Control of brain state transitions with a photoswitchable muscarinic agonist

• DOI: 10.5281/zenodo.6532510
• Publication Date: 2021-05-21
• Authors: Enrique Claro; Aida Garrido-Charles; Fabio Riefolo; Pau Gorostiza; Julia F. Weinert; Pedro Mateos‐Apar...; Almudena Barbero-...; Carlo Matera; Sara Caldas-Martinez; Maria V. Sanchez-...; Maria V. Sanchez-...
• Keywords: 0301 basic medicine; General Chemical Engineering; Science; Photopharmacology; General Physics and Astronomy; Medicine (miscellaneous); Stimulation; Biology; Optogenetics; Muscarinic Agonists; Light-mediated control; Biochemistry, Genetics and Molecular Biology (miscellaneous); Muscarinic agonist; Neurologia; Mice; 03 medical and health sciences; brain states; In vivo; Muscarinic acetylcholine receptor; muscarinic acetylcholine receptors; Neurociències; Animals; General Materials Science; photopharmacology; Research Articles; 0303 health sciences; Neuromodulation; Q; General Engineering; Brain states; Neurosciences; Ferrets; Brain; Neuromodulation (medicine); 3. Good health; Mice, Inbred C57BL; Neurology; Cerebral cortex; light‐mediated control; neuromodulation; Models, Animal; Cholinergic; brain states; light-mediated control; muscarinic acetylcholine receptors; neuromodulation; photopharmacology;; Muscarinic acetylcholine receptors; Neuroscience

AbstractThe ability to control neural activity is essential for research not only in basic neuroscience, as spatiotemporal control of activity is a fundamental experimental tool, but also in clinical neurology for therapeutic brain interventions. Transcranial‐magnetic, ultrasound, and alternating/direct current (AC/DC) stimulation are some available means of spatiotemporal controlled neuromodulation. There is also light‐mediated control, such as optogenetics, which has revolutionized neuroscience research, yet its clinical translation is hampered by the need for gene manipulation. As a drug‐based light‐mediated control, the effect of a photoswitchable muscarinic agonist (Phthalimide‐Azo‐Iper (PAI)) on a brain network is evaluated in this study. First, the conditions to manipulate M2 muscarinic receptors with light in the experimental setup are determined. Next, physiological synchronous emergent cortical activity consisting of slow oscillations—as in slow wave sleep—is transformed into a higher frequency pattern in the cerebral cortex, both in vitro and in vivo, as a consequence of PAI activation with light. These results open the way to study cholinergic neuromodulation and to control spatiotemporal patterns of activity in different brain states, their transitions, and their links to cognition and behavior. The approach can be applied to different organisms and does not require genetic manipulation, which would make it translational to humans.