Optogenetic versus Electrical Stimulation of Human Cardiomyocytes: Modeling Insights

Abstract

Optogenetics provides an alternative to electrical stimulation to manipulate membrane voltage, and trigger or modify action potentials (APs) in excitable cells. We compare biophysically and energetically the cellular responses to direct electrical current injection versus optical stimulation mediated by genetically expressed light-sensitive ion channels, e.g., Channelrhodopsin-2 (ChR2). Using a computational model of ChR2(H134R mutant), we show that both stimulation modalities produce similar-in-morphology APs in human cardiomyocytes, and that electrical and optical excitability vary with cell type in a similar fashion. However, whereas the strength-duration curves for electrical excitation in ventricular and atrial cardiomyocytes closely follow the theoretical exponential relationship for an equivalent RC circuit, the respective optical strength-duration curves significantly deviate, exhibiting higher nonlinearity. We trace the origin of this deviation to the waveform of the excitatory current-a nonrectangular self-terminating inward current produced in optical stimulation due to ChR2 kinetics and voltage-dependent rectification. Using a unifying charge measure to compare energy needed for electrical and optical stimulation, we reveal that direct electrical current injection (rectangular pulse) is more efficient at short pulses, whereas voltage-mediated negative feedback leads to self-termination of ChR2 current and renders optical stimulation more efficient for long low-intensity pulses. This applies to cardiomyocytes but not to neuronal cells (with much shorter APs). Furthermore, we demonstrate the cell-specific use of ChR2 current as a unique modulator of intrinsic activity, allowing for optical control of AP duration in atrial and, to a lesser degree, in ventricular myocytes. For self-oscillatory cells, such as Purkinje, constant light at extremely low irradiance can be used for fine control of oscillatory frequency, whereas constant electrical stimulation is not feasible due to electrochemical limitations. Our analysis offers insights for designing future new energy-efficient stimulation strategies in heart or brain.

Optogenetic recruitment of spinal reflex pathways from large‐diameter primary afferents in non‐transgenic rats transduced with AAV9/Channelrhodopsin 2

“…Then, upon confirmation of the successful delivery of ChR2 into the large‐sized DRG neurons, we tested whether their activity could be manipulated by light stimulation. We specifically compared the afferent volley induced by optical and electrical stimulation because the properties of action potentials induced by the two methods were reported to be different in vitro or in silico preparation (Williams & Entcheva, ; Ratnadurai‐Giridharan et al . ).…”

“…Then, upon confirmation of the successful delivery of ChR2 into the large-sized DRG neurons, we tested whether their activity could be manipulated by light stimulation. We specifically compared the afferent volley induced by optical and electrical stimulation because the properties of action potentials induced by the two methods were reported to be different in vitro or in silico preparation (Williams & Entcheva, 2015;Ratnadurai-Giridharan et al 2017). Our results show that (1) AAV9 preferentially transduces medium-to-large-sized DRG neurons, (2) compared with electrically elicited responses, the optically generated volleys in transduced DRG neurons have a higher sensitivity with amplitude of optical stimulation, but a lower sensitivity with stimulus frequency, and (3) afferent volleys evoked by light are sufficient to activate and recruit spinal reflex circuits.…”

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

“…The authors showed that this effect was attributable to variation in the native ionic currents active during the early stages of the AP, with the inward rectifying potassium current (I K1 ) playing a particularly prominent role; indeed, when the native I K1 formulation for the ventricular model was replaced by the one from the Purkinje fiber model, there was a significant improvement in optical excitability (lower threshold for excitation) in such ventricular myocytes. In a follow-up study (83), the same group demonstrated that, in spite of fundamental differences between the mechanisms of cellular depolarization, the primary determinants of electrical and optical excitability are the same (namely, dynamic variations in cardiomyocyte membrane resistance and inward rectifier current due to intrinsic properties of different cell types).…”

Biological Considerations of Optical Interfaces for Neuromodulation

“…A growing range of optogenetic ion channels with various characteristics are available for researchers to experiment with, including both excitatory and inhibitory channels, and channels with different time constants . Among other applications, optogenetic techniques have been applied in the control of seizures in mice, control of cardiomyocytes, and control of behaviors in freely behaving mice …”