MECHANISMS OF FIRING PATTERN
REGULATION IN MIDBRAIN DOPAMINE NEURONS
Dopamine
(DA) neurons have a great importance in different aspects of brain function such
as reward-mediated learning, movement control, cognition and motivation; they
are involved in such clinical disorders as Parkinson's disease, schizophrenia
and drug addiction. DA neurons exhibit two major patterns of membrane potential
discharge: spiking and bursting. Bursting patterns in these neurons are likely
to have special significance for information processing in the circuits
modulated by DA. In these studies, the multicompartmental models were developed
in order to investigate the roles of different factors such as activation
of NMDA and GABAA
receptors, modulation of small conductance Ca-activated potassium channel (SK)
and electrical coupling between DA neurons in their firing pattern regulation.
It
was shown, that while NMDA evoked currents are required for a bursting
oscillation, currents evoked by GABAA act as
linear dampeners leading from bursting to spiking or silence. The model
predicts that a higher level of NMDA receptor activation does not always leads
to more bursting because excessive depolarization, in this case GABAA
receptors activation may be required for burst generation. Other prediction of
the model that blocking the SK channel current in vivo will facilitate
bursting, but not as robustly as blocking of GABAA
receptors.
The
studies of system of two model DA neurons predicted that the level of
electrical coupling, within a range that is physiologically admissible for gap
junctions, is likely to have a significant modulatory effect on the firing
pattern in midbrain DA neurons, and specifically that electrical coupling in
many instances promotes burst firing. In the model, electrical coupling
facilitates NMDA-induced firing via two mechanisms. The first one observable in
pair of identical cells and
critically depends on action potential dynamics. Weak electrical coupling
destabilizes synchronous spiking solution of two neurons and leads to burst
that approximately in phase but spikes that are not in phase. The second
mechanism for the induction of burst firing requires a heterogeneous pair that is,
respectively, too depolarized and too hyperpolarized to burst. The net effect
of the coupling is to bias at least one cell into endogenously burst firing
regime. In this case, action potential dynamics are not critical to the
transitional mechanism.
Several
methods of investigations of nonlinear dynamic systems were used in these
studies (bifurcation diagram constructions, phase-plane analysis and nulcline
analysis, etc.).