Transient High-Frequency Firing in a Coupled-Oscillator Model of the Mesencephalic Dopaminergic Neuron

Abstract

Dopaminergic neurons of the midbrain fire spontaneously at rates <10/s and ordinarily will not exceed this range even when driven with somatic current injection. When driven at higher rates, these cells undergo spike failure through depolarization block. During spontaneous bursting of dopaminergic neurons in vivo, bursts related to reward expectation in behaving animals, and bursts generated by dendritic application of N-methyl-d-aspartate (NMDA) agonists, transient firing attains rates well above this range. We suggest a way such high-frequency firing may occur in response to dendritic NMDA receptor activation. We have extended the coupled oscillator model of the dopaminergic neuron, which represents the soma and dendrites as electrically coupled compartments with different natural spiking frequencies, by addition of dendritic AMPA (voltage-independent) or NMDA (voltage-dependent) synaptic conductance. Both soma and dendrites contain a simplified version of the calcium-potassium mechanism known to be the mechanism for slow spontaneous oscillation and background firing in dopaminergic cells. The compartments differ only in diameter, and this difference is responsible for the difference in natural frequencies. We show that because of its voltage dependence, NMDA receptor activation acts to amplify the effect on the soma of the high-frequency oscillation of the dendrites, which is normally too weak to exert a large influence on the overall oscillation frequency of the neuron. During the high-frequency oscillations that result, sodium inactivation in the soma is removed rapidly after each action potential by the hyperpolarizing influence of the dendritic calcium-dependent potassium current, preventing depolarization block of the spike mechanism, and allowing high-frequency spiking.

A reduced model of DA neuronal dynamics that displays quiescence, tonic firing and bursting

“…We introduce a single compartmental conductance based model for the dynamics of a DA neuron that combines conductance mechanisms previously included in [11,8]. The dynamics of the membrane potential are taken to be…”

“…Certain existing models only consider the subthreshold behavior of the DA cells [8,9] and argue by analogy the expected behavior of the DA cells. Other models depend on the interaction between the activity at the soma and the dendrites [10,11,9] in order to produce bursting dynamics (with this approach certain parameters may be unobservable). However, recent experimental findings [12,13] indicate that burst firing can be generated somatically with the dendrites silenced.…”

Mechanisms for multiple activity modes of VTA dopamine neurons

“…2) that combines modified conductance mechanisms previously introduced in [11,15,26,27]. 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.…”

“…Given the rich behavior of DA neuronal dynamics and due to their biological importance, a number of modeling efforts have been made to understand DA neural dynamics. Existing models can capture a variety of these behaviors [10][11][12], yet are not without their shortcomings. The models of [10][11][12] rely on somatodendritic interactions as underlying burst generation, however, two laboratories have experimental findings that suggest burst firing is somatically induced [13,14].…”

“…Existing models can capture a variety of these behaviors [10][11][12], yet are not without their shortcomings. The models of [10][11][12] rely on somatodendritic interactions as underlying burst generation, however, two laboratories have experimental findings that suggest burst firing is somatically induced [13,14]. These somatically induced bursts have characteristics consistent with normal bursting, suggesting that a single-compartmental model should be sufficient for generating the observed DA neuronal dynamics.…”