Photopharmacological Cholinergic Modulation of Cortical Activity in Human Brain Slices.

Overview

1. Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (J.M.S.-S.); (J.C.)
2. Unidad de Epilepsia, Hospital Clinic, 08036 Barcelona, Spain; (E.C.); (P.R.); (J.R.); (M.C.)
3. Institute for Bioengineering of Catalonia (IBEC), 08028 Barcelona, Spain; (F.R.); (C.M.); (P.G.)
4. Barcelona Institute of Science and Technology, 08028 Barcelona, Spain
5. CIBER-BBN (Bioingeniería, Biomateriales y Nanomedicina), 28029 Madrid, Spain
6. Catalan Institution for Research and Advanced Studies (ICREA), 08010 Barcelona, Spain

Abstract

Highlights: What are the main findings?

Photoactivation of Phthalimide-Azo-Iperoxo (PAI), a selective M2 muscarinic acetylcholine receptor agonist, can selectively modulate slow-oscillatory activity emerging from human cortical slices.

PAI photoactivation induced a significant increase in oscillatory frequency and a corresponding reduction in both Up- and Down-state duration, confirming that the cholinergic system plays a critical role in regulating brain state transitions.

What are the implications of the main findings?

To our knowledge, this is the first proof-of-concept study demonstrating the potential of photomodulation in human brain tissue, validating the feasibility of translating previous findings from animal models to human tissue.

Selective light-mediated activation of muscarinic receptors in human brain tissue establishes a proof of concept for optical control of cholinergic signaling with high spatiotemporal precision.

Abstract: Background/Objectives: Understanding the unique properties of human neurons is crucial for advancing knowledge of brain function and facilitating clinical translation. This study explores the use of photopharmacology, specifically a photoswitchable ligand, Phthalimide-Azo-Iperoxo (PAI), to modulate cortical activity in human brain slices. Methods: Human cortical tissue was obtained from patients undergoing resective neurosurgery for pharmacoresistant epilepsy. The inactive cis isomer of PAI (200 nM) was bath-applied to brain slices exhibiting slow-oscillatory activity, producing no effect on the ongoing network activity. Subsequent illumination of the slices with white light induced photoconversion to trans-PAI, the active form of the compound. Results: Photoactivation of PAI selectively activated M2 muscarinic acetylcholine receptors, resulting in a significant increase in oscillatory frequency accompanied by reductions in both Up-state and Down-state durations. Conclusions: In this proof-of-concept study, our findings provide preliminary evidence that photopharmacology can selectively modulate slow oscillations in human cortical circuits, highlighting its potential as a tool for investigating human cortical dynamics. By extending observations previously made in animal models to human tissue, this work establishes the feasibility of photopharmacological modulation in human cortical tissue and provides a foundation for future translational research.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• zenodo:20750122, at Zenodo; found in “Data Availability Statement”

Data Availability Statement

The data supporting the findings of this study are openly available in Zenodo at https://zenodo.org/records/20750122 (accessed on 29 July 2026).

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 10 authors, 7 keywords, 2 funders, 35 references.

Cite

This paper

Sanchez-Sanchez, J. M., Covelo, J., Conde, E., Roldán, P., Rumià, J., Carreño, M., Riefolo, F., Matera, C., Gorostiza, P., & Sanchez-Vives, M. V. (2026). Photopharmacological Cholinergic Modulation of Cortical Activity in Human Brain Slices. Brain sciences, 16(8), 822. https://doi.org/10.3390/brainsci16080822

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