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      Disinhibition Bursting of Dopaminergic Neurons

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          Abstract

          Substantia nigra pars compacta (SNpc) dopaminergic neurons receive strong tonic inputs from GABAergic neurons in the substantia nigra pars reticulata (SNpr) and globus pallidus (GP), and glutamatergic neurons in the subthalamic nucleus. The presence of these tonic inputs raises the possibility that phasic disinhibition may trigger phasic bursts in dopaminergic neurons. We first applied constant NMDA and GABA A conductances onto a two-compartment single cell model of the dopaminergic neuron (Kuznetsov et al., 2006). The model exhibited disinhibition bursting upon stepwise removal of inhibition. A further bifurcation analysis suggests that disinhibition may be more robust than excitation alone in that for most levels of NMDA conductance, the cell remains capable of bursting even after a complete removal of inhibition, whereas too much excitatory input will drive the cell into depolarization block. To investigate the network dynamics of disinhibition, we used a modified version of an integrate-and-fire based model of the basal ganglia (Humphries et al., 2006). Synaptic activity generated in the network was delivered to the two-compartment single cell dopaminergic neuron. Phasic activation of the D1-expressing medium spiny neurons in the striatum (D1STR) produced disinhibition bursts in dopaminergic neurons through the direct pathway (D1STR to SNpr to SNpc). Anatomical studies have shown that D1STR neurons have collaterals that terminate in GP. Adding these collaterals to the model, we found that striatal activation increased the intra-burst firing frequency of the disinhibition burst as the weight of this connection was increased. Our studies suggest that striatal activation is a robust means by which disinhibition bursts can be generated by SNpc dopaminergic neurons, and that recruitment of the indirect pathway via collaterals may enhance disinhibition bursting.

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          Most cited references29

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          The control of firing pattern in nigral dopamine neurons: burst firing.

          In addition to firing in a single spiking mode, dopamine (DA) cells have been observed to fire in a bursting pattern with consecutive spikes in a burst displaying progressively decreasing amplitude and increasing duration. In vivo intracellular recording demonstrated the bursts to typically ride on a depolarizing wave (5 to 15 mV amplitude). Although the burst-firing frequency of DA cells showed little correlation with the base line firing rate, increases in firing rate were usually associated with an increase in burst firing. Increases in burst firing could also be elicited by intracellular calcium injection and could be prevented by intracellular injection of EGTA, suggesting a calcium involvement in bursting. Blockade of potassium conductances with extracellular iontophoresis of barium or intracellular injection of tetraethylammonium bromide could also trigger an increased degree of burst firing in DA cells. These data suggest that the increased calcium influx accompanying an increased firing rate triggers burst firing, possibly by inactivating a potassium conductance. A switch from a single spiking mode to a burst-firing mode may be important in modulating striatal DA release, as shown for burst firing in other preparations.
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            Robust pacemaking in substantia nigra dopaminergic neurons.

            Dopaminergic neurons of the substantia nigra pars compacta are autonomous pacemakers. This activity is responsible for the sustained release of dopamine necessary for the proper functioning of target structures, such as the striatum. Somatodendritic L-type Ca2+ channels have long been viewed as important, if not necessary, for this activity. The studies reported here challenge this viewpoint. Using a combination of optical and electrophysiological approaches in brain slices, it was found that antagonism of L-type Ca2+ channel effectively stopped dendritic Ca2+ oscillations but left autonomous pacemaking unchanged. Moreover, damping intracellular Ca2+ oscillations with exogenous buffer had little effect on pacemaking rate. Although not necessary for pacemaking, L-type channels helped support pacemaking when challenged with cationic channel blockers. Simulations suggested that the insensitivity to antagonism of L-type channels reflected the multichannel nature of the pacemaking process. The robustness of pacemaking underscores its biological importance and provides a framework for understanding how therapeutics targeting L-type Ca2+ channels might protect dopaminergic neurons in Parkinson's disease without compromising their function.
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              A physiologically plausible model of action selection and oscillatory activity in the basal ganglia.

              The basal ganglia (BG) have long been implicated in both motor function and dysfunction. It has been proposed that the BG form a centralized action selection circuit, resolving conflict between multiple neural systems competing for access to the final common motor pathway. We present a new spiking neuron model of the BG circuitry to test this proposal, incorporating all major features and many physiologically plausible details. We include the following: effects of dopamine in the subthalamic nucleus (STN) and globus pallidus (GP), transmission delays between neurons, and specific distributions of synaptic inputs over dendrites. All main parameters were derived from experimental studies. We find that the BG circuitry supports motor program selection and switching, which deteriorates under dopamine-depleted and dopamine-excessive conditions in a manner consistent with some pathologies associated with those dopamine states. We also validated the model against data describing oscillatory properties of BG. We find that the same model displayed detailed features of both gamma-band (30-80 Hz) and slow (approximately 1 Hz) oscillatory phenomena reported by Brown et al. (2002) and Magill et al. (2001), respectively. Only the parameters required to mimic experimental conditions (e.g., anesthetic) or manipulations (e.g., lesions) were changed. From the results, we derive the following novel predictions about the STN-GP feedback loop: (1) the loop is functionally decoupled by tonic dopamine under normal conditions and recoupled by dopamine depletion; (2) the loop does not show pacemaking activity under normal conditions in vivo (but does after combined dopamine depletion and cortical lesion); (3) the loop has a resonant frequency in the gamma-band.
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                Author and article information

                Journal
                Front Syst Neurosci
                Front. Syst. Neurosci.
                Frontiers in Systems Neuroscience
                Frontiers Research Foundation
                1662-5137
                10 May 2011
                2011
                : 5
                : 25
                Affiliations
                [1] 1simpleNeurosciences Institute, University of Texas at San Antonio San Antonio, TX, USA
                Author notes

                Edited by: James M. Tepper, Rutgers, The State University of New Jersey, USA

                Reviewed by: Mark Bevan, Northwestern University, USA; Mark D. Humphries, University of Sheffield, UK

                *Correspondence: Carlos A. Paladini, Neurosciences Institute, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249, USA. e-mail: carlos.paladini@ 123456utsa.edu
                Article
                10.3389/fnsys.2011.00025
                3095811
                21617731
                0bd853a8-229f-4127-9890-cd06a9562077
                Copyright © 2011 Lobb, Troyer, Wilson and Paladini.

                This is an open-access article subject to a non-exclusive license between the authors and Frontiers Media SA, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and other Frontiers conditions are complied with.

                History
                : 26 January 2011
                : 26 April 2011
                Page count
                Figures: 7, Tables: 1, Equations: 0, References: 34, Pages: 8, Words: 4906
                Categories
                Neuroscience
                Original Research

                Neurosciences
                network,burst,dopamine,gaba,model
                Neurosciences
                network, burst, dopamine, gaba, model

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