkinje cell activity is either the basis of motor learning or an authentic mechanism of cerebellar function. An alternative view, based on the biophysical, anatomical and ensemble properties of olivary neurons, suggests an important role for the olivocerebellar system in the coordination of movements. Future work in this interesting area of neuroscience will distinguish these two hypotheses.     

Signals from the cerebellum guide the pathfinding of inferior olivary axons

During development, inferior olivary axons cross the floor plate and project from the caudal to the rostral hindbrain, whence they grow into the cerebellar plate. We have investigated the axon guidance signals involved in the formation of this projection in vitro. When the cerebellar plate was grafted ectopically along the margin of the hindbrain in organotypic cultures, inferior olivary axons could pathfind to the ectopic cerebellum, establishing a topographically normal projection. Following rostrocaudal reversal of a region of tissue in the axon pathway between the inferior olive and the cerebellum, olivary axons still navigated towards the cerebellum. Moreover, olivary axons could cross a bridging tissue explant (spinal cord) to reach a cerebellar explant. In collagen gel cultures of inferior olive explants, olivary axon outgrowth increased significantly in the presence of cerebellar explants and axons deflected towards the cerebellar tissue. These results show that the cerebellum is a source of diffusible axon guidance signals for olivary axons. We also found that, in organotypic cultures, olivary axons which had crossed the floor plate showed an increased tendency to respond to cerebellar cues. Taken together, these results indicate that the cerebellum is the source of cues that are chemoattractant and growth-promoting for inferior olivary axons; prior exposure to the floor plate increases responsiveness to these cues.     

Climbing Fiber Burst Size and Olivary Sub-threshold Oscillations in a Network Setting

The inferior olivary nucleus provides one of the two main inputs to the cerebellum: the so-called climbing fibers. Activation of climbing fibers is generally believed to be related to timing of motor commands and/or motor learning. Climbing fiber spikes lead to large all-or-none action potentials in cerebellar Purkinje cells, overriding any other ongoing activity and silencing these cells for a brief period of time afterwards. Empirical evidence shows that the climbing fiber can transmit a short burst of spikes as a result of an olivary cell somatic spike, potentially increasing the information being transferred to the cerebellum per climbing fiber activation. Previously reported results from in vitro studies suggested that the information encoded in the climbing fiber burst is related to the occurrence of the spike relative to the ongoing sub-threshold membrane potential oscillation of the olivary cell, i.e. that the phase of the oscillation is reflected in the size of the climbing fiber burst. We used a detailed three-compartmental model of an inferior olivary cell to further investigate the possible factors determining the size of the climbing fiber burst. Our findings suggest that the phase-dependency of the burst size is present but limited and that charge flow between soma and dendrite is a major determinant of the climbing fiber burst. From our findings it follows that phenomena such as cell ensemble synchrony can have a big effect on the climbing fiber burst size through dendrodendritic gap-junctional coupling between olivary cells.     

Localization of alcohol and aldehyde dehydrogenases in the human spinal cord and brain

Location of aldehyde dehydrogenase (AldDG) and alcohol dehydrogenase (ADG) has been studied in 38 nuclei of the human brain. Neurons with a high AldDG activity predominate in the nucleus of the descending root of the trigeminal nerve, motor nuclei of the craniocerebral nerves (trigeminal, facial, abducent, blocking, sublingual, supraspinal), motor nuclei of the anterior horns of the spinal cord, lateral vestibular nucleus, posterior nucleus of the vagus nerve, pedunculopontine nucleus, superior salivary nucleus, and in the nucleus of Westphal-Edinger-Jacobovich. Neurons with a moderate AldDG activity predominate in the superior olivary complex, nucleus of the lateral loop, parabrachial (pigmented) mesencephalic nucleus and reticular lateral nucleus. A low enzymatic activity is specific for neurons of the pons proper, inferior vestibular nucleus, trapezoid body of the inferior olivary complex, dentate nucleus of the cerebellum, reticular nucleus of the tegmen of Bekhterev's pons and posterior nucleus of Gudden's suture. A high ADG activity is revealed in piriform neurons of the cerebellar cortex. Functional importance of ADG and AldDG activity in the brain is discussed.     

Fine structural analysis of calcitonin gene-related peptide in the mouse inferior olivary complex

Climbing fiber afferents to the cerebellum, from the inferior olivary complex, have a powerful excitatory effect on Purkinje cells. Changes in the responsiveness of olivary neurons to their afferent inputs, leading to changes in the firing rate or pattern of activation in climbing fibers, have a significant effect on the activation of cerebellar neurons and ultimately on cerebellar function. Several neuropeptides have been localized in both varicosities and cell bodies of the mouse inferior olivary complex, one of which, calcitonin gene related peptide (CGRP), has been shown to modulate the activity of olivary neurons. The purpose of the present study was to investigate the synaptic relationships of CGRP-containing components of the caudal medial accessory olive and the principal olive of adult mice, using immunohistochemistry and electron microscopy. The vast majority of immunoreactive profiles were dendrites and dendritic spines within and outside the glial boundaries of synaptic glomeruli (clusters). Both received synaptic inputs from non-CGRP labeled axon terminals. CGRP was also present within the somata of olivary neurons as well as in profiles that had cytological characteristics of axons, some of which were filled with synaptic vesicles. These swellings infrequently formed synaptic contacts. At the LM level, few, if any, CGRP-immunoreactive climbing fibers, were seen, suggesting that CGRP is compartmentalized within the somata and dendrites of olivary neurons and is not transported to their axon terminals. Thus, in addition to previously identified extrinsic sources of CGRP, the widespread distribution of CGRP within olivary somata and dendrites identifies an intrinsic source of the peptide suggesting the possibility of dendritic release and a subsequent autocrine or paracrine function for this peptide within olivary circuits.     

Optimal feedback control to describe multiple representations of primary motor cortex neurons

Primary motor cortex (M1) neurons are tuned in response to several parameters related to motor control, and it was recently reported that M1 is important in feedback control. However, it remains unclear how M1 neurons encode information to control the musculoskeletal system. In this study, we examined the underlying computational mechanisms of M1 based on optimal feedback control (OFC) theory, which is a plausible hypothesis for neuromotor control. We modelled an isometric torque production task that required joint torque to be regulated and maintained at desired levels in a musculoskeletal system physically constrained by muscles, which act by pulling rather than pushing. Then, a feedback controller was computed using an optimisation approach under the constraint. In the presence of neuromotor noise, known as signal-dependent noise, the sensory feedback gain is tuned to an extrinsic motor output, such as the hand force, like a population response of M1 neurons. Moreover, a distribution of the preferred directions (PDs) of M1 neurons can be predicted via feedback gain. Therefore, we suggest that neural activity in M1 is optimised for the musculoskeletal system. Furthermore, if the feedback controller is represented in M1, OFC can describe multiple representations of M1, including not only the distribution of PDs but also the response of the neuronal population.     

Role of olivary electrical coupling in cerebellar motor learning

The level of electrotonic coupling in the inferior olive is extremely high, but its functional role in cerebellar motor control remains elusive. Here, we subjected mice that lack olivary coupling to paradigms that require learning-dependent timing. Cx36-deficient mice showed impaired timing of both locomotion and eye-blink responses that were conditioned to a tone. The latencies of their olivary spike activities in response to the unconditioned stimulus were significantly more variable than those in wild-types. Whole-cell recordings of olivary neurons in vivo showed that these differences in spike timing result at least in part from altered interactions with their subthreshold oscillations. These results, combined with analyses of olivary activities in computer simulations at both the cellular and systems level, suggest that electrotonic coupling among olivary neurons by gap junctions is essential for proper timing of their action potentials and thereby for learning-dependent timing in cerebellar motor control.     

Response of Neurons of The Inferior Colliculi of Cats To Changes in the Intensity of One of The Monaural Components of Binaurally Presented Stimuli

In spite of the large quantity of psychophysiological investigations of binaural hearing, a systematic study of its concrete mechanisms has only been begun comparatively recently (cf. review [1]). In particular, changes in neuron response under conditions of lateral differentiation brought about by varying the intensity of one of the monaural components of binaurally presented stimuli have been studied in detail only at the site of the superior olivary body (3, 4, 6) — the first section of the auditory system — where afferent fibers from the right and left cochlea converge (7, 9). Published data provide evidence that variations in the intensity of one of the monaural components of binaurally presented signals has an appreciable effect on the firing rate of single neurons of the inferior colli cuius (5, 8), which is situated directly behind the superior olivary body of the auditory system. in the present report, the types of response of neurons in the inferior colliculus to variations in the intensity of one of the monaural components of binaurally presented stimuli are systematically investigated.     

Co-cultures of inferior olive and cerebellum: electrophysiological evidence for multiple innervation of Purkinje cells by olivary axons.

Slices of inferior olive (IO) and cerebellum were co-cultured for several weeks by means of the roller tube technique. Recordings were carried out intracellularly from Purkinje cells (PCs) which were identified morphologically by intracellular injection of the fluorescent dye Lucifer yellow, or by immunohistochemical stainings with antibodies raised against the 28 kD Ca(2+)-binding protein calbindin. Following stimulation of olivary tissue, an all-or-none full complex spike response was recorded in some PCs consisting of a fast rising spike followed by a depolarizing potential. In other PCs, graded stimulation of the olivary explant induced synaptic potentials which were characterized by step-wise variation in their amplitude and resembled the ones occurring spontaneously. In contrast, only smoothly graded synaptic potentials were observed in cerebellar mono-cultures. These results indicate that some of the PCs in olivo-cerebellar co-cultures are innervated by several olivary neurons.     

Co-cultures of inferior olive and cerebellum: Electrophysiological evidence for multiple innervation of Purkinje cells by olivary axons

Slices of inferior olive (IO) and cerebellum were co-cultured for several weeks by means of the roller tube technique. Recordings were carried out intracellularly from Purkinje cells (PCs) which were identified morphologically by intracellular injection of the fluorescent dye Lucifer yellow, or by immunohistochemical stainings with antibodies raised against the 28 kD Ca²⁺-binding protein calbindin. Following stimulation of olivary tissue, an all-or-none full complex spike response was recorded in some PCs consisting of a fast rising spike followed by a depolarizing potential. In other PCs, graded stimulation of the olivary explant induced synaptic potentials which were characterized by step-wise variation in their amplitude and resembled the ones occurring spontaneously. In contrast, only smoothly graded synaptic potentials were observed in cerebellar mono-cultures. These results indicate that some of the PCs in olivo-cerebellar co-cultures are innervated by several olivary neurons.     

Dissociating object directed and non-object directed action in the human mirror system; implications for theories of motor simulation

Mirror neurons are single cells found in macaque premotor and parietal cortices that are active during action execution and observation. In non-human primates, mirror neurons have only been found in relation to object-directed movements or communicative gestures, as non-object directed actions of the upper limb are not well characterized in non-human primates. Mirror neurons provide important evidence for motor simulation theories of cognition, sometimes referred to as the direct matching hypothesis, which propose that observed actions are mapped onto associated motor schemata in a direct and automatic manner. This study, for the first time, directly compares mirror responses, defined as the overlap between action execution and observation, during object directed and meaningless non-object directed actions. We present functional MRI data that demonstrate a clear dissociation between object directed and non-object directed actions within the human mirror system. A premotor and parietal network was preferentially active during object directed actions, whether observed or executed. Moreover, we report spatially correlated activity across multiple voxels for observation and execution of an object directed action. In contrast to predictions made by motor simulation theory, no similar activity was observed for non-object directed actions. These data demonstrate that object directed and meaningless non-object directed actions are subserved by different neuronal networks and that the human mirror response is significantly greater for object directed actions. These data have important implications for understanding the human mirror system and for simulation theories of motor cognition. Subsequent theories of motor simulation must account for these differences, possibly by acknowledging the role of experience in modulating the mirror response.     

Cerebellar development: afferent organization and Purkinje cell heterogeneity.

Olivo- and spinocerebellar maps in the adult cerebellum of small rodents are discontinuous, with sharp boundaries. Cortical Purkinje cells constitute a heterogeneous population, organized into parasagittal, mutually exclusive compartments. The boundaries of the intrinsic cortical compartments and those of the projectional maps are congruent. During development; (i) The incoming olivary fibres, once they penetrate in the cerebellar parenchyma, are attracted toward their ultimate terminal fields, without passing through a stage of random dispersion. (ii) Migrating Purkinje cells and inferior olivary neurons begin, asynchronously, to express cellular markers in an independent manner, giving rise to a transient compartmentation of the cerebellar cortex and the inferior olivary complex respectively. In both instances, the biochemical heterogeneity disappears during the first postnatal week, simultaneously with the acquisition of adult-like cerebellar maps. (iii) The formation of the maps is an early event, prior to the establishment of the synaptology of the cerebellar cortical circuitry. Moreover, the organization of the spinocerebellar projection in adult mutant mice does not depend on the presence of granule cells (staggerer) but on the presence of normal Purkinje cells (weaver), indicating that synaptogenesis with their target neurons is not involved in the process of map formation. The matching of region specific chemical labels between incoming afferent fibres and heterogeneous sets of Purkinje cells is the most appealing mechanism for the formation of cerebellar maps.     

An optimisation-based model for full-body upright reaching movements

An optimal simulation 3D model for full-body upright reaching movements was developed using graphic-based modelling tools (SimMechanics) to generate an inverse dynamics model of the skeleton and using parameterisation methods for a sensory motor controller. The adaptive weight coefficient of the cost function based on the final motor task error (i.e. distance between end-effector and target at the end of movement) was used to correct motor task error and physiological measurements (e.g. joint power, centre of mass displacement, etc.). The output of the simulation models using various cost functions were compared to experimental data from 15 healthy participants performing full-body upright reaching movements. The proposed method can reasonably predict full-body voluntary movements in terms of final posture, joint power, and movement of the centre of mass (COM) using simple algebraic calculations of inverse dynamics and forward kinematics instead of the complicated integrals of the forward dynamics. We found that the combination of several control strategies, i.e. minimising end-effector error, total joint power and body COM produced the best fit of the full-body reaching task.     

Specificity of a target cell-derived stop signal for afferent axonal growth

With a novel model culture system in which afferents are co-cultured with purified populations of target neurons, we have demonstrated that a target cell within the central nervous system (CNS), the cerebellar granule neuron, poses a ?stop-growing signal”? for its appropriate afferents, the mossy fibers. To ask whether this stop signal is afferent specific, we co-cultured granule neurons with an other cerebellar afferent system, the climbing fibers from the inferior olivary nuclei, which normally contact Purkinje neurons, and with retinal ganglion cell afferents, which never enter the cerebellum. Granule neurons do not pose a stop signal to either of these afferents. In contrast to pontine mossy afferents that grow well on laminin and showed reduced outgrowth on granule neurons, both olivary and retinal fibers displayed similar growth on laminin alone or on granule neurons. In addition, each afferent showed different degrees of fasciculation and growth cone morphology on laminin. Thus, the growth arrest signal sent by granule neurons is specifically recognized by their appropriate afferents. Moreover, these three types of afferents exhibit varying growth patterns on the same noncellular and cellular substrates, implicating distinct molecular characteristics of growth regulation for different classes of neurons that would contribute to specificity of synapse formation. © 1992 John Wiley & Sons, Inc.     

Hypertrophy of inferior olivary neurons: a degenerative, regenerative or plasticity phenomenon

After contralateral hemi-cerebellectomy, neurons in the cat inferior olive may either degenerate, appear unchanged (affected) or become hypertrophic. Morphological and physiological aspects of the latter two cell types are studied by means of intracellular recording and injection techniques and compared to normal olivary neurons. It is demonstrated that affected and hypertrophic olivary neurons can be activated by mesodiencephalic stimulation. Affected olivary neurons are morphologically very similar to normal cells. However, they may respond with long latency action potentials only to mesodiencephalic stimulation. Hypertrophic olivary neurons have an enlarged dendritic tree and soma. The soma and proximal dendrites are studded with spine-like processes. Their reaction to mesodiencephalic stimulation is very diverse and may consist of short and/or long latency action potentials that may or may not trigger dendritic spikes. It is argued that olivary hypertrophy does not present either a degenerative or regenerative state, but that both hypertrophic as well as affected olivary neurons can survive axotomy due to a strong and continuous electrotonic coupling, made possible by destruction of the GABAergic cerebellar afferents.     

Specificity of a target cell-derived stop signal for afferent axonal growth.

With a novel model culture system in which afferents are co-cultured with purified populations of target neurons, we have demonstrated that a target cell within the central nervous system (CNS), the cerebellar granule neuron, poses a "stop-growing signal" for its appropriate afferents, the mossy fibers. To ask whether this stop signal is afferent specific, we co-cultured granule neurons with another cerebellar afferent system, the climbing fibers from the inferior olivary nuclei, which normally contact Purkinje neurons, and with retinal ganglion cell afferents, which never enter the cerebellum. Granule neurons do not pose a stop signal to either of these afferents. In contrast to pontine mossy afferents that grow well on laminin and showed reduced outgrowth on granule neurons, both olivary and retinal fibers displayed similar growth on laminin alone or on granule neurons. In addition, each afferent showed different degrees of fasciculation and growth cone morphology on laminin. Thus, the growth arrest signal sent by granule neurons is specifically recognized by their appropriate afferents. Moreover, these three types of afferents exhibit varying growth patterns on the same noncellular and cellular substrates, implicating distinct molecular characteristics of growth regulation for different classes of neurons that would contribute to specificity of synapse formation.     

Atrial natriuretic peptide-like immunoreactivity in neurons and astrocytes of human cerebellum and inferior olivary complex.

Atrial natriuretic peptide (ANP) has previously been localized in areas of mammalian brain associated with olfaction, cardiovascular function, and fluid/electrolyte homeostasis. Despite the presence of several types of natriuretic peptide receptors in mammalian cerebellum, neither intrinsic nor extrinsic sources of the natriuretic peptides have been described. In this report we describe the immunohistochemical localization of both intrinsic and extrinsic sources for ANP in human cerebellum. ANP-like immunoreactivity (ANP-LIR) was observed in climbing fibers in the cerebellar molecular layer that probably originated from isolated immunopositive neurons of the inferior olivary complex. Intrinsic sources of ANP-LIR included small subpopulations of protoplasmic and fibrous astrocytes and Bergmann glia, as well as Golgi and Lugaro neurons of the granule cell layer. These results suggest that, in addition to its presumptive roles in local vasoregulation, ANP may serve as a modulator of the activity of Purkinje neurons.     

Ontogeny of afferents to the fetal rat cerebellum.

Afferents to the fetal rat cerebellum have been studied in fixed tissue with the fluorescent tracer, 1,1'-dioctadecyl-3,3,3',3'tetramethylindocarbocyanine perchlorate (DiI). The dye was applied to the cerebellar anlage at ages from embryonic day (E) 12 to birth (P0). Central processes of vestibular ganglion cells were found to be the first identifiable afferents to the cerebellum, being present at least by E13 and perhaps as early as E12. Ipsilateral spinocerebellar fibres may be labelled from E15, vestibular nuclei (both ipsi- and contralateral) also from E15, while contralateral inferior olivary nuclei could not be retrogradely labelled until E17. Trigeminocerebellar neurons in the interpolaris subnucleus of the nucleus of the trigeminal spinal tract and neurons of the lateral reticular nucleus were not labelled until E22 and P0, respectively. Finally, contralateral pontine nuclei were retrogradely labelled from the cerebellum after birth.     

Neuronal chains for actions in the parietal lobe: a computational model

The inferior part of the parietal lobe (IPL) is known to play a very important role in sensorimotor integration. Neurons in this region code goal-related motor acts performed with the mouth, with the hand and with the arm. It has been demonstrated that most IPL motor neurons coding a specific motor act (e.g., grasping) show markedly different activation patterns according to the final goal of the action sequence in which the act is embedded (grasping for eating or grasping for placing). Some of these neurons (parietal mirror neurons) show a similar selectivity also during the observation of the same action sequences when executed by others. Thus, it appears that the neuronal response occurring during the execution and the observation of a specific grasping act codes not only the executed motor act, but also the agent's final goal (intention).In this work we present a biologically inspired neural network architecture that models mechanisms of motor sequences execution and recognition. In this network, pools composed of motor and mirror neurons that encode motor acts of a sequence are arranged in form of action goal-specific neuronal chains. The execution and the recognition of actions is achieved through the propagation of activity bursts along specific chains modulated by visual and somatosensory inputs.The implemented spiking neuron network is able to reproduce the results found in neurophysiological recordings of parietal neurons during task performance and provides a biologically plausible implementation of the action selection and recognition process.Finally, the present paper proposes a mechanism for the formation of new neural chains by linking together in a sequential manner neurons that represent subsequent motor acts, thus producing goal-directed sequences.