Researchers Control Brain States Via Photoswitchable Molecule

A team of scientists in Spain has directly photomodulated brain-state transitions in vivo using a photoswitchable molecule that was developed previously by researchers at the Institute for Bioengineering of Catalonia (IBEC). By applying a light-responsive molecule called phthalimide-azo-iper (PAI) to the intact brain and subsequently to white light, the researchers were able to modulate slow oscillations in neuronal circuits and reversibly manipulate the oscillatory frequency of the brain.

The chemically engineered mechanism allowed the researchers to induce and investigate brain transitions from sleep-like to awake-like states in detail, and in a noninvasive way.

The method for using light to enable PAI to modulate brain rhythms was developed by scientists at IBEC and the August Pi i Sunyer Biomedical Research Institute (IDIBAPS). The study represents the first time that brain-state transitions have been controlled using a molecule responsive to light, the researchers said.

PAI can specifically and locally control the muscarinic cholinergic receptors, that is, the acetylcholine receptors in the brain. These receptors are involved in several neuronal processes, such as learning, attention, and memory. When the researchers illuminated the photosensitive molecule PAI with white light, they were able to control and investigate cholinergic-dependent brain-state transitions in the neocortex.

Brain waves are synchronous activation and deactivation states of groups of neurons that belong to a circuit (represented by interconnected nodes in the brain scheme). They are repeated periodically, and their frequency is associated to the wakefulness state of the individual (slower waves are found in sleep or can be induced by anesthesia). The photoswitchable bioactive compound PAI adopts an inactive form under violet light (left) and changes its shape to act as a potent muscarinic activator under illumination with white light (right). This results in an increase in the wave frequency, which is an emerging property of the brain cortex. Courtesy of IBEC and IDIBAPS.

The researchers demonstrated the ability to selectively control slow oscillations both in vitro (in experiments using ferrets) and in vivo (in experiments using mice).

Unlike optogenetics, the method developed by the IBEC-IDIBAPS team does not depend on genetic manipulation to control brain activity. Unlike transcranial magnetic stimulation or ultrasound, the PAI-based method does not have spatiotemporal or spectral performance limitations and can be used to control spatiotemporal patterns of activity in different brain states.

The work of the IBEC-IDIBAPS team could provide a way to study cholinergic neuromodulation more completely, by controlling spatiotemporal patterns of activity in different brain states and in the transitions between states. It could help scientists better understand how brain states and brain-state transitions are linked to cognition and behavior. The PAI-based approach could be applied to different organisms, and since it does not require genetic manipulation, it could be translational to humans.

The ability to control neural activity is essential for research not only in basic neuroscience, but also in clinical neurology for therapeutic brain interventions. “The photocontrol of endogenous receptors and their functions in the central nervous system, such as the transition between different brain states, is an achievement for neuromodulation technologies,” IDIBAPS researcher Almudena Barbero-Castillo said.

In addition to improving the accuracy of basic neuroscience research, the use of PAI could lead to the development of selective, photomodulated drugs for the treatment of brain lesions or diseases such as depression, bipolar disorders, Parkinson’s, and Alzheimer’s.

“The control of neuronal activity in the brain is key to performing both basic and applied research, and to developing safe and accurate techniques to perform therapeutic brain interventions in clinical neurology,” IBEC researcher Fabio Riefolo said.

The researchers said that two-photon stimulation of PAI using pulsed infrared light could enable deep penetration and subcellular resolution in 3D. They believe that, compared to the local and often inhomogeneous expression patterns achieved with viral injections of optogenetic constructs, diffusible small molecules like PAI could in principle be applied to larger brain regions to control neuronal oscillations.

Further, the remote control of brain waves based on the photopharmacological manipulation of endogenous muscarinic receptors could reveal the complex 3D molecular signaling underlying brain states and their transitions.

The research was published in Advanced Science (www.doi.org/10.1002/advs.202005027).