Modeling nicotinic neuromodulation from global functional and network levels to nAChR based mechanisms

Abstract

Neuromodulator action has received increasing attention in theoretical neuroscience. Yet models involving both neuronal populations dynamics at the circuit level and detailed receptor properties are only now being developed. Here we review recent computational approaches to neuromodulation, focusing specifically on acetylcholine (ACh) and nicotine. We discuss illustrative examples of models ranging from functional top-down to neurodynamical bottom-up. In the top-down approach, a computational theory views ACh as encoding the uncertainty expected in an environment. A different line of models accounts for neural population dynamics treating ACh as toggling neuronal networks between read-in of information and recall of memory. Building on the neurodynamics idea we discuss two models of nicotine's action with increasing degree of biological realism. Both consider explicitly receptor-level mechanisms but with different scales of detail. The first is a large-scale model of nicotine-dependent modulation of dopaminergic signaling that is capable of simulating nicotine self-administration. The second is a novel approach where circuit-level neurodynamics of the ventral tegmental area (VTA) are combined with explicit models of the dynamics of specific nicotinic ACh receptor subtypes. We show how the model is constructed based on local anatomy, electrophysiology and receptor properties and provide an illustration of its potential. In particular, we show how the model can shed light on the specific mechanisms by which nicotine controls dopaminergic neurotransmission in the VTA. This model serves us to conclude that detailed accounts for neuromodulator action at the basis of behavioral and cognitive models are crucial to understand how neuromodulators mediate their functional properties.

A reduced model of DA neuronal dynamics that displays quiescence, tonic firing and bursting

“…Recent work by Graupner and Gutkin [21] suggested a simplified neural architecture for the VTA network, seen below in Figure 1, can account for the phasic increased response of the VTA circuit using an averaged activity model. We will adopt a similar network architecture as a backdrop to our construction of a DA neuronal model; however, in this work we will not be directly considering the effects nicotine on DA cell behavior.…”

Endogenous Cholinergic Inputs and Local Circuit Mechanisms Govern the Phasic Mesolimbic Dopamine Response to Nicotine

“…Please note that the desensitized fraction of α4β2 nAChRs is ∼70%; their response is not completely abolished at 0.5 µM Nic. While Nic reduces the maximum amplitudes for both receptors, it does not affect the effective half-maximum ACh concentrations [24]. In the absence of ACh, Nic evokes a small activation of the receptors [24] that has also been seen experimentally for α4β2 nAChRs [12].…”

“…We use a classical 4-state model of the nAChR adapted from Katz and Thesleff [22], [23] (see Text S2.) briefly described in [24]) accounting for subtype-specific activation and desensitization as recorded in response to Nic and ACh [25]–[30].…”

Mechanisms for multiple activity modes of VTA dopamine neurons

“…http://dx.doi.org/10.1101/008920 doi: bioRxiv preprint first posted online Sep. 9, 2014; and the averaged-activity of the GABA cells (as developed by Graupner and Gutkin [44]). This new framework would take into account a multitude of scales (i.e., linking the VTA mean field activity, detailed conductance-based representations of DA neurons, and the dynamics of the nAChRs) and could yield further insight to the mechanisms underlying burst firing in vivo and aid in elucidating the biophysical manifestations of nicotine addiction.…”