title: Contribution of synchronized GABAergic neurons to dopaminergic neuron firing and bursting.
abstract: In the ventral tegmental area (VTA), interactions between dopamine (DA) and γ-aminobutyric acid (GABA) neurons are critical for regulating DA neuron activity and thus DA efflux. To provide a mechanistic explanation of how GABA neurons influence DA neuron firing, we developed a circuit model of the VTA. The model is based on feed-forward inhibition and recreates canonical features of the VTA neurons. Simulations revealed that γ-aminobutyric acid (GABA) receptor (GABAR) stimulation can differentially influence the firing pattern of the DA neuron, depending on the level of synchronization among GABA neurons. Asynchronous activity of GABA neurons provides a constant level of inhibition to the DA neuron and, when removed, produces a classical disinhibition burst. In contrast, when GABA neurons are synchronized by common synaptic input, their influence evokes additional spikes in the DA neuron, resulting in increased measures of firing and bursting. Distinct from previous mechanisms, the increases were not based on lowered firing rate of the GABA neurons or weaker hyperpolarization by the GABAR synaptic current. This phenomenon was induced by GABA-mediated hyperpolarization of the DA neuron that leads to decreases in intracellular calcium (Ca2+) concentration, thus reducing the Ca2+-dependent potassium (K+) current. In this way, the GABA-mediated hyperpolarization replaces Ca2+-dependent K+current; however, this inhibition is pulsatile, which allows the DA neuron to fire during the rhythmic pauses in inhibition. Our results emphasize the importance of inhibition in the VTA, which has been discussed in many studies, and suggest a novel mechanism whereby computations can occur locally.
authors.affiliation: Department of Physics, Indiana University, Bloomington, Indiana; Department of Mathematical Sciences, Indiana University-Purdue University, Indianapolis, Indiana; emorozov@indiana.edu.
authors.forename: Ekaterina O
authors.identifier: 0000-0001-9131-7756
authors.initials: EO
authors.lastname: Morozova
authors.affiliation: Program in Neuroscience, Indiana University, Bloomington, Indiana; Addiction Neuroscience Program, Indiana University-Purdue University, Indianapolis, Indiana; and.
authors.forename: Maxym
authors.initials: M
authors.lastname: Myroshnychenko
authors.affiliation: Institute of Applied Physics, Russian Academy of Sciences, Nizhny Novgorod, Russia.
authors.forename: Denis
authors.initials: D
authors.lastname: Zakharov
authors.affiliation: Department of Mathematical Sciences, Indiana University-Purdue University, Indianapolis, Indiana; Group of Neural Theory, INSERM U960, Laboratoire de Neurosciences Cognitives, Institut d'Etude de Cognition, Ecole Normale Superieure, Paris Sciences et Lettres Research University, Paris, France.
authors.forename: Matteo
authors.initials: M
authors.lastname: di Volo
authors.affiliation: Group of Neural Theory, INSERM U960, Laboratoire de Neurosciences Cognitives, Institut d'Etude de Cognition, Ecole Normale Superieure, Paris Sciences et Lettres Research University, Paris, France; Center for Cognition and Decision Making, National Research University Higher School of Economics, Moscow, Russia.
authors.forename: Boris
authors.initials: B
authors.lastname: Gutkin
authors.affiliation: Addiction Neuroscience Program, Indiana University-Purdue University, Indianapolis, Indiana; and.
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Lapish
authors.affiliation: Department of Mathematical Sciences, Indiana University-Purdue University, Indianapolis, Indiana.
authors.forename: Alexey
authors.initials: A
authors.lastname: Kuznetsov
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002412:Cations / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000502:physiology*; D059330:GABAergic Neurons / Q000502:physiology*; D008297:Male; D008839:Microelectrodes; D008959:Models, Neurological; D009433:Neural Inhibition / Q000502:physiology; D009434:Neural Pathways / Q000502:physiology; D010507:Periodicity; D011188:Potassium / Q000378:metabolism; D020318:Rats, Long-Evans; D017208:Rats, Wistar; D018079:Receptors, GABA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000502:physiology*
chemical_list: D002412:Cations; D018079:Receptors, GABA; D016194:Receptors, N-Methyl-D-Aspartate; D011188:Potassium; D002118:Calcium; D004298:Dopamine
keywords: GABA; VTA; bursting; dopamine; synchronization