E. De Schutter

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.

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.

PATTERNS AND PAUSES IN PURKINJE CELL SIMPLE SPIKE TRAINS: EXPERIMENTS, MODELING AND THEORY

We review our recent experimental and modeling results on how cerebellar Purkinje cells encode information in their simple spike trains and present a theory of the function of pauses and regular spiking patterns. The regular spiking patterns were discovered in extracellular recordings of simple spikes in awake and anesthetized rodents, where it was shown that more than half of the spontaneous activity consists of short epochs of regular spiking. These periods of regular spiking are interrupted by pauses, which can be tightly synchronized among nearby Purkinje cells, while the spikes in the regular patterns are not. Interestingly, pauses are affected by long-term depression of the parallel fiber synapses. Both in modeling and slice experiments it was demonstrated that long-term depression causes a decrease in the duration of pauses, leading to an increase of the spike output of the neuron. Based on these results we propose that pauses in the simple spike train form a temporal code which can lead to a rebound burst in the target deep cerebellar nucleus neurons. Conversely, the regular spike patterns may be a rate code, which presets the amplitude of future rebound bursts.

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.

Computer software for development and simulation of compartmental models of neurons

Abstract A software package ‘Nodus’ for simulation and development of compartmental models of neurons is described. Passive or excitable membranes with voltage dependent ion conductances or synaptic conductances can be modeled. Detailed simulations of morphology and electrophysiology of neurons are possible. Neurophysiological experiments like voltage clamps and complex current injections can be simulated. Two integration methods are available: a fast hybrid method and an accurate fifth order Runge-Kutta method, with variable time steps. Nodus is implemented on Apple Macintosh microcomputers, with the standard user interface and interactive graphics. Simulations of simple test models demonstrate the accuracy and computation speed of the application.

Modulatory Effects of Parallel Fiber and Molecular Layer Interneuron Synaptic Activity on Purkinje Cell Responses to Ascending Segment Input: A Modeling Study

Based on anatomical, physiological, and model-based studies, it has been proposed that synapses associated with the ascending segment of granule cell axons provide the principle excitatory drive on Purkinje cells which is then modulated by the more numerous parallel fiber synapses. In this study we have evaluated this idea using a detailed compartmental model of a cerebellar Purkinje cell by providing identical ascending segment synaptic inputs during different levels of random parallel fiber and molecular interneuron input. Results suggest that background inputs from parallel fibers and molecular layer interneurons can have a substantial effect on the response of Purkinje cells to ascending segment inputs. Interestingly, these effects are not reflected in the average firing rate of the Purkinje cell and are thus entirely dendritic in effect. These results are considered in the context of the known segregated spatial distribution of the parallel fibers and ascending segment synapses and a new hypothesis concerning the functional organization of cerebellar cortical circuitry.

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.

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.

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.

NEOSIM: Portable large-scale plug and play modelling☆

NEOSIM is a new simulation framework addressed at building large scale and detailed models of the nervous system. Its essence is a set of interfaces and protocols that enable a plug and play architecture for incorporating existing simulation modules such as NEURON [4] and GENESIS [1] as well as future visualisation and data analysis modules. From the start it has been designed to exploit parallel and distributed computers to reduce simulation run times to manageable levels, without the additional modelling e!ort required for earlier publicly-available parallel simulation tools. In this paper, we present the design of the NEOSIM framework, and discuss its applicability to a range of modelling studies. 2001 Published by Elsevier Science B.V.