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Light-controlled Biology Methods in Nature Communications

Light-controlled technologies to probe and manipulate cellular activity have revolutionized basic life science research fields ranging from cell biology to neuroscience. These technologies are also being investigated as potential therapeutic approaches for illnesses like stroke and cancer. This cross-disciplinary collection brings together Nature Communications articles from biotechnology, optics, neuroscience, cell biology, and medicine that develop or apply light-controlled technologies.

In the Cell Biology section, we highlight articles that use engineered light-sensitive proteins or new inorganic and organic optical sensors  to gain insight into cellular processes such as intracellular signaling. Neuroscience is another discipline that has been revolutionized by light-controlled technologies, with optogenetics allowing neuroscientists to control genetically defined sets of neurons, and optical imaging of neuronal structure and activity during behavior becoming possible on larger scales. We highlight research and methods with especial relevance to the brain in the Neuroscience section. Although many light-controlled techniques now exist, methods developers continue to optimize and extend these non-invasive technologies (moving beyond light-control into thermo-, magneto- and sono- control), as we showcase in the Tool Development section. Finally, the Therapies section highlights Nature Communications papers that leverage light-controlled methods for disease applications.

This collection will be updated regularly with studies published in Nature Communications ​that feature new development and uses of light-controlled biology methods.

Cell Biology

Cellular mechanical forces are regulated by Rho GTPases. Here the authors develop an optogenetic system to control the spatiotemporal activity of RhoA, and show that directing a RhoA activator to the plasma membrane causes contraction and YAP nuclear localization, whereas directing it to the mitochondria causes relaxation.

Article | Open Access | | Nature Communications

Traditional methods for the assembly of plasmonic nanoparticles into photo-responsive probes suffer from multiple problems. Here the authors use split fluorescent protein fragments as molecular glue to form stable nanoclusters for surface enhanced Raman scattering and photoacoustic imaging in live cells.

Article | Open Access | | Nature Communications

Existing pH-sensitive red fluorescent protein probes don’t perform well in monitoring exocytosis and endocytosis. Here, the authors combine organic dyes with self-labeling tags or antibodies to develop semisynthetic protein conjugates that can image synaptic vesicle fusion events in living cells.

Article | Open Access | | Nature Communications

Studying interactions between lysosomes and mitochondria in living cells is difficult due to the limitations of existing probes. Here, the authors develop new cell-permeable fluorescent probes to image the dynamics of lysosomes and their physical interactions with mitochondria using super-resolution microscopy.

Article | Open Access | | Nature Communications

The ability to quantify the organization of cell membrane molecules is limited by the density of labeling and experimental conditions. Here, the authors use super-resolution optical fluctuation (SOFI) for molecular density and clustering analyses, and investigate nanoscale distribution of CD4 glycoprotein.

Article | Open Access | | Nature Communications

Optogenetics is opening the possibility to not only perturb morphogenesis, but also to guide it. Here, the authors use this technique to reconstruct epithelial folding in Drosophila embryos and study the relationship between strength of Rho activation, apical constrictions, and tissue invagination.

Article | Open Access | | Nature Communications

Autophagic degradation of mitochondria (mitophagy) is a key quality control mechanism in cellular homeostasis, and its misregulation is involved in neurodegenerative diseases. Here the authors develop an optogenetic system for reversible induction of mitophagy and validate its use in cell culture and zebrafish embryos.

Article | Open Access | | Nature Communications

Neuroscience

Transgenic approaches and improvements in functional imaging have necessitated an advance in the behavioral toolkit. Here the authors describe an automated high-throughput voluntary head fixation system for training mice on complex psychophysical decision tasks compatible with concurrent two-photon microscopy.

Article | Open Access | | Nature Communications

The noradrenergic system plays numerous physiological roles but tools to study it are scarce. Here the authors develop a fluorescent analogue of norepinephrine that can be used to label noradrenergic neurons and the synaptic vesicles, and use it to measure single synaptic vesicle release sites in living mice.

Article | Open Access | | Nature Communications

Oscillations in cortical activity during development are important for functional maturation. Here, the authors use optogenetics in neonatal mice to determine a causal role for pyramidal cell firing in different prelimbic cortex layers in generating beta–gamma range activity.

Article | Open Access | | Nature Communications

Tool Development

Bioluminescence resonance energy transfer (BRET) has been mostly employed in imaging applications. Here the authors use BRET to activate a ruthenium-based photocatalyst and perform a bioorthogonal chemical reaction, which can be used to uncage small molecule drugs in a cellular context.

Article | Open Access | | Nature Communications

Optogenetics, the optical stimulation of neurons, suffers from many technical challenges that limit the number of neurons that can be excited as well as their relative positions. Here, Pégard et al. develop a method to simultaneously stimulate an arbitrary number of neurons in 3D space with single neuron resolution.

Article | Open Access | | Nature Communications

Current approaches to thermogenetic manipulation of neuronal activity lack sufficient spatiotemporal resolution. Here the authors show that neurons expressing snake TRPA1 channels are activated at high temporal resolution with IR light and this technique can be used to elicit behaviour in zebrafish larvae.

Article | Open Access | | Nature Communications

Optogenetic applications would benefit from channelrhodopsins (ChRs) with faster photostimulation, increased tissue transparency and lower phototoxicity. Here, the authors develop fast red-shifted ChR variants and show the abilities for temporal precise spiking of cerebral interneurons and restoring auditory activity in deaf mice.

Article | Open Access | | Nature Communications

Non-destructive methods to image metabolism in situ in living tissues are limited. Here the authors combine deuterium oxide probing and stimulated Raman scattering microscopy to image lipid metabolic dynamics and protein synthesis in cells and in vivo in mice, C. elegans, and zebrafish.

Article | Open Access | | Nature Communications

Optical imaging and manipulation technologies cannot be easily integrated with electrical recordings due to generation of light-induced artifacts. Here the authors report the optimization of transparent graphene microelectrode fabrication to achieve artifact-free electrical recordings along with deep 2-photon imaging in vivo.

Article | Open Access | | Nature Communications

Red-shifted bioluminescence emission is needed to improve deep tissue imaging resolution. Here, the authors develop a click beetle red luciferase mutant and two naphthyl-luciferin substrates, and show the ability of the new luciferin/luciferase pairing for deep tissue multispectral tomography in mice.

Article | Open Access | | Nature Communications

Advanced diagnostic probes are required for monitoring disease progression. Here Galanzhaet al. demonstrate a 22 nm plasmonic nanolaser to serve as a super-bright, biocompatible probe capable of generating stimulated emission directly inside living cells and animal tissue, while targeting cancer cells.

Article | Open Access | | Nature Communications

Optogenetic tools enable precise experimental control of the behaviour of cells. Here, the authors introduce a genetically-encoded two-protein system that enables silencing of excitable cells such as neurons and cardiomyocytes using blue light, and demonstrate its utility both in vitro and In vivo.

Article | Open Access | | Nature Communications

Designing split protein approaches is time consuming and often results in high background activity due to spontaneous assembly. Here the authors present an automated approach which uses a split energy scoring function to identify optimal protein split sites and reduces spontaneous assembly.

Article | Open Access | | Nature Communications

Methods to directly label active neurons are still lacking. Here the authors develop CaMPARI2, a photoconvertible fluorescent protein sensor for neuronal activity with improved brightness and calcium binding kinetics, as well as an antibody to amplify the activated sensor signal in fixed samples.

Article | Open Access | | Nature Communications

Optogenetics is a promising alternative approach for restoration of neuromuscular function. Here the authors establish a closed-loop functional optogenetic stimulation for the control of limb joint angle in murine models, which demonstrates improved control and less fatigue than electrical stimulation systems.

Article | Open Access | | Nature Communications

Most approaches to control gene expression in vivo require generation of knock-in mouse lines and often lack spatiotemporal control. Here the authors develop a photo-activatable Flp recombinase system and demonstrate its use by controlling object-exploration behavior in mice through Cav3.1 silencing.

Article | Open Access | | Nature Communications

Studying adrenergic signalling in the heart requires perfusion with receptor agonists, which lacks cell specificity and spatiotemporal control. Here the authors use the light sensitive G-coupled receptor JellyOp to optogenetically control Gs-signaling in cardiomyocytes and intact hearts with high spatiotemporal precision.

Article | Open Access | | Nature Communications

Therapies

Stroke recovery requires circuit reorganization and therapeutic efforts have focused on rewiring cortical circuits after stroke, but what about thalamic inputs? Here, the authors examine how thalamocortical axons are affected by stroke and use optogenetic stimulation to promote recovery.

Article | Open Access | | Nature Communications

Targeting tumors with bacteria as vehicles for metabolite therapy suffers from low efficiency and robustness. Here, the authors combine carbon nitride with nitric oxide generation enzyme-positive E. coli for photo-controlled metabolite therapy (PMT) and observe increased effects both in vitro and in tumor-bearing mice.

Article | Open Access | | Nature Communications

Existing methods to improve motor function after stroke include non-specific neuromodulatory approaches. Here the authors use an automated method of analysis of reaching behaviour in rodents to show that optogenetic stimulation of intact corticospinal tract fibres leads to restoration of prior motor functions, rather than compensatory acquisition of new movements.

Article | Open Access | | Nature Communications

Cholinergic neurons in the diagonal band of Broca degenerate early in Alzheimer’s disease. Here the authors show that in healthy mice, these cholinergic inputs innervate newborn neurons in the hippocampus, and that loss of this innervation in an Alzheimer’s disease model leads to impairments in spatial memory.

Article | Open Access | | Nature Communications

It is known that descending facilitation of spinal responses may contribute to chronic pain, however many studies have focussed on brainstem mechanisms. Here the authors show that stimulation of the anterior cingulate cortex increases excitatory transmission in the dorsal horn, and that this may be via a direct pathway independent of the brainstem.

Article | Open Access | | Nature Communications

Optogenetic stimulation of damaged peripheral nerves has advantages over electrical stimulation but it’s limited to single-site stimulation. Here the authors develop a spiral-shaped LED implant for precise optogenetic stimulation of peripheral nerve bundles at multiple sites and use it to induce distinct limb movements in mice.

Article | Open Access | | Nature Communications