Abstract
Loss of dopamine from the striatum can cause both profound motor deficits, as in Parkinson's disease, and disrupt learning. Yet the effect of dopamine on striatal neurons remains a complex and controversial topic, and is in need of a comprehensive framework. We extend a reduced model of the striatal medium spiny neuron (MSN) to account for dopaminergic modulation of its intrinsic ion channels and synaptic inputs. We tune our D1 and D2 receptor MSN models using data from a recent large-scale compartmental model. The new models capture the input–output relationships for both current injection and spiking input with remarkable accuracy, despite the order of magnitude decrease in system size. They also capture the paired pulse facilitation shown by MSNs. Our dopamine models predict that synaptic effects dominate intrinsic effects for all levels of D1 and D2 receptor activation. We analytically derive a full set of equilibrium points and their stability for the original and dopamine modulated forms of the MSN model. We find that the stability types are not changed by dopamine activation, and our models predict that the MSN is never bistable. Nonetheless, the MSN models can produce a spontaneously bimodal membrane potential similar to that recently observed in vitro following application of NMDA agonists. We demonstrate that this bimodality is created by modelling the agonist effects as slow, irregular and massive jumps in NMDA conductance and, rather than a form of bistability, is due to the voltage-dependent blockade of NMDA receptors. Our models also predict a more pronounced membrane potential bimodality following D1 receptor activation. This work thus establishes reduced yet accurate dopamine-modulated models of MSNs, suitable for use in large-scale models of the striatum. More importantly, these provide a tractable framework for further study of dopamine's effects on computation by individual neurons.
Highlights
Loss of dopamine cells in Parkinson’s disease and its animal models leads to profound motor deficits (Schwarting and Huston, 1996; Kirik et al, 1998; Ferro et al, 2005)
We have proposed a framework for modelling dopaminergic modulation of medium spiny neuron (MSN) intrinsic and synaptic ion channels within the canonical neuron model recently introduced by Izhikevich (2007)
Using a principled procedure that minimised the number of free parameters at each stage, we showed that the neuron model and our extensions to it could provide excellent fits to both currentinjection and spike-input response curves from a 189-compartment model of the MSN (Moyer et al, 2007), across all of the dopaminefree, D1, and D2 receptor configurations of the two models
Summary
Loss of dopamine cells in Parkinson’s disease and its animal models leads to profound motor deficits (Schwarting and Huston, 1996; Kirik et al, 1998; Ferro et al, 2005). Much work on understanding these roles of dopamine has focussed on the striatum, the main input nucleus of the basal ganglia. The striatum is the main locus of dopamine’s action, as it contains by far the highest density of dopamine receptors in the vertebrate brain (Dawson et al, 1986; Richtand et al, 1995; Hurd et al, 2001). The striatum receives massive convergent input from the neocortex, thalamus, hippocampal formation, and amygdala (McGeorge and Faull, 1989; Groenewegen et al, 1999; Glynn and Ahmad, 2002; Smith et al, 2004), and dopamine modulates striatal neurons’ responses to them. The twin problems of understanding the computational roles of dopamine and the striatum are inseparably intertwined
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