Genetically Encoded Biosensors and All-Optical Interrogation of Neural Signalling

Genetically encoded biosensors have transformed the ability to observe molecular signalling events in the nervous system with cellular and subcellular resolution. Engineered fluorescent proteins now report neural activity and signalling in real time, including genetically encoded calcium indicators (GCaMP and its variants), voltage indicators (ASAP, Voltron), and a rapidly expanding family of GPCR-based sensors for neurotransmitters and neuromodulators such as dopamine, acetylcholine, norepinephrine, and serotonin (dLight, GRAB). Complementary probes track second messengers, kinase activity, neuropeptides, and metabolic state, extending optical readout from electrical activity to the biochemical signalling cascades that underlie it. When paired with optogenetic actuators such as channelrhodopsins, these tools enable all-optical interrogation, in which signalling is read and written simultaneously in defined cell types across intact circuits.These technologies are advancing at remarkable pace, driven by protein engineering, structure-guided sensor design, improved delivery, and innovations in two-photon and holographic microscopy. Together they allow researchers to link molecular signalling events to synaptic transmission, circuit dynamics, and behaviour in awake, behaving animals with a precision that was previously unattainable. Yet substantial challenges remain, including sensor kinetics and sensitivity, spectral multiplexing and crosstalk, quantitative calibration of fluorescent signals, deep-tissue and large-scale imaging, cell-type-specific expression, and the computational analysis of high-dimensional optical data. Addressing these challenges is central to using biosensors not merely as activity reporters but as quantitative tools for dissecting signalling pathway dynamics in the nervous system.This Research Topic aims to bring together studies that develop, benchmark, and apply genetically encoded biosensors and all-optical approaches to interrogate neural signalling. By uniting tool developers and the laboratories that deploy these probes, this collection seeks to clarify how optical measurement and manipulation of molecular signalling can reveal the mechanisms linking neurotransmission, neuromodulation, and intracellular signalling to circuit function and behaviour.We welcome submissions employing molecular, biochemical, imaging, electrophysiological, optical, and computational approaches, including sensor and actuator engineering, viral and genetic delivery strategies, and work in genetically engineered model organisms, human-derived cellular systems, organoids, and in vivo preparations. Studies that connect optically measured signalling events to defined molecular, synaptic, circuit-level, or behavioural outcomes, and methods or resource articles that advance the underlying toolkit, are particularly encouraged.Topics of interest include, but are not limited to:• Design and engineering of genetically encoded calcium, voltage, and neurotransmitter or neuromodulator sensors• GPCR-based biosensors for dopamine, acetylcholine, norepinephrine, serotonin, neuropeptides, and other signalling molecules• Sensors for second messengers, kinase activity, and intracellular signalling cascades in neurons and glia• All-optical interrogation combining biosensor imaging with optogenetic actuation for reading and writing neural signalling• Advances in two-photon, holographic, voltage, and large-scale or deep-tissue imaging of signalling dynamics• Strategies for cell-type-specific expression, viral delivery, and targeting of sensors and actuators• Quantitative calibration, spectral multiplexing, and analysis of optical signalling data• Application of biosensors to dissect neurotransmission, neuromodulation, and pathway dynamics in vivo• Use of biosensors and all-optical methods in disease models to reveal signalling dysfunction• Benchmarking studies, methods, and resources comparing sensor performance across contexts Topic editors: Marco Lorenzo Dal Maschio, Hui-Hao Lin Source: https://www.frontiersin.org/research-topics/84560/genetically-encoded-biosensors-and-all-optical-interrogation-of-neural-signalling