Dr. Alexey Kuznetsov: Research


Synaptic integration and firing patterns of the midbrain dopaminergic neuron

One of my main research projects is study of firing properties of the midbrain dopaminergic (DA) neuron and signal processing performed by this cell. The work has been initiated in collaboration with an experimentalist Charles Wilson (UTSA, Biology Department) and Nancy Kopell (BU, Mathematics Department) (Kuznetsov et al., J Neurophys 2006). The central dopamine system has been suggested to be involved with many behavioral and cognitive tasks. Dopamine neurotransmission has been found responsible for addictive behavior and is impaired in psychiatric disorders. However, a combination of experimental and modeling studies has not given a consistent picture of the DA neuron input-output relation (see Kuznetsov et al., Scholarpedia 2007 for discussion). Therefore, the role of the dopaminergic neuron and the role of dopamine itself are topics for active investigations for neuroscientists, pharmacists and physicians.

Our recent modeling study (Kuznetsov et al., J Neurophys 2006) has consolidated many experimental facts on firing properties of the DA neuron. The problem is that, in contrast to other types of neurons, burst firing of DA cells cannot be elicited in vitro by somatic current injections. Moreover, the spiking frequency cannot be elevated in this way to the rates attained during bursts either. Instead, as increasing amounts of depolarizing current are injected, a steady firing rate of 10 Hz is the maximum rate achieved before spiking ceases. We have suggested a novel mechanism for high-frequency firing. The mechanism is critically dependent on the activation of dendritic synaptic inputs (NMDA receptors), whereas it allows only small frequency increase in response to a somatic current injection, in concert with experimental data.

From the mathematical point of view, the model is a multidimensional system of differential equations, which has the structure of interconnected oscillators. Each oscillator has a distinct frequency and represents a sector of dendritic tree or the soma of the cell. We have shown that under different experimental conditions, the model behavior is dominated by ether the somatic or dendritic oscillator, determining the frequency range. The effect of dominance is novel, whereas the usual and expected result of the interaction between the compartments would be oscillations at a weighted average of the individual frequencies. We have shown that this effect is related to the phenomenon of localization, where intrinsic oscillations of one compartment are suppressed due to coupling with another.

The model has attracted considerable interest and attention and led to formulation of novel predictions. Several predictions have already been validated experimentally. This shows opening perspectives and the predictive power of our theoretical study. The continuation of this project involves new collaborations with Prof. Carlos Paladini and Dr. Anna Kuznetsova (UTSA Biology Department).

In its mathematical part, the proposed research advances analytical explanations to nontrivial biological phenomena and contributes to the extension of singular perturbation techniques to the vicinity of a bifurcation boundary.

In a longer-term perspective, our research will open new possibilities for investigation of various behavioral (dys-)functions involving dopamine regulation. Two areas on which I want to focus are the influence of antipsychotic drugs on the central dopamine system and mechanisms of addiction. Modeling of the central dopamine system will make a significant contribution to understanding of these phenomena and development of a theory that unifies various aspects of behavior.

 

This material is based upon work supported by the National Science Foundation under Grant No.  0817717. Any opinions, findings and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation (NSF).