Studying the mechanisms of the brain continues to be one of the most challenging endeavors in neuroscience. Experts have reviewed different methods for live imaging and stimulation of deep brain activity. One such approach is multiphoton excitation, which uses pulsed infrared light. This light is absorbed weakly by the bones and can penetrate through the bone and deep into organs such as the brain. However, this method has its limitations in producing focused images and in precisely controlling cellular activity.
Scientists explore three-photon excitation with ultrafast pulsed infrared light to address this challenge. They aim to achieve whole cortex imaging and observe neuronal activity. Yet, until now, in vivo, neuronal stimulation using three-photon excitation has not been reported.
Novel Method of Controlling Brain Activity
In groundbreaking research, experts from the Institute for Bioengineering of Catalonia (IBEC) and the Institute of Photonic Science have presented the first method for controlling brain activity in living organisms. Led by Professor Pau Gorostiza, the scientists utilized a method that uses drugs activated by three-photon excitation and mid-infrared light.
The method is also based on activating a specific receptor for acetylcholine, an important neurotransmitter involved in different brain processes like memory, attention, and learning. The experts utilized PAI, a light-responsive molecule with the lowest drug concentration and the longest photoactivation wavelength ever recorded, to achieve this.
Research findings reveal that the activity of drugs can be controlled with infrared light, according to Gorostiza. It also demonstrates that most photoswitchable ligands previously used with ultraviolet and visible light in photopharmacology are amenable to three-photon excitation that uses mid-infrared light, which is gentler on tissues.
As an infrared illumination technique, the method enables the experts to penetrate deep within the tissue using submicrometric resolutions in all three dimensions. In other words, the researchers can pinpoint the activation right at the focal point of the laser beam, illuminating it externally through the skull.
The study's results not only showcase the potential of three-photon pharmacology but also open up new horizons for fundamental research in neurobiology. Additionally, they allow the development of light-based neuromodulation therapies.
Harnessing the Power of Light
In photopharmacology, light can be harnessed to allow targeted drug action within certain body areas. This innovative method involves modifying a drug's chemical structure by adding a light-activated molecular switch. It ensures that the drug activates only when exposed to a light color.
In their previous research, the IBEC team attempted to activate PAI using one-photon and two-photon excitation with limited reversibility and control in vivo. In their recent study, they turned to longer wavelength infrared light and theoretical calculations to enhance the activation of PAI through multi-photon excitations.
Their calculations suggest that three-photon excitation can be more efficient than the two-photon alternatives and that the principle can be widely applicable. In the future, the research team plans to apply even shorter and more focused stimulation to investigate these endogenous responses more accurately.
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