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Publication Summary and Abstract

Humphries, M. D., Lepora, N., Wood, R. and Gurney, K. (2009), Capturing dopaminergic modulation and bimodal membrane behaviour of striatal medium spiny neurons in accurate, reduced models, Frontiers in Computational Neuroscience, 3:26. [Code]

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
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