Open research questions in Photoreceptor and optogenetics research

What the literature leaves open

• The localization of MscL-I92L to postsynaptic spines is assumed for functional exploration, although subcellular targeting strategies for mechanosensitive channels remain an open experimental direction. Also, factors such as variability in CapChR expression levels, cellular heterogeneity and biophysical constraints in real neural tissue may further influence the observed responses and should be explored in subsequent investigations.

  Theoretical analysis of low power synergistic sono-optogenetic control of calcium-dependent synaptic plasticity · 2026 · DOI

• photostimulation from for Despite rapid progress in materials and device engineering for non-genetic photostimulation, significant opportunities remain for advancing these technologies toward fully programmable and clinically scalable bioelectronic systems. Emerging research directions are increasingly focused on integrating nanomaterial innovation, biological functionality, and system-level programmability to create next-generation photoelectroceutical platforms [25, 95]. These developments are expected to expand the scope of photostimulation from isolated device demonstrations to adaptive, multifunctional therapeutic systems. 5.1 Living and engineered optoelectronic tissues

  Non-genetic biointerfaces for programmable photoelectroceuticals · 2026 · DOI

• Another limitation is that numerous behavioral paradigms remain to be tested to determine whether optogenetic stimulation generally influences animal task performance. One limitation of the present study is that we exclusively employed a ChR2-based optogenetic approach. Further systematic studies are warranted to elaborate and extend these findings in greater detail.

  Seizure-Inducible Risks of In Vivo Optogenetic Manipulations · 2026 · DOI

• Because seizure-like activities induced by optogenetic activation of a neuronal projection are rarely reported, these results indicate that optogenetic stimulation may induce seizures regardless of whether cell bodies or axon terminals are targeted.

  Seizure-Inducible Risks of In Vivo Optogenetic Manipulations · 2026 · DOI

• Light-gated anion channelrhodopsins are widely used as optogenetic silencers, yet the molecular events underlying gate opening and closing remain unclear.

  Proton-Coupled Gate Closing Mechanism in Guillardia theta Anion Channelrhodopsin 1 · 2026 · DOI

• Channelrhodopsin-1 from Chlamydomonas augustae (CaChR1) is a phylogenetically early member of this class of proteins with red-shifted absorption and pronounced photocurrent kinetics, but the exact correlation between its photocycle intermediate states and channel conductivity remains to be elucidated.

  A red-light gate for a cation channel: The conducting state of channelrhodopsin-1 from Chlamydomonas augustae · 2026 · DOI

• Despite extensive research on carotenoids and microbial rhodopsins in aquatic environments, a fundamental understanding of the binding requirements of carotenoids that serve as auxiliary light-harvesting antennas for rhodopsins is still lacking.

  Selective Choice of the Efficient Carotenoid Antenna by a Xanthorhodopsin: Controlling Factors for Binding and Excitation Energy Transfer · 2025 · DOI

• However, lingering questions about the off-target effects of IR stimulation on non-neuronal cells remain sparsely explored.

  Infrared Neural Stimulation Elicits Distinct Molecular Pathways in Astrocytes Based on Laser Pulse Parameters · 2025 · DOI

• However, the neural dynamics induced by INS stimulation remain poorly understood.

  Focal thalamic infrared neural stimulation propagates dynamical transformations in auditory cortex · 2025 · DOI

• While sleep disruption during the acute phase of stroke is known to hinder recovery, the relationship between region-specific changes in NREM delta activity and functional recovery remains poorly understood.

  Region-specific non-rapid eye movement delta activity is associated with stroke recovery · 2025 · DOI

• These findings suggest that region-specific NREM delta activity may play a crucial role in stroke recovery and warrant further investigation to determine whether modulating delta activity in targeted brain areas during NREM sleep could aid recovery.

  Region-specific non-rapid eye movement delta activity is associated with stroke recovery · 2025 · DOI

• However, the mechanisms underlying long-distance electron transport remain incompletely understood.

  End-to-end contact enables long-distance electron transport between filaments in cable bacteria · 2025 · DOI

• However, melanopsin spectral sensitivity has been defined for only a small number of species, and the molecular mechanisms determining this property remain poorly understood.

  Spectral Tuning in Mammalian Melanopsins · 2025 · DOI

• Experimental evidence suggests that stretch-activated channels (SACs) contribute to light-driven action potential (AP) generation, but the exact way this takes place remains unknown due to system complexity and lack of specific SAC blockers.

  Cardiac action potential generation mechanisms via an intramembrane photoswitch. A simulation study · 2025 · DOI

• Among them, bistable rhodopsins such as the jumping spider rhodopsin 1 (JSR1), are promising for optogenetic applications, but their transduction mechanisms remain poorly understood.

  Mapping signal transduction in bistable jumping spider rhodopsin 1 · 2025 · DOI

• Although organic PVs exhibit lower efficiency than silicon PVs, in many practical scenarios, stimulation current is primarily limited by the electrodes rather than the PV driver, leading to potential parity between the two types.

  Coupling of photovoltaics with neurostimulation electrodes—optical to electrolytic transduction · 2024 · DOI

• The technologies to examine the neuronal microenvironment label free remain critically underexplored.

  Exploring the structure, metabolism, and biochemistry of the neuronal microenvironment label-free using fast simultaneous multimodal optical microscopy · 2024 · DOI

• However, it remains unclear how cholinergic and non-cholinergic BF neurons modulate large-scale functional networks and their relevance in intrinsic and extrinsic behaviors.

  Cell-type-specific optogenetic fMRI on basal forebrain reveals functional network basis of behavioral preference · 2024 · DOI

• However, the diversity of cyanobacterial rhodopsins, particularly in accumulated metagenomic data, remains underexplored.

  Cyanorhodopsin-II represents a yellow-absorbing proton-pumping rhodopsin clade within cyanobacteria · 2024 · DOI

• We hypothesize that this complementary behavior, along with the ability to store excess energy produced by PPR in the vacuole as high energy polyphosphates, represents an important survival strategy in the ocean, where light, iron levels, and temperature vary widely on a variety of spatial and temporal scales.

  Proton-pumping rhodopsins promote the growth and survival of phytoplankton in a highly variable ocean · 2024 · DOI

• Although metabolic radiation is now thoroughly documented in research on ultraweak photon emissions (UPE), the original finding that UPE can enhance mitogenesis remains controversial.

  Open quantum systems theory of ultraweak ultraviolet photon emissions: Revisiting Gurwitsch's onion experiment as a prototype for quantum biology · 2024 · DOI

• Magnetoreception, the ability to sense magnetic fields, is widespread in animals but remains poorly understood.

  Cryptochrome magnetoreception: Time course of photoactivation from non-equilibrium coarse-grained molecular dynamics · 2024 · DOI

• BACKGROUND: Alcohol use disorder (AUD) is a complex condition, and it remains unclear which specific neuronal substrates mediate alcohol-seeking and -taking behaviors.

  Optogenetic inhibition of light‐captured alcohol‐taking striatal engrams facilitates extinction and suppresses reinstatement · 2024 · DOI

• Anatoxin-a is a globally occurring, yet understudied, chiral cyanobacterial toxin that threatens public health and the environment.

  (+) Anatoxin-a elicits differential survival, photolocomotor behavior, and gene expression in two alternative vertebrate models · 2024 · DOI

• The time evolutions of the spectral forms derived from the spectroscopic data are inconsistent with the single chain mechanism and are analyzed within the concept of parallel photocycles.

  Parallel photocycle kinetic model of anion channelrhodopsin GtACR1 function · 2024 · DOI

Most-cited papers in Photoreceptor and optogenetics research

• Crystal Structure of Rhodopsin: A G Protein-Coupled Receptor · Science · 2000 · 4,805 citations
• Phototransduction by Retinal Ganglion Cells That Set the Circadian Clock · Science · 2002 · 2,994 citations
• Visualizing secretion and synaptic transmission with pH-sensitive green fluorescent proteins · Nature · 1998 · 2,353 citations
• Partial recovery of visual function in a blind patient after optogenetic therapy · Nature Medicine · 2021 · 695 citations
• Non-invasive, opsin-free mid-infrared modulation activates cortical neurons and accelerates associative learning · Nature Communications · 2021 · 375 citations
• Visualization of cortical, subcortical and deep brain neural circuit dynamics during naturalistic mammalian behavior with head-mounted microscopes and chronically implanted lenses · Nature Protocols · 2016 · 328 citations
• Chemically Fueled Self‐Assembly in Biology and Chemistry · Angewandte Chemie International Edition · 2021 · 322 citations
• Nonthermal and reversible control of neuronal signaling and behavior by midinfrared stimulation · Proceedings of the National Academy of Sciences · 2021 · 269 citations
• Dynamic brain spectrum acquired by a real-time ultraspectral imaging chip with reconfigurable metasurfaces · Optica · 2022 · 266 citations
• Circularly polarised luminescence laser scanning confocal microscopy to study live cell chiral molecular interactions · Nature Communications · 2022 · 259 citations

Most recent work

• Transplanting light-dependent reactions for mammalian eye photosynthesis · Cell · 2026
• A mesoscale optogenetics system for precise and robust stimulation of the primate cortex · Neuron · 2026
• Nanophotonic neural probes for in vivo photostimulation, electrophysiology, and microfluidic delivery · Microsystems & Nanoengineering · 2026
• Neuropixels Opto: combining high-resolution electrophysiology and optogenetics · Nature Methods · 2026
• Zapit: Open Source Laser-Scanning Photostimulation For Neuroscience · bioRxiv · 2026
• Fiber-Less, Large-Scale Opto-Electrophysiology Interface for Micro-Scale Interaction of Multiple Brain Regions · IEEE Transactions on Biomedical Engineering · 2026
• Biologically informed cortical models predict optogenetic perturbations · eLife · 2026
• DNET: A Graph-Based Tool and Workflow for Dynamic Hydrogen-Bond Networks and Applications for Visual Rhodopsins · Journal of Chemical Theory and Computation · 2026
• Multiphoton Absorption Spectra of Channelrhodopsin-2 via Multiscale Simulation Methods · Journal of Chemical Theory and Computation · 2026
• Axially decoupled photo-stimulation and two photon readout (ADePT) for mapping functional connectivity of neural circuits · bioRxiv · 2026

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