Control of Brain State Transitions with a Photoswitchable Muscarinic Agonist

Abstract

The 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.

Three‐Photon Infrared Stimulation of Endogenous Neuroreceptors in Vivo

“…The power dependence of the AUC yields an exponential factor of 3.1 (R 2 = 0.996), unambiguously confirming that PAI photoisomerization at 1560 nm follows a third-order non-linear process (3PE). The amplitude and fraction of responding cells display similar values but lower correlation, probably We have previously shown that PAI can control cardiac function in tadpoles and rats, [18d] and brain wave activity in mice [25] through the use of continuous wave illumination (1PE). Recently, we demonstrated in vivo photoswitching by 2PE in invertebrates.…”

Three‐Photon Infrared Stimulation of Endogenous Neuroreceptors in Vivo

“…We have previously shown that PAI can control cardiac function in tadpoles and rats, [18d] and brain wave activity in mice [25] through the use of continuous wave illumination (1PE). Recently, we demonstrated in vivo photoswitching by 2PE in invertebrates [18e] .…”

The reduction of sleep-like perilesional cortical dynamics underlies clinical recovery in stroke

“…Finally, introducing external interventions specifically aimed at manipulating adaptation mechanisms [23] and/or reinstating a correct excitation/inhibition balance [36] may further strengthen the link between the observed reduction of pathological sleep-like cortical dynamics and patients’ recovery of function. To date, evidence suggests that various tools including drug administration, opto-pharmacology, optogenetics, transcranial electrical stimulation, and repetitive TMS can modulate slow electrophysiological transients in simplified and in vivo experimental models [58–60].…”