Abstract
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 1.7ms at induces a peak photocurrent of 1250pA. Optimal irradiance ( ) and pulse width ( ) to trigger action potential have been determined. At frequencies beyond 200Hz, higher values of expression level and irradiance result in spike failure. Singlet and doublet spiking fidelity can be maintained up to 400 and 150Hz, respectively. The combination of expression level and membrane capacitance is a crucial factor to achieve high-frequency firing above 500Hz. Its optimization enables 100% spike probability of up to 1kHz. 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.
Highlights
Optogenetics has revolutionized neuroscience and cell biology by controlling genetically modified cells in culture, tissue, and living animals with light
To describe the response of vf-Chrimsonexpressing neurons to light stimuli, we present a model that combines the kinetic model of the vf-Chrimson photocycle with a single compartment, slow and a fast-spiking neuron model, respectively (Fig. 1)
We demonstrate the efficacy of the model by comparing with the experimental results and use the model to investigate different stimulation profiles
Summary
Optogenetics has revolutionized neuroscience and cell biology by controlling genetically modified cells in culture, tissue, and living animals with light. Precise spike timing and high-frequency oscillations are associated with neural plasticity, behavior, and pathology that includes mediation of neural coding in auditory system and alteration of functions in Parkinson’s disease.[11,12,13] Dysfunction in the fast-spiking parvalbumin-positive (PVþ) interneurons may set low thresholds for impairment of fast network oscillations and higher brain functions and may cause cerebral aging as well as various acute and chronic brain diseases, such as stroke, vascular cognitive impairment, epilepsy, Alzheimer’s disease, and schizophrenia.[14,15,16,17] High-frequency spiking may govern whether spikes propagate throughout dendrites and affect localized cellular processes.[18] Another important aspect is to minimize the invasiveness of inserting optical fiber into the brain, which displaces brain tissue and can lead to undesirable side effects that include brain lesion, neural morphology changes, glial inflammation, glial motility, and compromise of asepsis.[19,20] Various red-shifted opsins have developed, including VChR1, C1V1, and ReaChR (590 to 630 nm), to enable deep penetration of light with reduced scattering and phototoxicity in tissue, noninvasive use, as well. Where V is the membrane voltage, E is the reversal potential, and gvf−Chrimson is the channel conductance, which is empirically expressed as gvf−Chrimson 1⁄4 g0ðλÞfφðφ; tÞ, where g0ðλÞ accounts
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