This novel chemically constructed tool enables researchers to use direct light to induce and examine the transitions of the brain from sleep to awake-like states in a controlled and non-invasive manner. Picture credit: IBEC/IDIBAPS
The interactions between billions of neurons in the brain induces various brain states. This network is the foundation of all our perceptions, memories, and behaviors. Because very restricted instruments are available to undertake precise and spaciotemporal investigations on brain neuronal behavior, it is sometimes referred to as a “black box,” with difficult access for physicians and researchers.
Now, researchers from the Institute for Bioengineering of Catalonia (IBEC), in conjunction with the August Pi i Sunyer Biomedical Research Institute (IDIBAPS), have shed some light on the topic by regulating neuronal activity in the brain for the first time using a light-responsive molecule.
The study, which included volunteers from the Autonomous University of Barcelona (UAB), was conducted as part of the European Union’s Human Brain Project. It demonstrates the first in vivo photomodulation of brain state transitions.
The study was recently published in the journal Advanced Science by ICREA Research Professors Pau Gorostiza (IBEC-CERCA, BIST, CIBER-BBN) and Mavi Sanchez-Vives (IDIBAPS).
The findings reveal that this novel chemical, dubbed PAI (for Phthalimide-Azo-Iper), has the ability to regulate the muscarinic cholinergic receptors, or acetylcholine receptors, which are crucial in activities such as learning, attention, and memory.
Transitions between brain states, such as waking up from a coma or transitioning from sleep to wakefulness, are dependent on the transmission of chemical and electrical impulses among groups of neurons involved in various activities. Current neural activity modulation methods, such as transcranial magnetic or ultrasonic stimulation, have spatiotemporal and spectral constraints. Optogenetics is another high-precision technology that utilizes light to control neurons, but it relies on genetic modification, making it difficult to translate to people for safety concerns.
To address these issues, researchers used photopharmacology. To do so, scientists employed PAI, a light-responsive chemical that allows for spatiotemporally controlled regulation of brain neurons by binding and regulating the activity of muscarinic cholinergic receptors, which are important receptors in neuronal contact and communication.
The cholinergic-innervation-dependent brain state transitions can be regulated by light utilizing molecules that are chemically engineered to be photosensitive using this technique.
“The control of neuronal activity in the brain is key to perform both basic and applied research, and to develop safe and accurate techniques to perform therapeutic brain interventions in clinical neurology” , explains Fabio Riefolo (IBEC), co-first author of the study.
Brain function is interrelated with brain states and transitions between them. Changes in brain activation patterns, which represent the activity and characteristics of certain neural networks, are intimately connected to them. Thus, spatiotemporal regulation of neurons is essential for determining the relationship between brain states and behavior, as well as studying the effect of neural circuits on specific behaviors. Furthermore, PAI is pharmacologically selective for the M2 muscarinic receptor subtype, which opens up new avenues for research into the pharmacology of brain waves.
Researchers were able to regulate the spontaneously occurring slow oscillations in neural networks and reversibly change the brain oscillatory frequency by administering PAI to the intact brain and then white light. This novel chemically constructed tool enables researchers to use direct light to induce and examine the transitions of the brain from sleep to awake-like states in a controlled and non-invasive manner.
Neuromodulators, such as acetylcholine (ACh), influence neuronal activity in our brain by attaching to cholinergic receptors. However, the role of various cells expressing ACh receptors in overall brain behavior is not entirely known. The use of selective and photoswitchable cholinergic medicines like PAI to accomplish a temporally precise regulation of brain activity paves the way for accurate basic neuroscience research as well as the development of future brain treatments and stimulation.
“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”, explains Dr. Almudena Barbero-Castillo (IDIBAPS), co-first author of the study.