Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.03.129627v1?rss=1 Authors: Rodgers, J., Bano-Otalora, B., Belle, M. D., Paul, S., Hughes, R., Wright, P., McDowell, R., Milosavljevic, N., Orlowska-Feuer, P., Martial, F., Wynne, J., Ballister, E. R., Storchi, R., Allen, A. E., Brown, T., Lucas, R. J. Abstract: There is no consensus on the best optogenetic tool for inhibiting neural activity. Lamprey parapinopsin (Lamplight) is a Gi/o-coupled bistable animal opsin that can be activated and deactivated by short and long wavelength light, respectively. Since native mechanisms of neuronal inhibition frequently employ Gi/o signalling, we asked here whether Lamplight could be used for optogenetic silencing. We show that brief short (405nm) and long (525nm) wavelength pulses repeatedly switch Lamplight between stable signalling active and inactive states, and that combining these wavelengths can be used to achieve intermediate levels of activity. We demonstrate that these properties can be applied to produce switchable and scalable neuronal hyperpolarisation, and suppression of spontaneous spike firing in the mouse hypothalamic suprachiasmatic nucleus. We show that expressing Lamplight in (predominantly) ON bipolar cells can photosensitise retinas following advanced photoreceptor degeneration, and that 405 and 525nm stimuli can produce responses of opposite sign in output neurons of the retina. Lamplight-driven responses to both activating (405nm) and deactivating (525nm) light can occur within 500ms. We conclude that Lamplight can co-opt endogenous signalling mechanisms to allow optogenetic inhibition that is scalable, sustained and rapidly reversible. Copy rights belong to original authors. Visit the link for more info