title: Enhanced Sensitivity to Hyperpolarizing Inhibition in Mesoaccumbal Relative to Nigrostriatal Dopamine Neuron Subpopulations.
abstract: Midbrain dopamine neurons recordedin vivopause their firing in response to reward omission and aversive stimuli. While the initiation of pauses typically involves synaptic or modulatory input, intrinsic membrane properties may also enhance or limit hyperpolarization, raising the question of how intrinsic conductances shape pauses in dopamine neurons. Using retrograde labeling and electrophysiological techniques combined with computational modeling, we examined the intrinsic conductances that shape pauses evoked by current injections and synaptic stimulation in subpopulations of dopamine neurons grouped according to their axonal projections to the nucleus accumbens or dorsal striatum in mice. Testing across a range of conditions and pulse durations, we found that mesoaccumbal and nigrostriatal neurons differ substantially in rebound properties with mesoaccumbal neurons displaying significantly longer delays to spiking following hyperpolarization. The underlying mechanism involves an inactivating potassium (IA) current with decay time constants of up to 225 ms, and small-amplitude hyperpolarization-activated currents (IH), characteristics that were most often observed in mesoaccumbal neurons. Pharmacological block of IAcompletely abolished rebound delays and, importantly, shortened synaptically evoked inhibitory pauses, thereby demonstrating the involvement of A-type potassium channels in prolonging pauses evoked by GABAergic inhibition. Therefore, these results show that mesoaccumbal and nigrostriatal neurons display differential responses to hyperpolarizing inhibitory stimuli that favors a higher sensitivity to inhibition in mesoaccumbal neurons. These findings may explain, in part, observations fromin vivoexperiments that ventral tegmental area neurons tend to exhibit longer aversive pauses relative to SNc neurons.SIGNIFICANCE STATEMENTOur study examines rebound, postburst, and synaptically evoked inhibitory pauses in subpopulations of midbrain dopamine neurons. We show that pauses in dopamine neuron firing, evoked by either stimulation of GABAergic inputs or hyperpolarizing current injections, are enhanced by a subclass of potassium conductances that are recruited at voltages below spike threshold. Importantly, A-type potassium currents recorded in mesoaccumbal neurons displayed substantially slower inactivation kinetics, which, combined with weaker expression of hyperpolarization-activated currents, lengthened hyperpolarization-induced delays in spiking relative to nigrostriatal neurons. These results suggest that input integration differs among dopamine neurons favoring higher sensitivity to inhibition in mesoaccumbal neurons and may partially explainin vivoobservations that ventral tegmental area neurons exhibit longer aversive pauses relative to SNc neurons.
authors.affiliation: Department of Neuroscience, Brown University, Providence, Rhode Island 02906 and.|Cellular Neurophysiology Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Rahilla A
authors.identifier: 0000-0002-8489-8959
authors.initials: RA
authors.lastname: Tarfa
authors.affiliation: Cellular Neurophysiology Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: Rebekah C
authors.identifier: 0000-0002-9476-150X
authors.initials: RC
authors.lastname: Evans
authors.affiliation: Cellular Neurophysiology Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892 zayd.khaliq@nih.gov.
authors.forename: Zayd M
authors.identifier: 0000-0002-1445-1457
authors.initials: ZM
authors.lastname: Khaliq
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000502:physiology*; D059290:Dopaminergic Neurons / Q000502:physiology*; D005260:Female; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D009415:Nerve Net / Q000502:physiology; D009433:Neural Inhibition / Q000502:physiology*; D009434:Neural Pathways / Q000502:physiology; D009714:Nucleus Accumbens / Q000502:physiology*; D013378:Substantia Nigra / Q000502:physiology*
keywords: action potential; dopamine; mesoaccumbal; nigrostriatal; potassium channel