All-Optical Interrogation of Neural Circuits: Linking Optogenetic Perturbation to Molecular and Functional Readouts

Understanding how neural circuit activity emerges from, and feeds back into, underlying molecular states is a central challenge in modern neuroscience. Optogenetics has transformed the ability to causally modulate neuronal populations with high spatial and temporal precision, providing direct access to circuit function and behavior. However, despite its transformative impact, the field still faces a major methodological bottleneck in connecting functional perturbations to molecular and cellular identity within the same experiment, in the same cells, and at compatible timescales. Advances in genetically encoded voltage and neurotransmitter indicators, all-optical physiology, activity-dependent molecular tagging, and CRISPR-based perturbation now offer unprecedented opportunities to bridge this gap, enabling integrative analysis of neuronal activity, gene expression, and cellular identity in defined model systems.This Research Topic aims to foster methodological contributions that pair optogenetic actuators with functional and molecular readouts in the same preparation. We welcome work in invertebrate and vertebrate model organisms, brain slices, iPSC-derived neurons, and other tractable systems where the method itself, and its validation in a defined model, is the central contribution. The goal is to consolidate the toolset that links circuit-level perturbation to molecular state, in both healthy and disease-relevant contexts. We particularly encourage detailed protocols, validation studies in standard model organisms, data-integration workflows, and reviews that benchmark or compare emerging methods. Submissions should make clear what is new at the methods level and how the approach can be adopted by other laboratories. To gather further insights into these mechanisms, we welcome articles addressing, but not limited to, the following themes:• All-optical physiology: optogenetic actuators paired with genetically encoded voltage, calcium, or neurotransmitter indicators, including new opsin and indicator pairings that minimise spectral crosstalk.• Closed-loop and holographic stimulation combined with simultaneous functional or molecular readouts in defined model systems.• Activity-dependent molecular tagging, such as FLARE, Cal-Light, CaMPARI, and scribe systems, coupled to optogenetic control and downstream transcriptomic, epigenomic, or imaging-based profiling.• Theoretical, computational, and causal-inference frameworks that connect optogenetic perturbation to multimodal molecular and functional data, including benchmarking studies and shared analysis pipelines. Topic editors: Ke Si, Sukhdev Roy Source: https://www.frontiersin.org/research-topics/82022/all-optical-interrogation-of-neural-circuits-linking-optogenetic-perturbation-to-molecular-and-functional-readouts