R. De Filippo, R. Gillis, D. Wyrick, M. Carlson, S. Durand, R. C. Peene, A. Bawany, A. Amaya, C. Grasso, W. Han, J. Kenney, C. Kiselycznyk, H. Loeffler, L. C. Marks, R. Naidoo, B. Ouellette, L. Suarez, J. Swapp, T. Johnson, J. Weber, J. Wilkes, P. A. Groblewski, A. Williford, M. Buice, C. Koch, I. Rembado, J. A. Lecoq, T. Ott
Psilocybin profoundly alters visual perception, yet the neuronal mechanisms underlying these effects remain unclear. Here we combined large-scale Neuropixels recordings with cell-type specific optogenetics in head-fixed mice performing a visual change-detection task. Psilocybin severely impaired task performance without overt motor deficits. In cortex, the drug modestly suppressed activity of layer 5 neurons while preserving representations of image identity. By contrast, psilocybin imposed a 4-Hz oscillation on visually evoked activity that preferentially affected neurons encoding image change rather than image identity. Under psilocybin, expected image repetitions aberrantly recruited change-encoding ensembles and shifted cortical population dynamics towards trajectories normally evoked by genuine stimulus changes. These effects were strongest in somatostatin-expressing (SST) interneurons in visual cortex. The strength of this modulation depended on image structure and was greatest for images with clear, continuous contours, which preferentially recruited change-encoding ensembles. These findings demonstrate that psilocybin drives internally generated cortical surprise signals, providing a circuit mechanism for altered perception in the acute psychedelic state.