Dopaminergic and Cholinergic Modulation of Large Scale Networks in silico Using Snudda

Abstract

Neuromodulation is present throughout the nervous system and serves a critical role for circuit function and dynamics. The computational investigations of neuromodulation in large scale networks require supportive software platforms. Snudda is a software for the creation and simulation of large scale networks of detailed microcircuits consisting of multicompartmental neuron models. We have developed an extension to Snudda to incorporate neuromodulation in large scale simulations. The extended Snudda framework implements neuromodulation at the level of single cells incorporated into large-scale microcircuits. We also developed Neuromodcell, a software for optimizing neuromodulation in detailed multicompartmental neuron models. The software adds parameters within the models modulating the conductances of ion channels and ionotropic receptors. Bath application of neuromodulators is simulated and models which reproduce the experimentally measured effects are selected. In Snudda, we developed an extension to accommodate large scale simulations of neuromodulation. The simulator has two modes of simulation – denoted replay and adaptive. In the replay mode, transient levels of neuromodulators can be defined as a time-varying function which modulates the receptors and ion channels within the network in a cell-type specific manner. In the adaptive mode, spiking neuromodulatory neurons are connected via integrative modulating mechanisms to ion channels and receptors. Both modes of simulating neuromodulation allow for simultaneous modulation by several neuromodulators that can interact dynamically with each other. Here, we used the Neuromodcell software to simulate dopaminergic and muscarinic modulation of neurons from the striatum. We also demonstrate how to simulate different neuromodulatory states with dopamine and acetylcholine using Snudda. All software is freely available on Github, including tutorials on Neuromodcell and Snudda-neuromodulation.

The roles of surround inhibition for the intrinsic function of the striatum, analyzed in silico

“…D1R mediates a net excitatory effect, while D2R instead produces a net inhibitory effect ( 24 ). To investigate how dopaminergic modulation would interact with the population units, a large-scale dopaminergic modulation was simulated ( 19 ) through the striatal microcircuit as described in Fig. 7 A .…”

“…The overarching goal of this study is to investigate the role of the surround inhibition for the processing within the striatum at both the cellular and network level. We have used the detailed network model of the mouse striatum developed earlier, which contains the two types of SPNs, FS, LTS, and ChINs represented by multicompartmental models being very close to their biological counterparts with appropriate sets of ion channels and synaptic connectivity ( 1 , 17 , 19 ). This platform represents as close as possible the dynamic operation of the striatum.…”

“…They have the potential of affecting the intrinsic properties of the striatal neurons ( 36 , 37 ). Our current striatal network is designed for fast synaptic interaction (GABA A , AMPA, and NMDA) and has not included the G-protein-mediated slow synaptic transmission (mGluRs, GABA B , M1, M4, or adenosine), but the subroutines for this are now available ( 18 , 19 , 38 – 40 ). These neuromodulators could modulate plateau-like potentials and synaptic transmission and affect the balance between the different neuron types within the striatum.…”

“…The repository includes the models for synaptic dynamics of corticostriatal and thalamostriatal for each neuron type. Details on the development, variability, and the validation can be found in previous publications ( 1 , 17 , 19 ).…”

“…We utilize detailed simulations of the striatal network with multicompartmental model neurons of SPNs and most of the interneuron subtypes, with validated intrinsic properties and models of GABAergic and glutamatergic synapses with validated synaptic properties. We make use of the detailed striatal simulation platform (Snudda) ( 1 , 17 – 19 ). Snudda was developed to facilitate investigations into the function and intrinsic complexity of the striatal microcircuit with its neuronal subtypes and their connection probability, morphology, and intrinsic properties as well as the extrastriatal inputs.…”