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E De Schutter

Publications and source records attributed to E De Schutter.

At least 19 recordsLinked to original sources
PubMed2005

Deletion of FMR1 in Purkinje cells enhances parallel fiber LTD, enlarges spines, and attenuates cerebellar eyelid conditioning in Fragile X syndrome.

Absence of functional FMRP causes Fragile X syndrome. Abnormalities in synaptic processes in the cerebral cortex and hippocampus contribute to cognitive deficits in Fragile X patients. So far, the potential roles of cerebellar deficits have not been investigated. Here, we demonstrate that both global and Purkinje cell-specific knockouts of Fmr1 show deficits in classical delay eye-blink conditioning in that the percentage of conditioned responses as well as their peak amplitude and peak velocity are reduced. Purkinje cells of these mice show elongated spines and enhanced LTD induction at the parallel fiber synapses that innervate these spines. Moreover, Fragile X patients display the same cerebellar deficits in eye-blink conditioning as the mutant mice. These data indicate that a lack of FMRP leads to cerebellar deficits at both the cellular and behavioral levels and raise the possibility that cerebellar dysfunctions can contribute to motor learning deficits in Fragile X patients.

Animals↗
PubMed2002

Peripheral stimuli excite coronal beams of Golgi cells in rat cerebellar cortex.

Cerebellar granule cells constitute the largest neurone population of the brain. Their axons run as parallel fibres along the coronal axis, and the one-dimensional spread of excitation that is expected to result from this arrangement is a key assumption of theories of cerebellar function. In many studies using various techniques, however, it was not possible to evoke such a beam-like propagation of excitation with natural stimuli. We recorded, in Crus I and II of anaesthetised rats, pairs of Golgi cells aligned along the parallel fibre axis and synchronising spontaneously. Each pair was subjected to two stimulation protocols: punctate and semi-continuous. Local punctate facial stimulation evoked distinct fast and late responses of variable strength and latency (fast: 4.0-10.2 ms; late: 13.6-22.7 ms). Semi-continuous stimulation with a brush increased the firing rate, and modified the precision and phase of synchronisation. Differences between a pair in response strength and phase to brush stimulation correlated strongly with the difference in latency to punctate stimulation. These observations were reproduced in a model of the granular layer. The stimulus activated a central patch of mossy fibres, and Golgi cells received short- and long-range excitation from mossy and parallel fibres, respectively. The strength and latency of the punctate response of a model Golgi cell were found to vary with its position, reflecting a systematic change in the contribution of mossy and parallel fibres to its excitation with distance from the activated patch. During brush stimulation, model Golgi cells inside the patch fired more precisely synchronised, whereas the other Golgi cells responded with a lag proportional to their distance from the patch, thereby reproducing the experimentally observed changes in synchronisation. Taken together with the previously reported large receptive fields of Golgi cells and with their spontaneous synchronisation, the variable, position-dependent latency of evoked Golgi cell responses indicates a beam-like spread of excitation along the parallel fibres in rat cerebellar cortex.

Animals↗
PubMed2002

Non-curated distributed databases for experimental data and models in neuroscience.

Neuroscience is generating vast amounts of highly diverse data which is of potential interest to researchers beyond the laboratories in which it is collected. In particular, quantitative neuroanatomical data is relevant to a wide variety of areas, including studies of development, aging, pathology and in biophysically oriented computational modelling. Moreover, the relatively discrete and well-defined nature of the data make it an ideal application for developing systems designed to facilitate data archiving, sharing and reuse. At present, the only widely used forms of dissemination are figures and tables in published papers which suffer from inaccessibility and the loss of machine readability. They may also present only an averaged or otherwise selected subset of the available data. Numerous database projects are in progress to address these shortcomings. They employ a variety of architectures and philosophies, each with its own merits and disadvantages. One axis on which they may be distinguished is the degree of top-down control, or curation, involved in data entry. Here we consider one extreme of this scale in which there is no curation, minimal standardization and a wide degree of freedom in the form of records used to document data. Such a scheme has advantages in the ease of database creation and in the equitable assignment of perceived intellectual property by keeping the control of data in the hands of the experts who collected it. It does, however, require a more sophisticated infrastructure than conventional databases since the software must be capable of organizing diverse and differently documented data sets in an effective way. Several components of a software system to provide this infrastructure are now in place. Examples are presented, showing how these tools can be used to archive and publish neuronal morphology data, and how they can give an integrated view of data stored at many different sites.

Animals↗
PubMed2001

Morphological and neurochemical differentiation of large granular layer interneurons in the adult rat cerebellum.

The granular layer of the cerebellar cortex consists of densely packed neuronal cells, classified into granule cells and large interneurons. In this study, we provide a comparative survey of large granular layer interneurons in the adult rat cerebellum based on both morphological and neurochemical criteria. To this end, double immunofluorescence histochemistry was performed by combining antibodies against the cytoplasmic antigen Rat-303, calretinin, the metabotropic glutamate receptor mGluR2 and somatostatin. Based on Rat-303/calretinin double immunohistochemistry, three distinct populations of large granular layer interneurons could be discerned: cells immunopositive for Rat-303, calretinin or both. Rat-303 or calretinin single-labeled cells represented Golgi cells and unipolar brush cells, respectively. Rat-303/calretinin double-labeled cells located just underneath the Purkinje cell layer represented Lugaro cells. Morphometrical analysis distinguished two populations of Rat-303-positive Golgi cells according to their location: vermis versus hemisphere. Immunostaining for the metabotropic glutamate receptor mGluR2 combined with Rat-303 or calretinin revealed that the majority of Golgi cells (about 90%) appeared to be mGluR2 positive. Lugaro cells were mGluR2 negative. In addition, a limited population of large polymorphous interneurons in the depth of the granular layer with morphological features resembling Golgi cells also displayed Rat-303/calretinin immunoreactivity and were mGluR2 negative. Double immunohistochemistry for Rat-303 and somatostatin revealed three populations of labeled cells in the depth of the granular layer. Besides double-labeled Golgi cells, Rat-303 or somatostatin single-labeled cells were present. Based on mGluR2/somatostatin and calretinin/somatostatin double immunostainings, Rat-303 single-labeled cells were found to correspond to Rat-303/calretinin-positive, mGluR2-negative Golgi-like cells, while the identity of somatostatin single-labeled cells remained unclear. The data presented in this article elaborate previous reports on the morphological and neurochemical differentiation of large interneurons in the rat cerebellar granular layer. In addition, they indicate that the current classification of these cells into Golgi cells, Lugaro cells and unipolar brush cells does not describe the observed neurochemical heterogeneity.

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PubMed2001

Comparing BOLD fMRI signal changes in the awake and anesthetized rat during electrical forepaw stimulation.

The difference between awake curarized and alpha-chloralose anesthetized animals was studied with respect to the BOLD signal response in an fMRI experiment. By studying the activation of the cortex upon electrical forepaw stimulation in the same rat, but following consecutively applied curarization and alpha-chloralose anesthesia protocols, it was possible to compare quantitatively the effect of both immobilization protocols on the fMRI data. The largest BOLD signal change as a result of forepaw stimulation was found in the awake condition, however the activated areas are less specific than those in the anesthetized state leaving it more difficult to interpret.

Anesthesia, General↗
PubMed2000

Rat somatosensory cerebropontocerebellar pathways: spatial relationships of the somatotopic map of the primary somatosensory cortex are preserved in a three-dimensional clustered pontine map.

In the primary somatosensory cortex (SI), the body surface is mapped in a relatively continuous fashion, with adjacent body regions represented in adjacent cortical domains. In contrast, somatosensory maps found in regions of the cerebellar hemispheres, which are influenced by the SI through a monosynaptic link in the pontine nuclei, are discontinuous ("fractured") in organization. To elucidate this map transformation, the authors studied the organization of the first link in the SI-cerebellar pathway, the SI-pontine projection. After injecting anterograde axonal tracers into electrophysiologically defined parts of the SI, three-dimensional reconstruction and computer-graphic visualization techniques were used to analyze the spatial distribution of labeled fibers. Several target regions in the pontine nuclei were identified for each major body representation. The labeled axons formed sharply delineated clusters that were distributed in an inside-out, shell-like fashion. Upper lip and other perioral representations were located in a central core, whereas extremity and trunk representations were found more externally. The multiple clusters suggest that the pontine nuclei contain several representations of the SI map. Within each representation, the spatial relationships of the SI map are largely preserved. This corticopontine projection pattern is compatible with recently proposed principles for the establishment of subcortical topographic patterns during development. The largely preserved spatial relationships in the pontine somatotopic map also suggest that the transformation from an organized topography in SI to a fractured map in the cerebellum takes place primarily in the mossy fiber pontocerebellar projection.

Animals↗
PubMed2000

Weak common parallel fibre synapses explain the loose synchrony observed between rat cerebellar golgi cells.

1. In anaesthetized rats, pairs of cerebellar Golgi cells fired synchronously at rest, provided they were aligned along the parallel fibre axis. The observed synchrony was much less precise, however, than that which would be expected to result from common, monosynaptic parallel fibre excitation. 2. To explain this discrepancy, the precision and frequency of spike synchronization (i.e. the width and area of the central peak on the spike train cross-correlogram) were computed in a generic model for varying input, synaptic and neuronal parameters. 3. Correlation peaks between model neurons became broader, and peak area smaller, when the number of afferents increased and each single synapse decreased proportionally in strength. Peak width was inversely proportional to firing rate, but independent of the percentage of shared afferents. Peak area, in contrast, scaled with the percentage of shared afferents but was almost firing rate independent. 4. Broad correlation peaks between pairs of model neurons resulted from the loose spike timing between single model neurons and their afferents. This loose timing reflected a need for long-term synaptic integration to fire the neurons. Model neurons could accomplish this through firing rate adaptation mediated by a Ca2+-activated K+ channel. 5. We conclude that loose synchrony may be entirely explained by shared input from monosynaptic, non-synchronized afferents. The inverse relationship between peak width and firing rate allowed us to distinguish common parallel fibre input from firing rate covariance as a primary cause of loose synchrony between cerebellar Golgi cells in anaesthetized rats.

Action Potentials↗
PubMed1999

Miniature carrier with six independently moveable electrodes for recording of multiple single-units in the cerebellar cortex of awake rats.

Ensemble recording in cerebellar cortex of awake rats presents unique methodological challenges not encountered when recording from the cerebral cortex or from deep brain structures with more homogeneous cell populations. Compared to the cerebral cortex, removal of dura over the cerebellum evokes pronounced swelling, and insertion of multiple closely spaced electrodes in the cerebellar cortex causes considerable dimpling (Welsh JP, Schwartz C. Multielectrode recording from the cerebellum. In: Nicolelis MAL, editor. Methods for Neural Ensemble Recordings, CRC Methods in Neuroscience Series. Boca Raton, FL: CRC Press LLC, 1999, pp. 79-100). Also, a repetitious and well-defined neural circuit characterizes the cerebellar cortex across its entire surface. With conventional multi-electrode methods, such as chronically implanted bundles or arrays of microwires, the risk of disrupting the cerebellar cytoarchitecture is high. In most conventional multi-electrode systems, electrodes have rather low impedance and cannot be moved independently after implantation. These limitations make proper unit isolation, necessary to identify each of the recorded cerebellar units, very difficult. We designed a lightweight (14 g), miniature (base plate: 19 x 23 mm; total height: 16 mm) multi-electrode system to allow for the chronic implantation of six independently moveable sharp electrodes with high impedance, in the cerebellar cortex. The six electrodes are arranged in a 2 x 3 matrix (inter-electrode distance: 0.6 mm). At any time after the implantation the vertical position of each individual electrode can be adjusted by screwing spring-loaded electrode heads up or down. The system preserves the integrity of the cerebellar cytoarchitecture, and enables easy isolation and identification of individual cerebellar units in awake, freely moving rats.

Animals↗
PubMed1999

Ascending granule cell axon: an important component of cerebellar cortical circuitry.

Physiologic evidence suggests that local activation of the cerebellar granule cell layer produces a much more restricted spatial activation of overlying Purkinje cells than would be expected from the parallel fiber system. These results have led to the suggestion that synapses associated with the ascending granule cell axon may provide a large, direct, excitatory input to Purkinje cells, whereas parallel fiber synapses may be more modulatory in nature. In the current experiments, serial electron microscopy was used to reconstruct synapses associated with these two segments of the granule cell axons in the cerebellar cortex of albino rats. The results indicate that there are significantly more presynaptic vesicles in ascending segment synapses than in parallel fiber synapses. Furthermore, a first-order linear regression analysis revealed positive correlations between all measures of pre- and postsynaptic morphology for parallel fibers, but not for ascending segment synapses. Perhaps most surprisingly, serial reconstructions of postsynaptic spines and their associated dendrites demonstrated that spines contacted by ascending segment synapses are located exclusively on the smallest diameter distal regions of the Purkinje cell dendrites, whereas parallel fiber synapses are found exclusively on intermediate- and large-diameter regions of the spiny branchlets. Based on two independent calculations, we estimate that 20% of the granule cell synapses onto a Purkinje cell are actually made by the ascending segment. By using computer simulations of a single Purkinje cell dendrite, we have also demonstrated that synchronous activation of these distal ascending segment inputs could produce a substantial somatic response. Taken together, these results suggest that the two different regions of granule cell axons may play very different physiologic roles in cerebellar cortex.

Animals↗
PubMed1999

Parallel fibers synchronize spontaneous activity in cerebellar Golgi cells.

Cerebellar Golgi cells inhibit their afferent interneurons, the excitatory granule cells. Such a feedback inhibition causes both inhibitory and excitatory neurons in the circuit to synchronize. Our modeling work predicts that the long granule cell axons, the parallel fibers, entrain many Golgi cells and their afferent granule cells in a single synchronous rhythm. Spontaneous activity of 42 pairs of putative Golgi cells was recorded in anesthetized rats to test these predictions. In 25 of 26 pairs of Golgi cells that were positioned along the transverse axis, and presumed to receive common parallel fiber input, spontaneous activity showed a high level of coherence (mean Z score > 6). Conversely, 12 of 16 Golgi cell pairs positioned along the parasagittal axis (no common parallel fiber input) were not synchronized; 4 of 16 of them showed only low levels of synchronicity (mean Z score < 4). For transverse pairs the accuracy of the coherence, measured as the width at half-height of the central peak of the cross-correlogram, was rather low (29.8 +/- 12.5 msec) but increased with Golgi cell firing rate, as predicted by the model. These results suggest that in addition to their role as gain controllers, cerebellar Golgi cells may control the timing of granule cell spiking.

Action Potentials↗
PubMed1999

Cerebellar Golgi cells in the rat: receptive fields and timing of responses to facial stimulation.

Golgi cells are the only elements within the cerebellar cortex that inhibit granule cells. Despite their unique position there is little information on how Golgi cells respond to afferent input. We studied responses of Golgi cells to mechanical stimulation of the face, in Crus I-II of ketamine-xylazine anaesthetized rats. In 41 rats, 87 putative Golgi cells were identified, based on spike characteristics and on location of electrolytic lesions in the granular layer. They displayed a slow firing rhythm at rest (8.4 spikes/s). Most Golgi cells (84%) showed excitatory responses to tactile input. Their receptive fields (RFs) included, in 78%, the entire ipsilateral infraorbital nerve territory, and extended, in 14%, to other trigeminal nerve branches and, in 48%, to the contralateral face. Excitatory responses consisted of multiple, precisely timed (+/- 1 ms) spikes. Most peristimulus time histograms (PSTHs) (69%) showed an early (5-10 ms) and a late (13-26 ms) excitatory component, with each component consisting of a single PSTH peak. In some PSTHs the early component was a double peak (< 4 ms interval). In others, only one, early or late, PSTH peak was observed. The excitatory components were followed by a silent period (28-69 ms latency), the duration of which (13-200 ms) varied with response amplitude. In single cells, response profiles changed with stimulus location. In simultaneously recorded cells, evoked profiles differed for identical stimuli. Differences in RF size between early 'double' and 'single' peaks suggested that they resulted from direct mossy fibre and parallel fibre input, respectively. Late PSTH peaks were assumed to reflect corticopontine activation.

Animals↗
PubMed1999

A patchy horizontal organization of the somatosensory activation of the rat cerebellum demonstrated by functional MRI.

Blood oxygenation level dependent contrast (BOLD) functional MRI (fMRI) responses, in a 7-T magnet, were observed in the cerebellum of alpha-chloralose anaesthetized rats in response to innocuous electrical stimulation of a forepaw or hindpaw. The responses were imaged in both coronal and sagittal slices which allowed for a clear delineation and localization of the observed activations. We demonstrate the validity of our fMRI protocol by imaging the responses in somatosensory cortex to the same stimuli and by showing reproducibility of the cerebellar responses. Widespread bilateral activations were found with mainly a patchy and mediolateral band organization, more pronounced ipsilaterally. Possible parasagittal bands were observed only in contralateral lobule VI. There was no overlap between the cerebellar activations caused by forepaw and hindpaw stimuli. The overall horizontal organization of these responses was quite remarkable. For both stimulation paradigms most of the activation patches were positioned in either a rostral or caudal broad plane running anteroposteriorly through both anterior and posterior cerebellum. The rostral planes were completely separated, with the forepaw activation closer to the surface, while the caudal plane was common to both stimulation protocols. We relate our findings to the known projection patterns of spinocerebellar and cuneocerebellar mossy fibres, and to human fMRI studies.

Animals↗
PubMed1999

Using realistic models to study synaptic integration in cerebellar Purkinje cells.

This review presents an approach to modeling which we call "experiments in computo". The use of realistic models makes it possible to generate new predictions that can be confirmed experimentally. Several examples are given of how this approach has improved our understanding of synaptic integration by the Purkinje cell active dendrite. The computer model was constructed to replicate neuronal behavior which has no direct relevance to synaptic integration: it was tuned to reproduce the response of Purkinje cells to current injection in vitro, which consists of a high frequency, regular rhythm of somatic Na+ spikes, interrupted by spontaneous dendritic Ca2+ spikes. The in vivo firing behavior of Purkinje cells is quite different as it consists of highly irregular simple spike firing only, without spontaneous dendritic Ca2+ spikes. The computer model predicted-that the Purkinje cell needs to receive a continuous background inhibitory synaptic drive in addition to the excitation by parallel fibers to obtain this typical in vivo firing. This prediction was confirmed by blocking inhibition during in vivo intracellular recordings. More recently, we demonstrated that the net inhibitory drive to the Purkinje cell dendrite has to be larger than the excitatory synaptic drive. Inhibition hyperpolarizes the dendrite compared to the soma, making it act as a current sink during most of the spiking cycle. These predictions have been confirmed with the dynamic clamp method in the cerebellar slice preparation. Synchronous focal excitatory input by parallel fiber leads in the model to activation of voltage-gated Ca2+ channels which amplify the somatic response by a variable amount. The variability of this graded amplification is due both to position of the input, effectively canceling the cable attenuation, and to the effect of preceding background input. Differences between the model and experimental results in this aspect can be explained by the relative hyperpolarized state of Purkinje cells in the in vitro experimental preparation. These studies led to a new theory about the function of long-term depression in the cerebellum which can explain recent experimental results. In conclusion, our modeling approach generated predictions which contradicted prevalent ideas on how the cerebellum, or neurons in general, works and led to experiments which otherwise would not have been carried out.

Animals↗
PubMed1998

Dendritic voltage and calcium-gated channels amplify the variability of postsynaptic responses in a Purkinje cell model.

The dendrites of most neurons express several types of voltage and Ca2+-gated channels. These ionic channels can be activated by subthreshold synaptic input, but the functional role of such activations in vivo is unclear. The interaction between dendritic channels and synaptic background input as it occurs in vivo was studied in a realistic computer model of a cerebellar Purkinje cell. It previously was shown using this model that dendritic Ca2+ channels amplify the somatic response to synchronous excitatory inputs. In this study, it is shown that dendritic ion channels also increased the somatic membrane potential fluctuations generated by the background input. This amplification caused a highly variable somatic excitatory postsynaptic potential (EPSP) in response to a synchronous excitatory input. The variability scaled with the size of the response in the model with excitable dendrite, resulting in an almost constant coefficient of variation, whereas in a passive model the membrane potential fluctuations simply added onto the EPSP. Although the EPSP amplitude in the active dendrite model was quite variable for different patterns of background input, it was insensitive to changes in the timing of the synchronous input by a few milliseconds. This effect was explained by slow changes in dendritic excitability. This excitability was determined by how the background input affected the dendritic membrane potentials in the preceding 10-20 ms, causing changes in activation of voltage and Ca2+-gated channels. The most important model variables determining the excitability at the time of a synchronous input were the Ca2+-activation of K+ channels and the inhibitory synaptic conductance, although many other model variables could be influential for particular background patterns. Experimental evidence for the amplification of postsynaptic variability by active dendrites is discussed. The amplification of the variability of EPSPs has important functional consequences in general and for cerebellar Purkinje cells specifically. Subthreshold, background input has a much larger effect on the responses to coherent input of neurons with active dendrites compared with passive dendrites because it can change the effective threshold for firing. This gives neurons with dendritic calcium channels an increased information processing capacity and provides the Purkinje cell with a gating function.

Action Potentials↗
PubMed1998

Synchronization of golgi and granule cell firing in a detailed network model of the cerebellar granule cell layer.

The granular layer of the cerebellum has a disproportionately large number of excitatory (granule cells) versus inhibitory neurons (Golgi cells). Its synaptic organization is also unique with a dense reciprocal innervation between granule and Golgi cells but without synaptic contacts among the neurons of either population. Physiological recordings of granule or Golgi cell activity are scarce, and our current thinking about the way the granular layer functions is based almost exclusively on theoretical considerations. We computed the steady-state activity of a large-scale model of the granular layer of the rat cerebellum. Within a few tens of milliseconds after the start of random mossy fiber input, the populations of Golgi and granule cells became entrained in a single synchronous oscillation, the basic frequency of which ranged from 10 to 40 Hz depending on the average rate of firing in the mossy fiber population. The long parallel fibers ensured, through alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-mediated synapses, a coherent excitation of Golgi cells, while the regular firing of each Golgi cell synchronized all granule cells within its axonal radius through transient activation of their gamma-aminobutyric acid-A (GABAA) receptor synapses. Individual granule cells often remained silent during a few successive oscillation cycles so that their average firing rates, which could be quite variable, reflected the average activities of their mossy fiber afferents. The synchronous, rhythmic firing pattern was robust over a broad range of biologically realistic parameter values and to parameter randomization. Three conditions, however, made the oscillations more transient and could desynchronize the entire network in the end: a very low mossy fiber activity, a very dominant excitation of Golgi cells through mossy fiber synapses (rather than through parallel fiber synapses), and a tonic activation of granule cell GABAA receptors (with an almost complete absence of synaptically induced inhibitory postsynaptic currents). These three conditions were associated with a reduction in the parallel fiber activity, and synchrony could be restored by increasing the mossy fiber firing rate. The model predicts that, under conditions of strong mossy fiber input to the cerebellum, Golgi cells do not only control the strength of parallel fiber activity but also the timing of the individual spikes. Provided that their parallel fiber synapses constitute an important source of excitation, Golgi cells fire rhythmically and synchronized with granule cells over large distances along the parallel fiber axis. According to the model, the granular layer of the cerebellum is desynchronized when the mossy fiber firing rate is low.

Animals↗