Computational models of optogenetic tools for controlling neural circuits with light

Abstract

Optogenetics is a new neurotechnology innovation based on the creation of light sensitivity of neurons using gene technologies and remote light activation. Optogenetics allows for the first time straightforward targeted neural stimulation with practically no interference between multiple stimulation points since either light beam can be finely confined or the expression of light sensitive ion channels and pumps can be genetically targeted. Here we present a generalised computational modeling technique for various types of optogenetic mechanisms, which was implemented in the NEURON simulation environment. It was demonstrated on the example of a two classical mechanisms for cells optical activation and silencing: channelrhodopsin-2 (ChR2) and halorhodopsin (NpHR).We theoretically investigate the dynamics of the neural response of a layer 5 cortical pyramidal neuron (L5) to four different types of illuminations: 1) wide-field whole cell illumination 2) wide-field apical dendritic illumination 3) focal somatic illumination and 4) focal axon initial segment (AIS) illumination. We show that whole-cell illumination of halorhodopsin most effectively hyperpolarizes the neuron and is able to silence the cell even when driving input is present. However, when channelrhodopsin-2 and halorhodopsin are concurrently active, the relative location of each illumination determines whether the response is modulated with a balance towards depolarization. The methodology developed in this study will be significant to interpret and design optogenetic experiments and in the field of neuroengineering in general.

Computational modeling of cardiac optogenetics: Methodology overview & review of findings from simulations

“…In contrast to ChR2, illumination of NpHR or ArchT results in an outward (repolarizing) current that has been used to silence electrical activation in spontaneously activating cardiac cells (11,12,51). Nikolic et al developed a three-state model of NpHR (open, closed, desensitized) and showed that light stimulation of a simulated NpHR-expressing neuron silenced excitation, even in the presence of a driving stimuli (52). Fig.…”

“…Fig. 2C shows NpHR current (I NpHR ) profiles in response to orange light pulses; the model used here is an original implementation by the authors of this paper, adapted from the Nikolic et al version (52) with some parameters calibrated to match photocurrent values recorded in NpHR-expressing myocyte (51), as summarized in Table 1. Consistent with experimental observations (6), the model produced peak and plateau I NpHR values that were much smaller in magnitude than I ChR2 for light stimuli with the same E e values.…”

Computational modeling of neurostimulation in brain diseases

“…In the second approach, the intrinsic channel dynamics of the opsin are specifically modeled to address questions regarding the detailed light-stimulation parameters required to achieve the desired change in membrane potential (Grossman et al, 2011). In terms of modeling, the detailed dynamics of the opsin, the main focus of attention has been the well-known channelrhodopsin (Foutz et al, 2012;Grossman et al, 2011;Nikolic et al, 2013;Stefanescu et al, 2013;. However, detailed models of other opsins (such as halorhodopsin, see Stefanescu et al, 2013) are in development.…”

Reconstruction and visualization of large-scale volumetric models of neocortical circuits for physically-plausible in silico optical studies

“…These polygonal models can accurately represent the cell membrane of the neurons, but they cannot characterize the light propagation in the tissue; they do not account for the intrinsic optical properties of the brain. Therefore, such models cannot be used to simulate optical experiments on a circuit level, for instance, microscopic [ABE * 15a] or optogenetic experiments [NJGS13]. Simulating those experiments is constrained to the presence of detailed and multi-scale volumetric models of the brain that are capable of addressing light interaction with the tissue including absorption and scattering.…”