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Steve A. Edgley - One of the best experts on this subject based on the ideXlab platform.
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Multiple extra-synaptic spillover mechanisms regulate prolonged activity in cerebellar Golgi Cell-granule Cell loops.
The Journal of Physiology, 2011Co-Authors: Tahl Holtzman, Vanessa Sivam, Tian Zhao, Oivier Frey, Peter D. Van Der Wal, Nico F. De Rooij, Jeffrey W. Dalley, Steve A. EdgleyAbstract:Despite a wealth of in vitro and modelling studies it remains unclear how neuronal populations in the cerebellum interact in vivo. We address the issue of how the cerebellar input layer processes sensory information, with particular focus on the granule Cells ( input relays) and their counterpart inhibitory interneurones, Golgi Cells. Based on the textbook view, granule Cells excite Golgi Cells via glutamate forming a negative feedback loop. However, Golgi Cells express inhibitory mGluR2 receptors suggesting an inhibitory role for glutamate. We set out to test this glutamatergic paradox in Golgi Cells. Here we show that granule Cells and Golgi Cells interact through extra-synaptic signalling mechanisms during sensory information processing, as well as synaptic mechanisms. We demonstrate that such interactions depend on granule Cell-derived glutamate acting via inhibitory mGluR2 receptors leading causally to the suppression of Golgi Cell activity for several hundreds of milliseconds. We further show that granule Cell-derived inhibition of Golgi Cell activity is regulated by GABA-dependent extra-synaptic Golgi Cell inhibition of granule Cells, identifying a regulatory loop in which glutamate and GABA may be critical regulators of Golgi Cell-granule Cell functional activity. Thus, granule Cells may promote their own prolonged activity via paradoxical feed-forward inhibition of Golgi Cells, thereby enabling information processing over long timescales.
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cerebellar Golgi Cells in the rat receive convergent peripheral inputs via a lateral reticular nucleus relay
European Journal of Neuroscience, 2010Co-Authors: Wei Xu, Steve A. EdgleyAbstract:: Golgi Cells are important players in the function of the cerebellar cortex, controlling the flow of incoming information from mossy fibres to the granule Cells, which excite other cortical neurons. We recently showed that in anaesthetized rats most Golgi Cells respond to stimulation of afferents from a very wide peripheral receptive field with a long-lasting depression of firing. These responses are mediated via a crossed ascending afferent pathway but the supraspinal part of this pathway is unknown. Here we have examined the hypothesis that the lateral reticular nucleus, a brainstem nucleus with known broad afferent convergence that projects mossy fibres to much of the cerebellum, is involved. First, we showed that single-pulse electrical microstimulation within the lateral reticular nucleus can elicit long-lasting depressions in Golgi Cells, which are qualitatively similar to those evoked by peripheral afferent stimulation. Second, we showed that the amplitude of the depressions of Golgi Cell firing evoked by peripheral stimulation can be reduced by pharmacological manipulation of the lateral reticular nucleus, either ipsilateral or contralateral to the stimulus site, with local injections of either the GABA(A) receptor agonist muscimol or the AMPA receptor blocker 6-cyano-7-nitroquinoxaline-2,3-dione. This evidence suggests that the lateral reticular nucleus is a relay nucleus in the brainstem for peripheral afferent information in a pathway that generates Golgi Cell long-lasting depression responses.
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Characterization in vivo of bilaterally branching pontocerebellar mossy fibre to Golgi Cell inputs in the rat cerebellum.
The European journal of neuroscience, 2008Co-Authors: Tahl Holtzman, Steve A. Edgley, Nadia L Cerminara, Richard AppsAbstract:Golgi Cells regulate the flow of information from mossy fibres to the cerebellar cortex, through a mix of feedback and feedforward inhibitory actions on granule Cells. The aim of the current study was to examine mossy fibre input to Golgi Cells, in order to assess their impact on switching Golgi Cells into feedforward behaviour. In urethane-anaesthetized rats, extraCellular recordings were made from Golgi Cells in Crus II (n = 18). Spikes were evoked in all Golgi Cells by microstimulation within the contralateral hemispheral cortex, via branches of mossy fibres that terminate in both cerebellar hemispheres. The latencies of these responses were very short, consistent with a monosynaptic mossy fibre contact [average onset latency 2.3 +/- 0.1 ms (SEM)]. The same stimuli had no measurable effect on spike responses of nearby Purkinje Cells (n = 12). Systematic mapping in the contralateral cerebellar hemisphere (Crus Ib, IIa, IIb and the paramedian lobule) usually revealed one low-intensity stimulus 'hotspot' (12-35 microA) from which short-latency spikes could be evoked in an individual Golgi Cell. Microinjections of red and green retrograde tracers (latex beads, approximately 50-150 nL injection volume) made at the recording site and the stimulation hotspot resulted in double-labelled neurons within the pontine nuclei. Overall, this suggests that subsets of pontine neurons supply mossy fibres that branch to both hemispheres, some of which directly target Golgi Cells. Such an arrangement may provide a common feedforward inhibitory link to temporally couple activity on both sides of the cerebellum during behaviour.
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Climbing fibre-dependent changes in Golgi Cell responses to peripheral stimulation.
The Journal of physiology, 2008Co-Authors: Steve A. EdgleyAbstract:Golgi Cells are important elements of the cerebellar cortex, controlling the flow of mossy fibre information to other Cells via granule Cells. Several anatomical reports suggest that climbing fibre afferents contact Golgi Cells, and electrophysiological studies suggest that they depress Golgi Cell firing. We reinvestigated this issue and, given that climbing fibres mediate synaptic plasticity in the cerebellar cortex, we have examined the effects of conjunctive stimulation of peripheral afferents and climbing fibres on Golgi Cell responses. The results confirm that climbing fibre stimulation depresses Golgi Cell firing at short latency. Golgi Cells responded to stimulation of peripheral afferents with longer latency depressions of firing and after conjunctive stimulation with climbing fibres these were significantly reduced. The reductions developed progressively over 20 min of conjunctive stimulation and were persistent (up to 84 min). Temporal conjunction of the inputs was important because non-synchronous stimulation of climbing fibres and peripheral afferents failed to alter the peripheral afferent-evoked response in Golgi Cells. In control experiments using either the same climbing fibre stimulation alone, or peripheral afferent stimulation paired with brainstem stimulation that did not activate climbing fibres, responses were not depressed. The results thus show that conjunctive stimulation of climbing fibres with other inputs to Golgi Cells can induce long-term changes in Golgi Cell responses in vivo. This raises the possibility that changes in Golgi Cell peripheral responses mediated by climbing fibres can potentially contribute to cerebellar motor learning.
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Cerebellar Golgi Cells in the rat receive multimodal convergent peripheral inputs via the lateral funiculus of the spinal cord
The Journal of Physiology, 2006Co-Authors: Tahl Holtzman, Abteen Mostofi, Chia-ling Phuah, Steve A. EdgleyAbstract:We recently showed that the activity of cerebellar Golgi Cells can be powerfully modulated by stimulation of peripheral afferents, in a pattern different to local Purkinje Cells. Here we have examined the pathways underlying these responses. Graded electrical stimulation of muscle and cutaneous nerves revealed that long-lasting depressions and short-lasting excitations of Golgi Cells were evoked by stimulation of cutaneous nerves at stimulus intensities that activated large mechanoreceptive afferents, and grew as additional afferents were recruited. In contrast, none of the neurones responded to stimulation of muscle nerves at intensities that activated group I afferents, although about half responded with long-lasting depressions, but not excitations, to stimuli that recruited group II and III afferents. Selective lesions of the spinal dorsal columns did not affect either of these types of response. After lesions of one lateral funiculus in the lumbar cord the responses evoked by stimulation of the hindlimb contralateral to the lesion were reduced or abolished, leaving responses evoked by ipsilateral hindlimb afferents unaltered. Since both ipsi- and contralateral afferents generate responses in Golgi Cells, the convergence from the two sides must occur supraspinally. It is difficult to reconcile these properties with any of the direct spinocerebellar pathways or spinoreticulocerebellar pathways that have been described. Instead, it is likely that the responses are evoked via the multimodal ‘wide dynamic range’ neurones of the anterolateral system. Golgi Cell activity may thus be powerfully enhanced or depressed during arousal via the anterolateral system.
Tahl Holtzman - One of the best experts on this subject based on the ideXlab platform.
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Multiple extra-synaptic spillover mechanisms regulate prolonged activity in cerebellar Golgi Cell-granule Cell loops.
The Journal of Physiology, 2011Co-Authors: Tahl Holtzman, Vanessa Sivam, Tian Zhao, Oivier Frey, Peter D. Van Der Wal, Nico F. De Rooij, Jeffrey W. Dalley, Steve A. EdgleyAbstract:Despite a wealth of in vitro and modelling studies it remains unclear how neuronal populations in the cerebellum interact in vivo. We address the issue of how the cerebellar input layer processes sensory information, with particular focus on the granule Cells ( input relays) and their counterpart inhibitory interneurones, Golgi Cells. Based on the textbook view, granule Cells excite Golgi Cells via glutamate forming a negative feedback loop. However, Golgi Cells express inhibitory mGluR2 receptors suggesting an inhibitory role for glutamate. We set out to test this glutamatergic paradox in Golgi Cells. Here we show that granule Cells and Golgi Cells interact through extra-synaptic signalling mechanisms during sensory information processing, as well as synaptic mechanisms. We demonstrate that such interactions depend on granule Cell-derived glutamate acting via inhibitory mGluR2 receptors leading causally to the suppression of Golgi Cell activity for several hundreds of milliseconds. We further show that granule Cell-derived inhibition of Golgi Cell activity is regulated by GABA-dependent extra-synaptic Golgi Cell inhibition of granule Cells, identifying a regulatory loop in which glutamate and GABA may be critical regulators of Golgi Cell-granule Cell functional activity. Thus, granule Cells may promote their own prolonged activity via paradoxical feed-forward inhibition of Golgi Cells, thereby enabling information processing over long timescales.
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Characterization in vivo of bilaterally branching pontocerebellar mossy fibre to Golgi Cell inputs in the rat cerebellum.
The European journal of neuroscience, 2008Co-Authors: Tahl Holtzman, Steve A. Edgley, Nadia L Cerminara, Richard AppsAbstract:Golgi Cells regulate the flow of information from mossy fibres to the cerebellar cortex, through a mix of feedback and feedforward inhibitory actions on granule Cells. The aim of the current study was to examine mossy fibre input to Golgi Cells, in order to assess their impact on switching Golgi Cells into feedforward behaviour. In urethane-anaesthetized rats, extraCellular recordings were made from Golgi Cells in Crus II (n = 18). Spikes were evoked in all Golgi Cells by microstimulation within the contralateral hemispheral cortex, via branches of mossy fibres that terminate in both cerebellar hemispheres. The latencies of these responses were very short, consistent with a monosynaptic mossy fibre contact [average onset latency 2.3 +/- 0.1 ms (SEM)]. The same stimuli had no measurable effect on spike responses of nearby Purkinje Cells (n = 12). Systematic mapping in the contralateral cerebellar hemisphere (Crus Ib, IIa, IIb and the paramedian lobule) usually revealed one low-intensity stimulus 'hotspot' (12-35 microA) from which short-latency spikes could be evoked in an individual Golgi Cell. Microinjections of red and green retrograde tracers (latex beads, approximately 50-150 nL injection volume) made at the recording site and the stimulation hotspot resulted in double-labelled neurons within the pontine nuclei. Overall, this suggests that subsets of pontine neurons supply mossy fibres that branch to both hemispheres, some of which directly target Golgi Cells. Such an arrangement may provide a common feedforward inhibitory link to temporally couple activity on both sides of the cerebellum during behaviour.
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Cerebellar Golgi Cells in the rat receive multimodal convergent peripheral inputs via the lateral funiculus of the spinal cord
The Journal of Physiology, 2006Co-Authors: Tahl Holtzman, Abteen Mostofi, Chia-ling Phuah, Steve A. EdgleyAbstract:We recently showed that the activity of cerebellar Golgi Cells can be powerfully modulated by stimulation of peripheral afferents, in a pattern different to local Purkinje Cells. Here we have examined the pathways underlying these responses. Graded electrical stimulation of muscle and cutaneous nerves revealed that long-lasting depressions and short-lasting excitations of Golgi Cells were evoked by stimulation of cutaneous nerves at stimulus intensities that activated large mechanoreceptive afferents, and grew as additional afferents were recruited. In contrast, none of the neurones responded to stimulation of muscle nerves at intensities that activated group I afferents, although about half responded with long-lasting depressions, but not excitations, to stimuli that recruited group II and III afferents. Selective lesions of the spinal dorsal columns did not affect either of these types of response. After lesions of one lateral funiculus in the lumbar cord the responses evoked by stimulation of the hindlimb contralateral to the lesion were reduced or abolished, leaving responses evoked by ipsilateral hindlimb afferents unaltered. Since both ipsi- and contralateral afferents generate responses in Golgi Cells, the convergence from the two sides must occur supraspinally. It is difficult to reconcile these properties with any of the direct spinocerebellar pathways or spinoreticulocerebellar pathways that have been described. Instead, it is likely that the responses are evoked via the multimodal ‘wide dynamic range’ neurones of the anterolateral system. Golgi Cell activity may thus be powerfully enhanced or depressed during arousal via the anterolateral system.
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Different responses of rat cerebellar Purkinje Cells and Golgi Cells evoked by widespread convergent sensory inputs.
The Journal of Physiology, 2006Co-Authors: Tahl Holtzman, Thimali Rajapaksa, Abteen Mostofi, Steve A. EdgleyAbstract:The precise geometric organization of the cerebellar cortical circuitry has allowed connectivity between the individual neurones to be well studied (Eccles et al. 1966; Ito, 1984). Most electrophysiological analyses of cerebellar processing focus on Purkinje Cell activity (Llinas & Sasaki, 1989; Keating & Thach, 1995; Welsh et al. 1995; Lang et al. 1999). While Purkinje Cells are the output Cells of the cerebellar cortex, these studies usually assume that Purkinje Cell activity is a ‘simple read-out’ of the underlying activity in the granular layer. Golgi Cells are an important element of the granular layer, being activated by mossy fibres both directly and via parallel fibres (Palay & Chan-Palay, 1974). Golgi Cells inhibit local granule Cells, so modulate excitatory transmission through mossy fibre–parallel fibre pathways. At the synaptic level, Golgi Cell inhibition of granule Cells has both fast synaptic and slower extrasynaptic ‘spillover’ components (e.g. Rossi & Hamann, 1998; Mitchell & Silver, 2000; Watanabe & Nakanishi, 2003). The circumstances in which Golgi Cell firing is modulated in vivo are poorly understood, therefore their contribution to granule Cell and Purkinje Cell firing remains elusive. Based on connectivity, and assuming that Golgi Cells sample inputs from parallel fibres that also excite local Purkinje Cells, it was proposed that Golgi Cells mediate feedback inhibition to exert ‘gain control’ over mossy fibre–granule Cell transmission. In this scheme, if more granule Cells become active, they excite Golgi Cells and as a result produce greater inhibition of granule Cells, which modulates overall excitation (Marr, 1969; Albus, 1971; Ito, 1984; see Maex & De Schutter, 1998). This feedback inhibition will be accompanied by feedforward inhibition driven by direct mossy fibre connections to the Golgi Cells (Precht & Llinas, 1969). Several lines of evidence suggest that Golgi Cells are not well suited for gain control, and modelling studies (Maex & De Schutter, 1998; De Schutter et al. 2000) have suggested an alternative role for Golgi Cells; that is, to synchronize granule Cell activity through closed loops formed by the granule Cell–Golgi Cell pathway, so that granule Cell spiking is precisely timed by Golgi Cell inhibition. Such patterns of Golgi Cell–granule Cell firing should be represented in the simple spike output of Purkinje Cells. Modulated activity of putative Golgi Cells in vivo has been described during vestibulo-occular reflex adaptation (Miles et al. 1980), locomotion in cats (Edgley & Lidierth, 1987) and limb movement in monkeys (Van Kan & Gibson, 1993). De Schutter and coworkers have investigated the response properties of putative Golgi Cells in Crus I and II of the rat cerebellar hemispheres (Vos et al. 1999, 2000; Volny-Luraghi et al. 2002). However, only recently have data been reported from Golgi Cells identified definitively using juxtaCellular labelling (Simpson et al. 2005). Here we have employed juxtaCellular labelling to characterize Golgi Cells. We show that in addition to brief excitatory responses from focal, mainly trigeminal afferents (Vos et al. 1999), Golgi Cell firing is frequently depressed over several hundred milliseconds after peripheral afferent stimulation, while the same stimuli frequently evoke modest increases in Purkinje Cell firing over a similar time course. These responses can be evoked with or without preceding excitations, are of long duration and can be evoked by stimuli from much of the body suggesting a highly convergent sensory input to the cerebellar cortex. These responses have not been described before and imply a functional role for Golgi Cells that is very different from current models.
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Different responses of rat cerebellar Purkinje Cells and Golgi Cells evoked by widespread convergent sensory inputs.
The Journal of physiology, 2006Co-Authors: Tahl Holtzman, Thimali Rajapaksa, Abteen Mostofi, Steve A. EdgleyAbstract: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.
Egidio D'angelo - One of the best experts on this subject based on the ideXlab platform.
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Cerebellar Golgi Cell models predict dendritic processing and mechanisms of synaptic plasticity
2020Co-Authors: Stefano Masoli, Alessandra Ottaviani, Egidio D'angeloAbstract:The Golgi Cells are the main inhibitory interneurons of the cerebellar granular layer. Although recent works have highlighted the complexity of their dendritic organization and synaptic inputs, the mechanisms through which these neurons integrate complex input patterns remained unknown. Here we have used 8 detailed morphological reconstructions to develop multicompartmental models of Golgi Cells, in which Na, Ca, and K channels were distributed along dendrites, soma, axonal initial segment and axon. The models faithfully reproduced a rich pattern of electrophysiological and pharmacological properties and predicted the operating mechanisms of these neurons. Basal dendrites turned out to be more tightly electrically coupled to the axon initial segment than apical dendrites. During synaptic transmission, parallel fibers caused slow Ca-dependent depolarizations in apical dendrites that boosted the axon initial segment encoder and Na-spike backpropagation into basal dendrites, while inhibitory synapses effectively shunted backpropagating currents. This oriented dendritic processing set up a coincidence detector controlling voltage-dependent NMDA receptor unblock in basal dendrites, which, by regulating local calcium influx, may provide the basis for spike-timing dependent plasticity anticipated by theory.
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Calcium channel-dependent induction of long-term synaptic plasticity at excitatory Golgi Cell synapses of cerebellum
2019Co-Authors: Francesca Locatelli, Teresa Soda, Ileana Montagna, Simona Tritto, Laura Botta, Francesca Prestori, Egidio D'angeloAbstract:The Golgi Cells, together with granule Cells and mossy fibers, form a neuronal microcircuit regulating information transfer at the cerebellum input stage. Despite theoretical predictions, little was known about long-term synaptic plasticity at Golgi Cell synapses. Here we have used whole-Cell patch-clamp recordings and calcium imaging to investigate long-term synaptic plasticity at excitatory synapses impinging on Golgi Cells. In acute mouse cerebellar slices, mossy fiber theta-burst stimulation (TBS) could induce either long-term potentiation (LTP) or long-term depression (LTD) at mossy fiber-Golgi Cell and granule Cell-Golgi Cell synapses. This synaptic plasticity showed a peculiar voltage-dependence, with LTD or LTP being favored when TBS induction occurred at depolarized or hyperpolarized potentials, respectively. LTP required, in addition to NMDA channels, activation of T-type Ca2+ channels, while LTD required uniquely activation of L-type Ca2+ channels. Notably, the voltage-dependence of plasticity at the mossy fiber-Golgi Cell synapses was inverted with respect to pure NMDA receptor-dependent plasticity at the neighboring mossy fiber-granule Cell synapse, implying that the mossy fiber presynaptic terminal can activate different induction mechanisms depending on the target Cell. In aggregate, this result shows that Golgi Cells show Cell-specific forms of long-term plasticity at their excitatory synapses, that could play a crucial role in sculpting the response patterns of the cerebellar granular layer.
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Complex dynamics in simplified neuronal models: reproducing Golgi Cell electroresponsiveness
2018Co-Authors: Alice Geminiani, Francesca Locatelli, Francesca Prestori, Claudia Casellato, Alessandra Pedrocchi, Egidio D'angeloAbstract:Brain neurons exhibit complex electroresponsive properties - including intrinsic subthreshold oscillations and pacemaking, resonance and phase-reset - which are thought to play a critical role in controlling neural network dynamics. Although these properties emerge from detailed representations of molecular-level mechanisms in "realistic" models, they cannot usually be generated by simplified neuronal models (although these may show spike-frequency adaptation and bursting). We report here that this whole set of properties can be generated by the extended generalized leaky integrate-and-fire (E-GLIF) neuron model. E-GLIF derives from the GLIF model family and is therefore mono-compartmental, keeps the limited computational load typical of a linear low-dimensional system, admits analytical solutions and can be tuned through gradient-descent algorithms. Importantly, E-GLIF is designed to maintain a correspondence between model parameters and neuronal membrane mechanisms through a minimum set of equations. In order to test its potential, E-GLIF was used to model a specific neuron showing rich and complex electroresponsiveness, the cerebellar Golgi Cell, and was validated against experimental electrophysiological data recorded from Golgi Cells in acute cerebellar slices. During simulations, E-GLIF was activated by stimulus patterns, including current steps and synaptic inputs, identical to those used for the experiments. The results demonstrate that E-GLIF can reproduce the whole set of complex neuronal dynamics typical of these neurons - including intensity-frequency curves, spike-frequency adaptation, depolarization-induced and post-inhibitory rebound bursting, spontaneous subthreshold oscillations, resonance and phase-reset, - providing a new effective tool to investigate brain dynamics in large-scale simulations.
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Regulation of output spike patterns by phasic inhibition in cerebellar granule Cells
Frontiers in cellular neuroscience, 2014Co-Authors: Thierry Nieus, Lisa Mapelli, Egidio D'angeloAbstract:The complex interplay of multiple molecular mechanisms taking part to synaptic integration is hard to disentangle experimentally. Therefore, we developed a biologically realistic computational model based on the rich set of data characterizing the cerebellar glomerulus microcircuit. A specific issue was to determine the relative role of phasic and tonic inhibition in dynamically regulating granule Cell firing, which has not been clarified yet. The model comprised the excitatory mossy fiber - granule Cell and the inhibitory Golgi Cell - granule Cell synapses and accounted for vesicular release processes, neurotransmitter diffusion and activation of different receptor subtypes. Phasic inhibition was based on stochastic GABA release and spillover causing activation of two major classes of postsynaptic receptors, α1 and α6, while tonic inhibition was based on steady regulation of a Cl- leakage. The glomerular microcircuit model was validated against experimental responses to mossy fiber bursts while metabotropic receptors were blocked. Simulations showed that phasic inhibition controlled the number of spikes during burst transmission but predicted that it specifically controlled time-related parameters (firing initiation and conclusion and first spike precision) when the relative phase of excitation and inhibition was changed. In all conditions, the overall impact of α6 was larger than that of α1 subunit-containing receptors. However, α1 receptors controlled granule Cell responses in a narrow ±10 ms band while α6 receptors showed broader ±50 ms tuning. Tonic inhibition biased these effects without changing their nature substantially. These simulations imply that phasic inhibitory mechanisms can dynamically regulate output spike patterns, as well as calcium influx and NMDA currents, at the mossy fiber - granule Cell relay of cerebellum without the intervention of tonic inhibition.
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The cerebellar Golgi Cell and spatiotemporal organization of granular layer activity
Frontiers in neural circuits, 2013Co-Authors: Egidio D'angelo, Lisa Mapelli, Sergio Solinas, Jonathan Mapelli, Daniela Gandolfi, Francesca PrestoriAbstract:The cerebellar granular layer has been suggested to perform a complex spatiotemporal reconfiguration of incoming mossy fiber signals. Central to this role is the inhibitory action exerted by Golgi Cells over granule Cells: Golgi Cells inhibit granule Cells through both feedforward and feedback inhibitory loops and generate a broad lateral inhibition that extends beyond the afferent synaptic field. This characteristic connectivity has recently been investigated in great detail and been correlated with specific functional properties of these neurons. These include theta-frequency pacemaking, network entrainment into coherent oscillations and phase resetting. Important advances have also been made in terms of determining the membrane and synaptic properties of the neuron, and clarifying the mechanisms of activation by input bursts. Moreover, voltage sensitive dye imaging and multi-electrode array (MEA) recordings, combined with mathematical simulations based on realistic computational models, have improved our understanding of the impact of Golgi Cell activity on granular layer circuit computations. These investigations have highlighted the critical role of Golgi Cells in: generating dense clusters of granule Cell activity organized in center-surround structures, implementing combinatorial operations on multiple mossy fiber inputs, regulating transmission gain, and cut-off frequency, controlling spike timing and burst transmission, and determining the sign, intensity and duration of long-term synaptic plasticity at the mossy fiber-granule Cell relay. This review considers recent advances in the field, highlighting the functional implications of Golgi Cells for granular layer network computation and indicating new challenges for cerebellar research.
Stephane Dieudonne - One of the best experts on this subject based on the ideXlab platform.
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A novel inhibitory nucleo-cortical circuit controls cerebellar Golgi Cell activity
eLife, 2015Co-Authors: Lea Ankri, Stephane Dieudonne, Zoé Husson, Katarzyna Pietrajtis, Rémi Proville, Clément Léna, Yosi Yarom, Uusisaari MarylkaAbstract:The cerebellum, a crucial center for motor coordination, is composed of a cortex and several nuclei. The main mode of interaction between these two parts is considered to be formed by the inhibitory control of the nuclei by cortical Purkinje neurons. We now amend this view by showing that inhibitory GABA-glycinergic neurons of the cerebellar nuclei (CN) project profusely into the cerebellar cortex, where they make synaptic contacts on a GABAergic subpopulation of cerebellar Golgi Cells. These spontaneously firing Golgi Cells are inhibited by optogenetic activation of the inhibitory nucleo-cortical fibers both in vitro and in vivo. Our data suggest that the CN may contribute to the functional recruitment of the cerebellar cortex by decreasing Golgi Cell inhibition onto granule Cells.
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A novel inhibitory nucleo-cortical circuit controls cerebellar Golgi Cell activity
eLife, 2015Co-Authors: Lea Ankri, Stephane Dieudonne, Zoé Husson, Katarzyna Pietrajtis, Rémi Proville, Clément Léna, Yosi Yarom, Marylka UusisaariAbstract:The cerebellum is a region in the brain that plays a central role in controlling posture and movement. The cerebellum is composed of a cortex and several nuclei. The nuclei are thought to ‘compute’ the signals that are sent from the cerebellum to other parts of the brain to control posture and movement. They do this under the supervision of the cortex. The main interaction between the cortex and the nuclei involves cortical neurons called Purkinje Cells inhibiting the activity of the nuclei. Ankri, Husson et al. have now used various genetic techniques and mutant mice to identify a new population of neurons in the nuclei of the cerebellum and to express fluorescent markers into these Cells. This approach reveals that the axons of these neurons ‘climb’ from the nuclei to the cortex to form a new circuit called the inhibitory nucleo-cortical (iNC) pathway. Moreover, activating the iNC axons with light reveals that they selectively target and silence a population of neurons called the Golgi Cells, which control the transmission of information in the cerebellar cortex. Ankri, Husson et al. go on to show that the Golgi Cells silenced by the iNC pathway differ from other Golgi Cells in a number of ways: in particular, these Golgi Cells use a chemical called GABA to communicate with neurons. The next challenge is to explore how the iNC pathway fine-tunes how sensory inputs are processed in the cerebellum, and to better understand its role in the execution of complex movements, including in people with conditions that affect motor function, such as ataxias.
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Electrical Coupling Mediates Tunable Low-Frequency Oscillations and Resonance in the Cerebellar Golgi Cell Network
Neuron, 2009Co-Authors: Guillaume P. Dugué, Clément Léna, Nicolas Brunel, Vincent Hakim, Eric J. Schwartz, Mireille Chat, Maxime Lévesque, Richard Courtemanche, Stephane DieudonneAbstract:Summary Tonic motor control involves oscillatory synchronization of activity at low frequency (5–30 Hz) throughout the sensorimotor system, including cerebellar areas. We investigated the mechanisms underpinning cerebellar oscillations. We found that Golgi interneurons, which gate information transfer in the cerebellar cortex input layer, are extensively coupled through electrical synapses. When depolarized in vitro, these neurons displayed low-frequency oscillatory synchronization, imposing rhythmic inhibition onto granule Cells. Combining experiments and modeling, we show that electrical transmission of the spike afterhyperpolarization is the essential component for oscillatory population synchronization. Rhythmic firing arises in spite of strong heterogeneities, is frequency tuned by the mean excitatory input to Golgi Cells, and displays pronounced resonance when the modeled network is driven by oscillating inputs. In vivo, unitary Golgi Cell activity was found to synchronize with low-frequency LFP oscillations occurring during quiet waking. These results suggest a major role for Golgi Cells in coordinating cerebellar sensorimotor integration during oscillatory interactions.
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Target-dependent use of co-released inhibitory transmitters at central synapses.
Journal of Neuroscience, 2005Co-Authors: Guillaume Dugué, Andréa Dumoulin, Antoine Triller, Stephane DieudonneAbstract:Corelease of GABA and glycine by mixed neurons is a prevalent mode of inhibitory transmission in the vertebrate hindbrain. However, little is known of the functional organization of mixed inhibitory networks. Golgi Cells, the main inhibitory interneurons of the cerebellar granular layer, have been shown to contain GABA and glycine. We show here that, in the vestibulocerebellum, Golgi Cells contact both granule Cells and unipolar brush Cells, which are excitatory relay interneurons for vestibular afferences. Whereas IPSCs in granule Cells are mediated by GABA(A) receptors only, Golgi Cell inhibition of unipolar brush Cells is dominated by glycinergic currents. We further demonstrate that a single Golgi Cell can perform pure GABAergic inhibition of granule Cells and pure glycinergic inhibition of unipolar brush Cells. This specialization results from the differential expression of GABA(A) and glycine receptors by target Cells and not from a segregation of GABA and glycine in presynaptic terminals. Thus, postsynaptic selection of coreleased fast transmitters is used in the CNS to increase the diversity of individual neuronal outputs and achieve target-specific signaling in mixed inhibitory networks.
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Target-Dependent Use of Coreleased Inhibitory Transmitters at Central Synapses
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2005Co-Authors: Guillaume P. Dugué, Andréa Dumoulin, Antoine Triller, Stephane DieudonneAbstract:Corelease of GABA and glycine by mixed neurons is a prevalent mode of inhibitory transmission in the vertebrate hindbrain. However, little is known of the functional organization of mixed inhibitory networks. Golgi Cells, the main inhibitory interneurons of the cerebellar granular layer, have been shown to contain GABA and glycine. We show here that, in the vestibulocerebellum, Golgi Cells contact both granule Cells and unipolar brush Cells, which are excitatory relay interneurons for vestibular afferences. Whereas IPSCs in granule Cells are mediated by GABA(A) receptors only, Golgi Cell inhibition of unipolar brush Cells is dominated by glycinergic currents. We further demonstrate that a single Golgi Cell can perform pure GABAergic inhibition of granule Cells and pure glycinergic inhibition of unipolar brush Cells. This specialization results from the differential expression of GABA(A) and glycine receptors by target Cells and not from a segregation of GABA and glycine in presynaptic terminals. Thus, postsynaptic selection of coreleased fast transmitters is used in the CNS to increase the diversity of individual neuronal outputs and achieve target-specific signaling in mixed inhibitory networks.
Erik De Schutter - One of the best experts on this subject based on the ideXlab platform.
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Spatiotemporal network coding of physiological mossy fiber inputs by the cerebellar granular layer.
PLOS Computational Biology, 2017Co-Authors: Shyam Kumar Sudhakar, Sungho Hong, Ivan Raikov, Rodrigo Publio, Claus Lang, Thomas G Close, Mario Negrello, Erik De SchutterAbstract:The granular layer, which mainly consists of granule and Golgi Cells, is the first stage of the cerebellar cortex and processes spatiotemporal information transmitted by mossy fiber inputs with a wide variety of firing patterns. To study its dynamics at multiple time scales in response to inputs approximating real spatiotemporal patterns, we constructed a large-scale 3D network model of the granular layer. Patterned mossy fiber activity induces rhythmic Golgi Cell activity that is synchronized by shared parallel fiber input and by gap junctions. This leads to long distance synchrony of Golgi Cells along the transverse axis, powerfully regulating granule Cell firing by imposing inhibition during a specific time window. The essential network mechanisms, including tunable Golgi Cell oscillations, on-beam inhibition and NMDA receptors causing first winner keeps winning of granule Cells, illustrate how fundamental properties of the granule layer operate in tandem to produce (1) well timed and spatially bound output, (2) a wide dynamic range of granule Cell firing and (3) transient and coherent gating oscillations. These results substantially enrich our understanding of granule Cell layer processing, which seems to promote spatial group selection of granule Cell activity as a function of timing of mossy fiber input.
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Na+/K+-ATPase inhibition partially mimics the ethanol-induced increase of the Golgi Cell-dependent component of the tonic GABAergic current in rat cerebellar granule Cells.
PloS one, 2013Co-Authors: Marvin R. Diaz, Erik De Schutter, Aya Wadleigh, Shyam Kumar, C. Fernando ValenzuelaAbstract:Cerebellar granule Cells (CGNs) are one of many neurons that express phasic and tonic GABAergic conductances. Although it is well established that Golgi Cells (GoCs) mediate phasic GABAergic currents in CGNs, their role in mediating tonic currents in CGNs (CGN-Itonic) is controversial. Earlier studies suggested that GoCs mediate a component of CGN-Itonic that is present only in preparations from immature rodents. However, more recent studies have detected a GoC-dependent component of CGN-Itonic in preparations of mature rodents. In addition, acute exposure to ethanol was shown to potentiate the GoC component of CGN-Itonic and to induce a parallel increase in spontaneous inhibitory postsynaptic current frequency at CGNs. Here, we tested the hypothesis that these effects of ethanol on GABAergic transmission in CGNs are mediated by inhibition of the Na+/K+-ATPase. We used whole-Cell patch-clamp electrophysiology techniques in cerebellar slices of male rats (postnatal day 23–30). Under these conditions, we reliably detected a GoC-dependent component of CGN-Itonic that could be blocked with tetrodotoxin. Further analysis revealed a positive correlation between basal sIPSC frequency and the magnitude of the GoC-dependent component of CGN-Itonic. Inhibition of the Na+/K+-ATPase with a submaximal concentration of ouabain partially mimicked the ethanol-induced potentiation of both phasic and tonic GABAergic currents in CGNs. Modeling studies suggest that selective inhibition of the Na+/K+-ATPase in GoCs can, in part, explain these effects of ethanol. These findings establish a novel mechanism of action of ethanol on GABAergic transmission in the central nervous system.
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Long-term depression at parallel fiber to Golgi Cell synapses.
Journal of neurophysiology, 2010Co-Authors: Quinten Robberechts, Mike Wijnants, Michele Giugliano, Erik De SchutterAbstract:Golgi Cells (GoCs) are the primary inhibitory interneurons of the granular layer of the cerebellum. Their inhibition of granule Cells is central to operate the relay of excitatory inputs to the cer...
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Alcohol excites cerebellar Golgi Cells by inhibiting the Na+/K+ ATPase.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2010Co-Authors: Paolo Botta, Erik De Schutter, Fabio M. Simões De Souza, Thomas Sangrey, C. Fernando ValenzuelaAbstract:Alcohol-induced alterations of cerebellar function cause motor coordination impairments that are responsible for millions of injuries and deaths worldwide. Cognitive deficits associated with alcoholism are also a consequence of cerebellar dysfunction. The mechanisms responsible for these effects of ethanol are poorly understood. Recent studies have identified neurons in the input layer of the cerebellar cortex as important ethanol targets. In this layer, granule Cells (GrCs) receive the majority of sensory inputs to the cerebellum through the mossy fibers. Information flow at these neurons is gated by a specialized pacemaker interneuron known as the Golgi Cell, which provides divergent GABAergic input to thousands of GrCs. In vivo electrophysiological experiments have previously shown that acute ethanol exposure abolishes GrC responsiveness to sensory inputs carried by mossy fibers. Slice electrophysiological studies suggest that ethanol causes this effect by potentiating GABAergic transmission at Golgi Cell-to-GrC synapses through an increase in Golgi Cell excitability. Using patch-clamp electrophysiological techniques in cerebellar slices and computer modeling, we show here that ethanol excites Golgi Cells by inhibiting the Na+/K+ ATPase. Voltage-clamp recordings of Na+/K+ ATPase currents indicated that ethanol partially inhibits this pump and this effect could be mimicked by low concentrations of ouabain. Partial inhibition of Na+/K+ ATPase function in a computer model of the Golgi Cell reproduced these experimental findings. These results establish a novel mechanism of action of ethanol on neuronal excitability, which likely has a role in ethanol-induced cerebellar dysfunction and may also contribute to neuronal functional alterations in other brain regions.
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Computational reconstruction of pacemaking and intrinsic electroresponsiveness in cerebellar Golgi Cells
Frontiers in cellular neuroscience, 2007Co-Authors: Sergio Solinas, Erik De Schutter, Jonathan Mapelli, Lia Forti, Elisabetta Cesana, Egidio D‘angeloAbstract:The Golgi Cells have been recently shown to beat regularly in vitro (Forti et al., 2006. J. Physiol. 574, 711-729). Four main currents were shown to be involved, namely a persistent sodium current (INa-p), an h current (Ih), an SK-type calcium-dependent potassium current (IK-AHP), and a slow M-like potassium current (IK-slow). These ionic currents could take part, together with others, also to different aspects of neuronal excitability like responses to depolarizing and hyperpolarizing current injection. However, the ionic mechanisms and their interactions remained largely hypothetical. In this work, we have investigated the mechanisms of Golgi Cell excitability by developing a computational model. The model predicts that pacemaking is sustained by subthreshold oscillations tightly coupled to spikes. INa-p and IK-slow emerged as the critical determinants of oscillations. Ih also played a role by setting the oscillatory mechanism into the appropriate membrane potential range. IK-AHP, though taking part to the oscillation, appeared primarily involved in regulating the ISI following spikes. The combination with other currents, in particular a resurgent sodium current (INa-r) and an A-current (IK-A), allowed a precise regulation of response frequency and delay. These results provide a coherent reconstruction of the ionic mechanisms determining Golgi Cell intrinsic electroresponsiveness and suggests important implications for cerebellar signal processing, which will be fully developed in a companion paper (Solinas et al., 2008. Front. Neurosci. 1:4).