Abstract
Stimulation and continuous monitoring of neural activities at cellular resolution are required for the understanding of the sensory processing of stimuli and development of effective neuromodulation therapies. We present bioluminescence multi-characteristic opsin (bMCOII), a hybrid optogenetic actuator, and a bioluminescence Ca2+ sensor for excitation-free, continuous monitoring of neural activities in the visual cortex, with high spatiotemporal resolution. An exceptionally low intensity (10 μW/mm2) of light could elicit neural activation that could be detected by Ca2+ bioluminescence imaging. An uninterrupted (>14 h) recording of visually evoked neural activities in the cortex of mice enabled the determination of strength of sensory activation. Furthermore, an artificial intelligence-based neural activation parameter transformed Ca2+ bioluminescence signals to network activity patterns. During continuous Ca2+-bioluminescence recordings, visual cortical activity peaked at the seventh to eighth hour of anesthesia, coinciding with circadian rhythm. For both direct optogenetic stimulation in cortical slices and visually evoked activities in the visual cortex, we observed secondary delayed Ca2+-bioluminescence responses, suggesting the involvement of neuron-astrocyte-neuron pathway. Our approach will enable the development of a modular and scalable interface system capable of serving a multiplicity of applications to modulate and monitor large-scale activities in the brain.
Highlights
Understanding the activation paradigm of sensory processing requires stimulation and continuous monitoring of neural activities at cellular resolution
We describe the development and implementation of bioluminescent Multi-Characteristics Opsin, a hybrid optogenetic actuator and bioluminescence Ca2+sensor, for excitation-free continuous monitoring of optically activated neural activities in cortical slices as well as in the visual cortex, with high spatiotemporal resolution that fundamentally extends the realm of neuromodulation and imaging
The opsin channel opens to allow for the passage of calcium into the transfected cells, which can be immediately detected and reported by the Ca2+-green nano-lanterns (GeNLs) sensor
Summary
Understanding the activation paradigm of sensory processing requires stimulation and continuous monitoring of neural activities at cellular resolution. Widely used in clinical settings, current methods for the modulation and detection of neural activities are based on electromagnetic fields (Peterchev et al, 2012), Bioluminescent MCO for Activity Monitoring which have low spatial resolution for both stimulation and imaging (Luan et al, 2014) and lack cellular specificity. Cellspecific genetic targeting of neurons for optical stimulation and imaging with high spatial and temporal resolution (Pama et al, 2013) has emerged as a research tool and provides opportunities for clinical translation such as restoration of vision (Baker and Flannery, 2018). In order to restore vision that is lost because of an enucleated eye or optic nerve damage, current attempts based on electrical stimulation of primary visual cortex are limited by invasiveness, poor resolution (as higher electrode density requires more current, leading to heat production), and scartissue formation around implanted electrodes. Optogenetics has potential for non-contact, cell specific stimulation and recording, enabling bidirectional control over neural activities in visual cortex
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