Cerebellar Cortical Activity Research Articles

Cortico-cerebellar coordination facilitates neuroprosthetic control.

Temporally coordinated neural activity is central to nervous system function and purposeful behavior. Still, there is a paucity of evidence demonstrating how this coordinated activity within cortical and subcortical regions governs behavior. We investigated this between the primary motor (M1) and contralateral cerebellar cortex as rats learned a neuroprosthetic/brain-machine interface (BMI) task. In neuroprosthetic task, actuator movements are causally linked to M1 "direct" neurons that drive the decoder for successful task execution. However, it is unknown how task-related M1 activity interacts with the cerebellum. We observed a notable 3 to 6 hertz coherence that emerged between these regions' local field potentials (LFPs) with learning that also modulated task-related spiking. We identified robust task-related indirect modulation in the cerebellum, which developed a preferential relationship with M1 task-related activity. Inhibiting cerebellar cortical and deep nuclei activity through optogenetics led to performance impairments in M1-driven neuroprosthetic control. Together, these results demonstrate that cerebellar influence is necessary for M1-driven neuroprosthetic control.

Modulation of cerebellar cortical, cerebellar nuclear and vestibular nuclear activity using alternating electric currents.

Cerebellar transcranial alternating current stimulation (ctACS) has shown promise as a therapeutic modality for treating a variety of neurological disorders, and for affecting normal learning processes. Yet, little is known about how electric fields induced by applied currents affect cerebellar activity in the mammalian cerebellum under in vivo conditions. Alternating current (AC) stimulation with frequencies from 0.5 to 20 Hz was applied to the surface of the cerebellum in anesthetized rats. Extracellular recordings were obtained from Purkinje cells (PC), cerebellar and vestibular nuclear neurons, and other cerebellar cortical neurons. AC stimulation modulated the activity of all classes of neurons. Cerebellar and vestibular nuclear neurons most often showed increased spike activity during the negative phase of the AC stimulation. Purkinje cell simple spike activity was also increased during the negative phase at most locations, except for the cortex directly below the stimulus electrode, where activity was most often increased during the positive phase of the AC cycle. Other cortical neurons showed a more mixed, generally weaker pattern of modulation. The patterns of Purkinje cell responses suggest that AC stimulation induces a complex electrical field with changes in amplitude and orientation between local regions that may reflect the folding of the cerebellar cortex. Direct measurements of the induced electric field show that it deviates significantly from the theoretically predicted radial field for an isotropic, homogeneous medium, in both its orientation and magnitude. These results have relevance for models of the electric field induced in the cerebellum by AC stimulation.

Elettrocortical spectral analysis and fractal methods for assessing the effects of unilateral brain injury on rat cerebellum

We used electrocortical spectral analysis and fractal methods for assessing the effects of unilateral, single brain injury on cerebellum. Cerebellar electrocortical activity was recorded in control state (before the injury) and after a single brain injury of the cerebellar cortex in anesthetized rats. We noticed that the mean power in gamma high-frequency domain (32-128 Hz) of the cerebellum, was increased after the first brain injury, while after a two-week recovery, it was larger than before the injury. The unilateral brain injury induced a permanent increase of the mild gamma activity in both the left and the right side of cerebellum cortex, but there was no further increase after the lesion was repeated. Our recent electrophysiological study on the cerebellum (Culic et al., 2005) suggested that the mean power spectra of the cerebellar cortical activity in the gamma frequency range might be the indicator of acute single focal brain injury. However, there is insufficient information on the effects of the repeated brain injury on the cerebellar electrocortical activity and morphology. There was no significant difference between the absolute and the relative mean power of the left and the right paravermal cortical activity (before, as well as, after the injury), in each of the animals tested afterwards, but there were differences between the left and the right side of cerebellum in experimental animals. Repeated injury of the cerebellar cortical areas, is strengthened by morphological changes in the cerebellar hemisphere, and shows a decrease in delta and an increase in gamma range.

Evolving Models of Pavlovian Conditioning: Cerebellar Cortical Dynamics in Awake Behaving Mice.

SummaryThree decades of electrophysiological research on cerebellar cortical activity underlying Pavlovian conditioning have expanded our understanding of motor learning in the brain. Purkinje cell simple spike suppression is considered to be crucial in the expression of conditional blink responses (CRs). However, trial-by-trial quantification of this link in awake behaving animals is lacking, and current hypotheses regarding the underlying plasticity mechanisms have diverged from the classical parallel fiber one to the Purkinje cell synapse LTD hypothesis. Here, we establish that acquired simple spike suppression, acquired conditioned stimulus (CS)-related complex spike responses, and molecular layer interneuron (MLI) activity predict the expression of CRs on a trial-by-trial basis using awake behaving mice. Additionally, we show that two independent transgenic mouse mutants with impaired MLI function exhibit motor learning deficits. Our findings suggest multiple cerebellar cortical plasticity mechanisms underlying simple spike suppression, and they implicate the broader involvement of the olivocerebellar module within the interstimulus interval.

Spillover-Mediated Feedforward Inhibition Functionally Segregates Interneuron Activity

Neurotransmitter spillover represents a form of neural transmission not restricted to morphologically defined synaptic connections. Communication between climbing fibers (CFs) and molecular layer interneurons (MLIs) in the cerebellum is mediated exclusively by glutamate spillover. Here, we show how CF stimulation functionally segregates MLIs based on their location relative to glutamate release. Excitation of MLIs that reside within the domain of spillover diffusion coordinates inhibition of MLIs outside the diffusion limit. CF excitation of MLIs is dependent on extrasynaptic NMDA receptors that enhance the spatial and temporal spread of CF signaling. Activity mediated by functionally segregated MLIs converges onto neighboring Purkinje cells (PCs) to generate a long-lasting biphasic change in inhibition. These data demonstrate how glutamate release from single CFs modulates excitability of neighboring PCs, thus expanding the influence of CFs on cerebellar cortical activity in a manner not predicted by anatomical connectivity.

Post-training cerebellar cortical activity plays an important role for consolidation of memory of cerebellum-dependent motor learning

Adaptation of mouse horizontal optokinetic response (HOKR) eye movement provides an experimental model for cerebellum-dependent motor learning. Our previous study revealed that the memory trace of HOKR adaptation is initially encoded in the cerebellar flocculus after hours of optokinetic training, and transferred to the vestibular nuclei to be consolidated to long-term motor memory after days of training [28]. To reveal how the cerebellar cortex operates in the transfer of the memory trace of adaptation, we examined the effects of shutdown of the cerebellar cortex after daily training. Three groups of mice received 1 h of optokinetic training daily for 4 days, and showed similar amounts of adaptation after the end of 1 h of training throughout 4 days. However, in the mice which daily received bilateral floccular muscimol infusion under gas anesthesia in the post-training period, consolidation of memory of the adaptation was markedly impaired, compared with the control mice which daily received bilateral floccular Ringer's solution infusions under gas anesthesia or those which daily received only gas anesthesia. These results are consistent with the studies of the effects of inactivation of cerebellar cortex on the consolidation of motor memory of rabbit eyeblink conditioning [2,4,18], and suggest that the post-training cerebellar cortex activity play an important for the consolidation of motor memory of HOKR adaptation.

Non‐invasive magnetic stimulation of the human cerebellum facilitates cortico‐bulbar projections in the swallowing motor system

Animal and human brain imaging studies suggest that the cerebellum plays an important role in the control of swallowing. In this study, we probed the interaction between cerebellar and pharyngeal motor cortical activity with transcranial magnetic stimulation (TMS) to determine if the cerebellum can modulate cortical swallowing motor circuitry. Healthy volunteers (n=16, eight men, mean age=32, range 19-57years) underwent TMS measurements of pharyngeal electromyography (EMG) recorded from a swallowed intraluminal catheter to assess cortical and cerebellar excitability. Subjects then underwent a paired pulse paradigm, where active or sham TMS conditioning pulses over the cerebellum and control sites were followed by suprathreshold TMS over the cortical pharyngeal area. Paired pulses were delivered at varying inter-stimulus intervals (ISIs) with the cortical response amplitudes being assessed. Stimulation of the cerebellum over its midline or hemispheres evoked distinct pharyngeal EMG responses. There was no difference in EMG amplitudes following cerebellar hemispheric or midline stimulation (mean 55.5±6.9 vs 42.8±5.9μV, P=0.08). In contrast, after cerebellar preconditioning, the cortically evoked responses underwent maximal facilitation at ISIs of 50-200ms (P<0.05), an effect not seen with sham or trigeminal nerve preconditioning. Posterior fossa stimulation excites the cerebellum and evokes direct motor responses within the pharynx. When conditioned with TMS, the cerebellum strongly facilitates the cortical swallowing motor pathways. This finding suggests that the cerebellum exerts a modulatory effect on human swallowing and raises the possibility that excitatory neurostimulation of the cerebellum may be therapeutically useful in promoting recovery of dysphagia after neural damage.

Cerebellar plasticity and the automation of first-order rules.

Theories of corticocerebellar function propose roles for the cerebellum in automating motor control, a process thought to depend on plasticity in cerebellar circuits that exchange information with the motor cortex. Little is known, however, about automating behaviors beyond the motor domain. The present study tested the hypothesis that cerebellar plasticity also subserves the development of automaticity in behavior based on low-order rules. Human subjects were required to learn two sets of first-order rules in which visual stimuli of different shapes each arbitrarily instructed a particular finger movement. We used event-related functional magnetic resonance imaging to scan subjects while these response rules became increasingly automatic with practice, as assessed with a dual-task procedure. We found that the amplitude of the blood oxygenation level-dependent signal gradually decreased as a function of practice, as responses became increasingly automatic, and that this effect was greater for a set of rules that became automatic rapidly compared with a second set, which became automatic more slowly. These trial-by-trial activity changes occurred in Crus I of cerebellar cortical lobule HVIIA, in which neurons exchange information with the prefrontal cortex rather than the motor cortex. Activity in Crus I was time locked specifically to the processing of these rules, rather than to subsequent actions. The results support the hypothesis that decreases in cerebellar cortical activity underlie the automation of behavior, whether related to motor control and motor cortex or to response rules and prefrontal cortex.

Long-term changes in cerebellar activation during functional recovery from transient peripheral motor paralysis

Localized altered cerebellar cortical activity can be associated with short-term changes in motor learning that take place in the course of hours, but it is unknown whether it can be correlated to long-term recovery from transient peripheral motor diseases, and if so, whether it occurs concomitantly in related brain regions. Here we show in a longitudinal fMRI study of patients with unilateral Bell's palsy that increases in ipsilateral cerebellar activity follow the recovery course of facial motor functions over at least one and a half years. These findings hold true for changes in brain activity related to both oral and peri-orbital activation, even though these processes are differentially mediated by unilateral and bilateral brain connectivities, respectively. Activation of non-facial musculature, which was studied for control, does not show any change in cerebellar activity over time. The localized changes in cerebellar activities following activation of facial functions occur concomitantly with increases in activity of the facial region in the contralateral primary motor cortex suggesting that the cerebellum acts together with the cerebral cortex in long-term adaptation to transient pathological sensorimotor processing.

High-Frequency Organization and Synchrony of Activity in the Purkinje Cell Layer of the Cerebellum

The cerebellum controls complex, coordinated, and rapid movements, a function requiring precise timing abilities. However, the network mechanisms that underlie the temporal organization of activity in the cerebellum are largely unexplored, because in vivo recordings have usually targeted single units. Here, we use tetrode and multisite recordings to demonstrate that Purkinje cell activity is synchronized by a high-frequency (approximately 200 Hz) population oscillation. We combine pharmacological experiments and modeling to show how the recurrent inhibitory connections between Purkinje cells are sufficient to generate these oscillations. A key feature of these oscillations is a fixed population frequency that is independent of the firing rates of the individual cells. Convergence in the deep cerebellar nuclei of Purkinje cell activity, synchronized by these oscillations, likely organizes temporally the cerebellar output.

Cerebellar cortical activity in the cat anterior lobe during hindlimb stepping

We recorded from over 250 single cortical neurons throughout the medial anterior lobe of the cat cerebellum during passive movements of the ipsilateral hindlimb resembling stepping on a moving treadmill. We applied three different quantitative analysis techniques to determine the extent of neuronal modulation that could be accounted for by the stepping movements. The analyses all indicated that up to half the recorded neurons in all five lobules responded to these passive hindlimb movements. We reconstructed the locations of the recorded neurons on a 2-D map of the cerebellar cortex in order to determine the spatial distribution of responsive cells. Cells that were located in the classical hindlimb projection areas of the anterior lobe (in lobules 2 and 3) were generally most responsive to the limb movement with activity patterns that generally had a linear relationship to hindlimb kinematics. Cells in lobules 4 and 5, considered as classical forelimb areas of the cerebellum, were also responsive. Although these cells tended to have noisier firing patterns, many were found to be modulated nevertheless by the hindlimb movements. We also found a clear demarcation between zones b and c, with a higher fraction of responsive cells in all lobules located in zone b.

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.

Flavoprotein autofluorescence imaging in the cerebellar cortex in vivo

Autofluorescence optical imaging is rapidly becoming a widely used tool for mapping activity in the central nervous system function in vivo and investigating the coupling among neurons, glia, and metabolism. This paper provides a brief review of autofluorescence and of our recent work using flavoprotein imaging in the cerebellar cortex. Stimulation of the parallel fibers evokes an intrinsic fluorescence signal that is tightly coupled to neuronal activation and primarily generated postsynaptically. The signal originates from mitochondrial flavoproteins. The signal is biphasic, with the initial increase in fluorescence (light phase) resulting from the oxidation of flavoproteins and the subsequent decrease (dark phase) from the reduction of flavoproteins. The light phase is primarily neuronal, and the dark phase is primarily glial. Exploiting the spatial properties of molecular layer inhibition in the cerebellar cortex, we show that flavoprotein autofluorescence can monitor both excitatory and inhibitory activity in the cerebellar cortex. Furthermore, flavoprotein autofluorescence has revealed that molecular layer inhibition is organized into parasagittal domains that differentially modulate the spatial pattern of cerebellar cortical activity. The reduction in flavoprotein autofluorescence occurring in the inhibitory bands most likely reflects a decrease in intracellular Ca(2+) in the neurons inhibited by the molecular layer interneurons. Therefore, flavoprotein autofluorescence imaging is providing new insights into cerebellar cortical function and neurometabolic coupling.

Cerebellar Cortical Molecular Layer Inhibition Is Organized in Parasagittal Zones

Molecular layer inhibitory interneurons generate on-beam and off-beam inhibition in the cerebellar cortex that is hypothesized to control the timing and/or spatial patterning of Purkinje cell discharge. On- and off-beam inhibition has been assumed to be spatially uniform and continuous within a folium. Using flavoprotein autofluorescence optical imaging in the mouse cerebellar cortex in vivo, this study demonstrates that the inhibition evoked by parallel fiber and peripheral stimulation results in parasagittal bands of decreases in fluorescence that correspond to zebrin II-positive bands. The parasagittal bands of decreased fluorescence are abolished by GABA(A) antagonists and reflect the activity of molecular layer interneurons on their targets. The same banding pattern was observed using Ca2+ imaging. The bands produce spatially specific decreases in the responses to peripheral input. Therefore, molecular layer inhibition is compartmentalized into zebrin II parasagittal domains that differentially modulate the spatial pattern of cerebellar cortical activity.

Different responses of rat cerebellar Purkinje cells and Golgi cells evoked by widespread convergent sensory inputs

While the synaptic properties of Golgi cell-mediated inhibition of granule cells are well studied, less is known of the afferent inputs to Golgi cells so their role in information processing remains unclear. We investigated the responses of cerebellar cortical Golgi cells and Purkinje cells in Crus I and II of the posterior lobe cerebellar hemisphere to activation of peripheral afferents in vivo, using anaesthetized rats. Recordings were made from 70 Golgi cells and 76 Purkinje cells. Purkinje cells were identified by the presence of climbing fibre responses. Golgi cells were identified by both spontaneous firing pattern and response properties, and identification was confirmed using juxtacellular labelling of single neurones (n = 16). Purkinje cells in Crus II showed continuous firing at relatively high rates (25-60 Hz) and stimulation of peripheral afferents rarely evoked substantial responses. The most common response was a modest, long-latency, long-lasting increase in simple spike output. By comparison, the most common response evoked in Golgi cells by the same stimuli was a long-latency, long-lasting depression of firing, found in approximately 70% of the Golgi cells tested. The onsets of Golgi cell depressions had shorter latencies than the Purkinje cell excitations. Brief, short-latency excitations and reductions in firing were also evoked in some Golgi cells, and rarely in Purkinje cells, but in most cases long-lasting depressions were the only significant change in spike firing. Golgi cell responses could be evoked using air puff or tactile stimuli and under four different anaesthetic regimens. Long-lasting responses in both neurone types could be evoked from wide receptive fields, in many cases including distal afferents from all four limbs, as well as from trigeminal afferents. These Golgi cell responses are not consistent with the conventional feedback inhibition or 'gain control' models of Golgi cell function. They suggest instead that cerebellar cortical activity can be powerfully modulated by the general level of peripheral afferent activation from much of the body. On this basis, Golgi cells may act as a context-specific gate on transmission through the mossy fibre-granule cell pathway.

New view on cerebellar cortical background activity in rat: simulation

AbstractThe aim of this study was to reveal the nature and meaning of interspike background activity (RBA) recorded in Prukinje cell layer of rat cerebellum. We compared Fourier amtplitude spectra of recorded, extracted and averaged simple spike(s)—SS and complex spike(s)—CS with the mean amplitude spectrum of the remaining interspike RBA. A much greater similarity of spectral characteristics was noticed between SS and RBA, than between CS and RBA. Then, we simulated background activity (SBA), by superimposing averaged SS with randomized amplitudes and time delays. There was a significant correlation (p&lt;0.005) between linearly transformed simulated and recorded amplitude spectra. Mean amplitude spectra of SBA were positively correlated with the number of superimposed SS. We propose to use this fact as a qualitative indication about the direction of change in the mean activity of surrounding neuronal population.

Federation of European Neuroscience Societies 2000 meeting

Many AAA members conducting neuroscience research have productive collaborative relationships with their European colleagues. It therefore seems appropriate to announce that the Federation of European Neuroscience Societies (FENS) will hold its annual meeting in Brighton, UK, June 24-28, 2000, at the Metropole Hotel and Brighton Conference Center. There will be a Special Interest Workshop on Three-Dimensional Microscopy on June 29. The organizers have put together an outstanding meeting that is only briefly summarized here. Details are available at http://www.fens2000.org. Prior to the FENS meeting, there will be two days of Satellite Symposia covering topics such as Synaptic Plasticity (contact Prof. Zafar Bashir, email z.i.bashir@bristol.ac.uk;), Knockouts and Mutants: Genetically Dissecting Brain and Behavior (contact Prof. W.E. Crusio, crusio@cnrs-orleans.fr), The Artificial Intelligence-Neuroscience Interface (contact Prof. M.O. Shea, email m.o-shea@sussex.ac.uk), and Space Motion Processing in the Auditory Systems (contact Prof. D. McAlpine, email d.mcalpine@ucl.ac.uk). A Satellite Symposium of particular interest has been organized by Prof. Richard Apps and Prof. D. Marple- Horvat of the University of Bristol and Prof. Chris Miall of Oxford and is entitled The Significance of Inferior Olivary and Cerebellar Cortical Activity for Motor Control. The participants and their respective topics are: Dr. Tom Ruigrok (Rotterdam) Anatomical and physiological organization of olivary circuits Dr. Martin Garwicz (Lund) Functional organization of olivocerebellar zones and microzones Dr. Kris Horn (Phoenix) Inferior olive neuronal activity during behavior Dr. Shigeru Kitazawa (Tsukuba) Information conveyed by olivocerebellar afferents Dr. Steve Lee (Bristol) Gating of olivocerebellar afferent pathways Dr. Markus Juptner (Essen) What do the cerebellum and basal ganglia contribute to motor control: lessons from PET experiments Dr. Dilwyn Marple-Horvat (Bristol) Signal processing in paravermal and hemispheral cortex during visually guided stepping and reaching Dr. Yasushi Kobayashi (Okazaki) Temporal firing patterns of complex spikes of Purkinje cells in the cerebellar ventral paraflocculus during ocular following responses in moneys Dr. Timothy Ebner (Minneapolis) Combining movement direction and speed signals in the discharge of Purkinje cells: encoding velocity Dr. Chris Miall (Oxford) The lateral cerebellum and visually guided movements: evidence of a forward model For further information on this symposium please contact Prof. D. Marple-Horvat, email d.e.marple-horvat@ bristol.ac.uk. The overall FENS meeting will consist of Special Interest Workshops, Technical Workshops, several Plenary Lectures, 43 Symposia, and Special Interest Symposia. In addition there will be several other special presentations and lectures. For further information on this meeting, including general information on potential travel routes to Bristol, visit the web site http://www.fens2000.org.

Development of an fMRI Paradigm to Assess Cerebellar Cortical vs. Deep Nuclei Activity in Schizophrenia

Development of an fMRI Paradigm to Assess Cerebellar Cortical vs. Deep Nuclei Activity in Schizophrenia

Changes in Rabbit Cerebellar Cortical and Interpositus Nucleus Activity during Acquisition, Extinction, and Backward Classical Eyelid Conditioning

Multiple- and single-unit neuronal activities were recorded from cerebellar cortex (Larsell's lobule HVI and adjacent ansiform cortex) and the cerebellar interpositus nucleus during forward (CS-US), backward (US-CS), and explicitly unpaired classical eyeblink conditioning in several rabbits. Whereas learning-related activity was observed in the interpositus nucleus only during forward pairing of the conditioning stimuli, a variety of patterns of learning-related neuronal firings were observed in cerebellar cortex during forward, backward, and even unpaired presentations of the conditioning stimuli. These data suggest that the cerebellar cortex and the deep cerebellar nuclei play different roles during classical eyeblink conditioning.

Chronic NMDA receptor blockade or muscimol inhibition of cerebellar cortical neuronal activity alters the development of spinocerebellar afferent topography

The requirement for cerebellar cortical neuronal activity in the development of spinocerebellar afferent topography was investigated in neonatal rats. In adult rats lower thoracic-upper lumbar spinocerebellar projections are localized to sharply circumscribed patches in the granule cell layer of the cerebellar anterior lobe. In transverse sections these patches appear as sagittally oriented stripes. This pattern develops postnatally as many spinal axons which initially project between the incipient stripes are eliminated thereby sharpening the stripe boundaries. We attempted to alter cerebellar cortical neuronal activity in neonatal animals to study the effects of these changes on the development of spinocerebellar stripes. In some experiments glutaminergic excitatory synaptic transmission was chronically blocked with the N- methyl- d-aspartate (NMDA) receptor antagonist 2-aminophosphovaleric acid (APV). In other experiments postsynaptic activity was directly inhibited by the γ-aminobutyric acid agonist muscimol. Chronic exposure to APV or to muscimol did not affect the initial development of spinocerebellar projections; many spinal axons were present in the anterior lobe and arranged in incipient stripes. Both the APV and the muscimol appeared to prevent the elimination of interstripe projections; consequently the boundaries of the stripes remained poorly defined. These findings suggest that cerebellar cortical neuronal activity is a necessary requirement for the refinement of spinal afferent topography in the anterior lobe.