A real-time all-optical interface for dynamic perturbation of neural activity during behavior

Zihui Zhang; Patrycja Dzialecka; Lloyd E Russell; Riccardo Ratto; Christina Buetfering; Oliver M Gauld; David R Selviah; Michael Häusser

doi:10.1016/j.crmeth.2025.101180

A real-time all-optical interface for dynamic perturbation of neural activity during behavior

Cell Rep Methods. 2025 Oct 20;5(10):101180. doi: 10.1016/j.crmeth.2025.101180. Epub 2025 Sep 18.

Authors

Zihui Zhang¹, Patrycja Dzialecka², Lloyd E Russell³, Riccardo Ratto³, Christina Buetfering³, Oliver M Gauld³, David R Selviah⁴, Michael Häusser⁵

Affiliations

¹ Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK; Department of Electronic and Electrical Engineering, University College London, Torrington Place, London WC1E 7JE, UK; Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: zihui.zhang.15@gmail.com.
² Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK; Department of Psychiatry & Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
³ Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK.
⁴ Department of Electronic and Electrical Engineering, University College London, Torrington Place, London WC1E 7JE, UK.
⁵ Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK; School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China. Electronic address: m.hausser@ucl.ac.uk.

Abstract

We developed a strategy for implementing a dream experiment in systems neuroscience, where circuit manipulation is guided by the real-time readout of neural activity in behaving mice. The system integrates a state-of-the-art calcium imaging analysis package that achieves rapid online activity readout from two-photon calcium imaging, a custom hologram generation program that targets two-photon optogenetic stimulation of specific neuronal ensembles, and software modules that automate essential steps in running complex all-optical experiments. Proof-of-principle experiments demonstrate that neurons can be automatically detected and recruited into a photostimulation ensemble, closed-loop photoinhibition can be implemented immediately after fast mapping of the functional properties of cortical neurons, and targeted activation can be guided by readout of ongoing activity patterns in behaviorally relevant neuronal ensembles during decision-making.

Keywords: CP: Neuroscience; barrel cortex; behavior; calcium imaging; closed-loop; holographics; neural circuits; optogenetics; real-time; two-photon microscopy; visual cortex.

MeSH terms

Animals
Behavior, Animal* / physiology
Calcium / metabolism
Mice
Neurons* / metabolism
Neurons* / physiology
Optogenetics* / methods
Software

Substances

Calcium