Control of brain state transitions with a photoswitchable muscarinic agonist

The ability to control neural activity is essential for research in basic neuroscience, as it affects the mental state of an individual, but also in clinical neurology for brain therapies or stimulation. Available forms of spatiotemporally controlled neuromodulation include transcranial-magnetic or current (AC/DC) stimulation as well as light-mediated control. Among the latter, optogenetics has revolutionized neuroscience, yet its clinical translation is hampered by the need of gene therapy. As a drug-based alternative, the development of a new photoswitchable muscarinic agonist (PAI) and its effect on a brain network is evaluated in this work. First, the conditions to manipulate muscarinic receptors with light in the experimental setup are determined. Then, the emergent cortical activity consisting on synchronous slow oscillations –as in slow wave sleep– is transformed into a higher frequency pattern in the cerebral cortex both in vitro and in vivo. 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 makes it translational to humans.