Erik De Schutter

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.

Complex parameter landscape for a complex neuron model.

The electrical activity of a neuron is strongly dependent on the ionic channels present in its membrane. Modifying the maximal conductances from these channels can have a dramatic impact on neuron behavior. But the effect of such modifications can also be cancelled out by compensatory mechanisms among different channels. We used an evolution strategy with a fitness function based on phase-plane analysis to obtain 20 very different computational models of the cerebellar Purkinje cell. All these models produced very similar outputs to current injections, including tiny details of the complex firing pattern. These models were not completely isolated in the parameter space, but neither did they belong to a large continuum of good models that would exist if weak compensations between channels were sufficient. The parameter landscape of good models can best be described as a set of loosely connected hyperplanes. Our method is efficient in finding good models in this complex landscape. Unraveling the landscape is an important step towards the understanding of functional homeostasis of neurons.

Anomalous Diffusion in Purkinje Cell Dendrites Caused by Spines

We combined local photolysis of caged compounds with fluorescence imaging to visualize molecular diffusion within dendrites of cerebellar Purkinje cells. Diffusion of a volume marker, fluorescein dextran, within spiny dendrites was remarkably slow in comparison to its diffusion in smooth dendrites. Computer simulations indicate that this retardation is due to a transient trapping of molecules within dendritic spines, yielding anomalous diffusion. We considered the influence of spine trapping on the diffusion of calcium ions (Ca(2+)) and inositol-1,4,5-triphospate (IP(3)), two synaptic second messengers. Diffusion of IP(3) was strongly influenced by the presence of dendritic spines, while Ca(2+) was removed so rapidly that it could not diffuse far enough to be trapped. We conclude that an important function of dendritic spines may be to trap chemical signals and thereby create slowed anomalous diffusion within dendrites.

Computational neuroscience : realistic modeling for experimentalists

Foreword Introduction Introduction to Equation Solving and Parameter Fitting Modeling Networks of Signaling Pathways Modeling Local and Global Calcium Signals Using Reaction-Diffusion Systems Monte Carlo methods for Simulating Realistic Synaptic Microphysiology Using Mcell Which Formalism to Use for Modeling Voltage-Dependent Conductances Accurate Reconstruction of Neuronal Morphology Modeling Dendritic Geometry and the Development of Nerve Connections Passive Cable Modeling - a Practical Introduction Modeling Simple and Complex Active Neurons Realistic Modeling of Small Neuronal Circuits Modeling of Large Networks Modeling of Interactions Between Neural Networks and Musculoskeletal Systems

Microcircuits in action – from CPGs to neocortex

To understand the interface between global brain function and molecular neuroscience--that is, the microcircuit level--a major challenge. Such understanding is prerequisite if we are to account for neural function in cellular terms. Very few vertebrate microcircuits are yet understood because their analysis is demanding technically. In this review of the TINS Microcircuits Special Feature, we attempt to shed light on the problem by comparing the operation of four types of microcircuit, to identify common molecular and cellular components. Central pattern generator (CPG) networks underlying rhythmic movements and hippocampal microcircuits that generate gamma and theta rhythms are compared with the neocortical microcircuits used in cognitive tasks and a cerebellar network. The long-term goal is to identify the components of a molecular and synaptic tool kit for the design of different microcircuits.

Cerebellar long-term depression might normalize excitation of Purkinje cells: a hypothesis.

Long-term depression (LTD) of parallel-fibre (PF) synapses on Purkinje cells is usually interpreted in the context of a specific theory of motor learning by the cerebellum proposed by Marr, Albus and Ito. Several arguments suggest that this theory might be false. A new hypothesis about the role of cerebellar LTD proposes that, under physiological conditions, LTD is autoinduced by PF inputs. This proposal is based on the capacity of PF inputs to trigger influx of Ca2+ into the dendrite. Long-term depression and other forms of Purkinje-cell synaptic plasticity are part of a local negative feedback loop that prevents overstimulation of Purkinje cells by PF inputs. This theory explains why it is difficult to induce LTD when a normal level of inhibition is present, and why inhibitory inputs are potentiated by the same conditions that can induce LTD of PF synapses.

A Higher Order Motion Region in Human Inferior Parietal Lobule: Evidence from fMRI

The proposal that motion is processed by multiple mechanisms in the human brain has received little anatomical support so far. Here, we compared higher- and lower-level motion processing in the human brain using functional magnetic resonance imaging. We observed activation of an inferior parietal lobule (IPL) motion region by isoluminant red-green gratings when saliency of one color was increased and by long-range apparent motion at 7 Hz but not 2 Hz. This higher order motion region represents the entire visual field, while traditional motion regions predominantly process contralateral motion. Our results suggest that there are two motion-processing systems in the human brain: a contralateral lower-level luminance-based system, extending from hMT/V5+ into dorsal IPS and STS, and a bilateral higher-level saliency-based system in IPL.

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.

Regular Patterns in Cerebellar Purkinje Cell Simple Spike Trains

Background Cerebellar Purkinje cells (PC) in vivo are commonly reported to generate irregular spike trains, documented by high coefficients of variation of interspike-intervals (ISI). In strong contrast, they fire very regularly in the in vitro slice preparation. We studied the nature of this difference in firing properties by focusing on short-term variability and its dependence on behavioral state. Methodology/Principal Findings Using an analysis based on CV2 values, we could isolate precise regular spiking patterns, lasting up to hundreds of milliseconds, in PC simple spike trains recorded in both anesthetized and awake rodents. Regular spike patterns, defined by low variability of successive ISIs, comprised over half of the spikes, showed a wide range of mean ISIs, and were affected by behavioral state and tactile stimulation. Interestingly, regular patterns often coincided in nearby Purkinje cells without precise synchronization of individual spikes. Regular patterns exclusively appeared during the up state of the PC membrane potential, while single ISIs occurred both during up and down states. Possible functional consequences of regular spike patterns were investigated by modeling the synaptic conductance in neurons of the deep cerebellar nuclei (DCN). Simulations showed that these regular patterns caused epochs of relatively constant synaptic conductance in DCN neurons. Conclusions/Significance Our findings indicate that the apparent irregularity in cerebellar PC simple spike trains in vivo is most likely caused by mixing of different regular spike patterns, separated by single long intervals, over time. We propose that PCs may signal information, at least in part, in regular spike patterns to downstream DCN neurons.

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. J. Comp. Neurol. 408:580–596, 1999.