Mechanisms for multiple activity modes of VTA dopamine neurons.

Andrew Oster,Philippe Faure,Boris S Gutkin

doi:10.3389/fncom.2015.00095

Abstract

Midbrain ventral segmental area (VTA) dopaminergic neurons send numerous projections to cortical and sub-cortical areas, and diffusely release dopamine (DA) to their targets. DA neurons display a range of activity modes that vary in frequency and degree of burst firing. Importantly, DA neuronal bursting is associated with a significantly greater degree of DA release than an equivalent tonic activity pattern. Here, we introduce a single compartmental, conductance-based computational model for DA cell activity that captures the behavior of DA neuronal dynamics and examine the multiple factors that underlie DA firing modes: the strength of the SK conductance, the amount of drive, and GABA inhibition. Our results suggest that neurons with low SK conductance fire in a fast firing mode, are correlated with burst firing, and require higher levels of applied current before undergoing depolarization block. We go on to consider the role of GABAergic inhibition on an ensemble of dynamical classes of DA neurons and find that strong GABA inhibition suppresses burst firing. Our studies suggest differences in the distribution of the SK conductance and GABA inhibition levels may indicate subclasses of DA neurons within the VTA. We further identify, that by considering alternate potassium dynamics, the dynamics display burst patterns that terminate via depolarization block, akin to those observed in vivo in VTA DA neurons and in substantia nigra pars compacta (SNc) DA cell preparations under apamin application. In addition, we consider the generation of transient burst firing events that are NMDA-initiated or elicited by a sudden decrease of GABA inhibition, that is, disinhibition.

Highlights

Dopamine is a key neurotransmitter involved in motivation, memory, and motor function
Pacemaking and Burst Firing Experimentally (Ping and Shepard, 1996) observed that application of the drug apamin induces burst firing in slice preparations by blocking the SK-channels, which reduces the flow of K+, that is, DA cell dynamics depend critically on the strength of the SK-conductance
From a state that exhibits low neural firing due to the degree of high GABAergic tone, a release from inhibition results in transient burst firing event followed by repetitive firing in a slow tonic or burst firing pattern, dependent on the the SK-conductance of the neuron, Figure 14

Summary

Introduction

Dopamine is a key neurotransmitter involved in motivation, memory, and motor function. Conductance-based DA Neuronal Model We present a single compartmental conductance-based model for the dynamics of a DA neuron (a schematic shown in Figure 2) that combines modified conductance mechanisms previously introduced in Amini et al (1999), Kuznetsov et al (2006), Canavier et al (2007), and Oster and Gutkin (2011) Such a model serves to consolidate these approaches to a simplified framework and allows the use of computer simulation to uncover the mechanisms behind the generation of DA activity modes. Two tetrodotoxin (TTX) dependent sodium currents are included that can be parametrically regulated via the parameter χTTX: (i) a spike-generating sodium current, INa, modeled in a Morris-Lecar-like fashion with fast activation, m∞, and slow inactivation, h, (ii) and a persistent sodium current, INpears, suggested to be of particular import to VTA DAergic neurons (Khaliq and Bean, 2010). Note that since intracellular Ca2+ buffering is strong, u can be considered a slow variable

Synaptic Currents

Model Results

Depolarization Block

DA Activity Modes

NMDA-induced Firing

Discussion