A detailed theoretical analysis and optimization of high-fidelity, high-frequency firing of the red-shifted very-fast-Chrimson (vf-Chrimson) expressing neurons is presented. A four-state model for vf-Chrimson photocycle has been formulated and incorporated in Hodgkin–Huxley and Wang–Buzsaki spiking neuron circuit models. The effect of various parameters that include irradiance, pulse width, frequency, expression level, and membrane capacitance has been studied in detail. Theoretical simulations are in excellent agreement with recently reported experimental results. The analysis and optimization bring out additional interesting features. A minimal pulse width of 1.7 ms at 23 mW / mm2 induces a peak photocurrent of 1250 pA. Optimal irradiance (0.1 mW / mm2) and pulse width (50 μs) to trigger action potential have been determined. At frequencies beyond 200 Hz, higher values of expression level and irradiance result in spike failure. Singlet and doublet spiking fidelity can be maintained up to 400 and 150 Hz, respectively. The combination of expression level and membrane capacitance is a crucial factor to achieve high-frequency firing above 500 Hz. Its optimization enables 100% spike probability of up to 1 kHz. The study is useful in designing new high-frequency optogenetic neural spiking experiments with desired spatiotemporal resolution, by providing insights into the temporal spike coding, plasticity, and curing neurodegenerative diseases.
A detailed theoretical analysis of low-power, fast optogenetic control of firing of Chronos-expressing neurons has been presented. A three-state model for the Chronos photocycle has been formulated and incorporated in a fast-spiking interneuron circuit model. The effect of excitation wavelength, pulse irradiance, pulse width, and pulse frequency has been studied in detail and compared with ChR2. Theoretical simulations are in excellent agreement with recently reported experimental results and bring out additional interesting features. At very low irradiances (0.005 mW / mm2), the plateau current in Chronos exhibits a maximum. At 0.05 mW / mm2, the plateau current is 2 orders of magnitude smaller and saturates at longer pulse widths (∼700 ms) compared to ChR2 (∼350 ms). Ipeak in Chronos saturates at much shorter pulse widths (1775 pA at 1.5 ms and 5 mW / mm2) than in ChR2. Spiking fidelity is also higher at lower irradiances and longer pulse widths compared to ChR2. Chronos exhibits an average maximal driven rate of over 200 spikes / s in response to 100 pulses / s stimuli, each of 1-ms pulse-width, in the intensity range 0 to 200 mW / mm2. The analysis is important to not only understand the photodynamics of Chronos and Chronos-expressing neurons but also to design opsins with optimized properties and perform precision experiments with required spatiotemporal resolution.