Dopamine Neurons Change the Type of Excitability in Response to Stimuli

Abstract

The dynamics of neuronal excitability determine the neuron’s response to stimuli, its synchronization and resonance properties and, ultimately, the computations it performs in the brain. We investigated the dynamical mechanisms underlying the excitability type of dopamine (DA) neurons, using a conductance-based biophysical model, and its regulation by intrinsic and synaptic currents. Calibrating the model to reproduce low frequency tonic firing results in N-methyl-D-aspartate (NMDA) excitation balanced by γ-Aminobutyric acid (GABA)-mediated inhibition and leads to type I excitable behavior characterized by a continuous decrease in firing frequency in response to hyperpolarizing currents. Furthermore, we analyzed how excitability type of the DA neuron model is influenced by changes in the intrinsic current composition. A subthreshold sodium current is necessary for a continuous frequency decrease during application of a negative current, and the low-frequency “balanced” state during simultaneous activation of NMDA and GABA receptors. Blocking this current switches the neuron to type II characterized by the abrupt onset of repetitive firing. Enhancing the anomalous rectifier Ih current also switches the excitability to type II. Key characteristics of synaptic conductances that may be observed in vivo also change the type of excitability: a depolarized γ-Aminobutyric acid receptor (GABAR) reversal potential or co-activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) leads to an abrupt frequency drop to zero, which is typical for type II excitability. Coactivation of N-methyl-D-aspartate receptors (NMDARs) together with AMPARs and GABARs shifts the type I/II boundary toward more hyperpolarized GABAR reversal potentials. To better understand how altering each of the aforementioned currents leads to changes in excitability profile of DA neuron, we provide a thorough dynamical analysis. Collectively, these results imply that type I excitability in dopamine neurons might be important for low firing rates and fine-tuning basal dopamine levels, while switching excitability to type II during NMDAR and AMPAR activation may facilitate a transient increase in dopamine concentration, as type II neurons are more amenable to synchronization by mutual excitation.

Dynamical ventral tegmental area circuit mechanisms of alcohol‐dependent dopamine release

“…The exact number of projecting GABA neurons to DA neurons is not known. As we described in our previous paper (Morozova et al ., ,b) and since GABA neurons modulate DA neuron activity through monosynaptic inhibitory connections (Bourdy & Barrot, ; van Zessen et al ., ), one can expect multiple GABA neurons to make connections with a single DA neuron. We made a judicious choice of GABA to DA convergence and we verified that our results do not depend qualitatively on the specific choice of this number.…”

“…Under acute ETOH, our model VTA circuit becomes more ‘synchronizable' and hence facilitates bursting. The mechanism of this boost in synchronization relies on a combination of several complementary effects: first, on the EtOH‐mediated enhancement of AMPAR current that increases the probability to evoke spikes in response to the synchronous Glu pulses; second, on an increase in I h , which renders the DA neurons intrinsically more sensitive to input synchrony (Morozova et al ., 2016b); and third, on the possible ETOH‐induced increase in GABAergic neurotransmission. The latter has a double effect in our model: the increased asynchronous inhibition outside the input bursts suppresses the tonic DA spikes, while the synchronized GABA input to the DA neuron during the input ‘bursts' promotes high frequency spikes in DA neurons.…”

“…The constants are calibrated for the channels to open at 4 and higher simultaneous presynaptic spikes. In our previous work (Morozova et al ., ,b) the opening was considered as a step function activating at two simultaneous spikes while here we use a continuous activation. This choice allows for summation effects of several spikes instead of a dichotomous role.…”

High-frequency forced oscillations in neuronlike elements

“…In our previous biophyscial modeling study [17], where interaction between two neuronal networks in the ventral tegmental area was studied, we found a surprising increase in the frequency of a slower neuron driven by a pulsatile inhibitory input. Thus, the influence of an inhibitory neuronal network on a neurons firing pattern may differ significantly from the traditionally considered decrease in the firing frequency of the target neuron.…”

“…If, for example, the elements of a fast layer transiently synchronize, they are able to provide a strong high frequency input to a slower layer. Such situation could be widely observed in the brain, where often a low-frequency neuron is driven by high-frequency input [17,20]. One can treat multiple neuron types as intrinsic oscillators and their electrical activity can be described by models with periodic, limit cycle-like behavior [19].…”