PSILOCYBIN MODULATES VISUAL PROCESSING VIA REORGANIZATION OF CORTICAL INHIBITION

Interest in psychedelic compounds has grown due to their potential therapeutic applications; however, mechanistic understanding of their action remains limited by a lack of large-scale, cell-resolved recordings. Here, we examined how psilocybin alters cortical population activity by recording from multiple cortical areas in head-fixed mice during a visual change-detection task. Using six Neuropixels probes per animal, we recorded 4,872 neurons in saline sessions and 7,645 neurons following psilocybin administration (1 mg/kg, i.p.) across visual and frontal cortical regions.
Psilocybin profoundly impaired task performance, characterized by a pronounced reduction in hit rates. At the neural population level, psilocybin induced a robust oscillatory modulation of visually evoked activity. This modulation was highly cell-type specific, with the strongest effects observed in inhibitory interneurons, particularly somatostatin-expressing (SST) neurons. Spatially, oscillatory modulation was significantly stronger in visual cortical areas than in frontal regions.
Critically, the magnitude of this oscillatory modulation correlated with changes in novelty encoding, quantified using mutual information between neural responses and stimulus change events, suggesting an alteration of sensory representations relevant for task performance.
Together, these results demonstrate that psilocybin reorganizes cortical dynamics in a cell-type- and area-specific manner. By providing large-scale, cell-resolved measurements of cortical activity during behavior, this work offers novel empirical constraints for the development of mechanistic models of psychedelic action linking population dynamics to altered perception and decision-making.