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Rosalba Sortino, first author of the study (Photo: IBEC).

Researchers induce brain activation using infrared light-controlled drugs

A pioneering study led  by the Institute for Bioengineering of Catalonia (IBEC), based in the Barcelona Science Park, in collaboration with the ICFO – Institute of Photonic Sciences,  has unveiled a method to control brain activity in living organisms using drugs activated by infrared light. This cutting-edge technique activates a specific neurotransmitter receptor using light that can penetrate deep into tissue and offers unparalleled pharmacological and spatiotemporal precision in three dimensions. The findings open new frontiers for neurobiology research and the development of light-based noninvasive neuromodulation therapies.

Studying the brain remains one of the most challenging endeavors in neuroscience. Researchers have explored various methods for live imaging and stimulation of deep brain activity. One such method is multiphoton excitation using pulsed infrared (IR) light. This type of light is weakly absorbed by tissues and can penetrate through the bone and deep into organs like the brain. However, it has its limitations to produce focused images and to control cellular activity with precision. To overcome this, scientists have been exploring three-photon excitation with ultrafast pulsed IR light, to achieve whole cortex imaging and the observation of neuronal activity. Yet, until now, in vivo neuronal stimulation using three-photon excitation had not been reported.

A groundbreaking study, led by IBEC in collaboration with ICFO, both members of BIST, has introduced the first method for controlling brain activity in living organisms using drugs activated by three-photon excitation and mid-infrared light. This method is based on activating a specific receptor for acetylcholine, a vital neurotransmitter involved in various brain processes such as learning, attention, and memory.

To achieve this, researchers utilized PAI, a light-responsive molecule previously developed at IBEC, employing the lowest drug concentration and the longest photoactivation wavelength ever recorded.

The study, published at Angewandte Chemie journal, was led by Dr. Pau Gorostiza, ICREA Research Professor, member of CIBER-BBN and leader of the Nanoprobes and nanoswitches group at IBEC and by Dr. Pablo Loza-Álvarez, head of the Super resolution microscopy and Nanoscopy (SNL) lab at ICFO.

“The novelty of these results lies in the demonstration that the activity of drugs can be controlled with IR light, and that most of the photoswitchable ligands previously used in photopharmacology with ultraviolet and visible light are amenable to three-photon excitation using mid-infrared light, which is gentler on tissues”, explains Gorostiza.

“Plus, this technique, being IR illumination, provides the opportunity to penetrate deep within the tissue with submicrometric resolutions in all three dimensions. In simple terms, it means we can pinpoint the activation right at the laser beam’s focal point, illuminating it externally through the skull”, adds Loza-Álvarez.

Zebrafish larvae brain activation with PAI after light stimulation (Image: IBEC).

“The first time we saw the brain responses we were really impressed. We administered the PAI compound in its inactive form, which was uptaken by the zebrafish brain, and when we excited it with the three-photon flashes, the entire brain lit up. Using our setup, we could clearly see the PAI activation as changes in brain activity,” highlights Rosalba Sortino, first author of the study and recently doctorated researcher from Gorostiza’s group at IBEC.

These results showcase the potential of three-photon pharmacology and open up new horizons for fundamental research in neurobiology and the development of light-based neuromodulation therapies.

» Link to the news: IBEC website [+]

» Reference article: Rosalba Sortino, Marina Cunquero, Gustavo Castro-Olvera, Ricard Gelabert, Miquel Moreno, Fabio Riefolo, Carlo Matera, Noèlia Fernàndez-Castillo, Luca Agnetta, Michael Decker, José Maria Lluch, Jordi Hernando, Pablo Loza-Alvarez and Pau Gorostiza. Three-Photon Infrared Stimulation of Endogenous Neuroreceptors in Vivo. Angewandte Chemie International Edition (2023). DOI: 10.1002/anie.202311181