The psychedelic DOI decreases the modularity of the cortical network by increasing cortico-cortical and thalamo-cortical functional influence

Psychedelics are powerful modulators of conscious perception, hypothesized to exert their effects by reorganizing large-scale brain functional connectivity. The circuit mechanisms underlying this reorganization remain unknown. Here, using widefield calcium imaging in awake mice, we found that the psychedelic DOI, in a 5-HT2A-dependent manner, acutely decreased the modularity of the cortical network by increasing correlations between anterolateral (AL) and posteromedial (PM) cortical domains. Functional influence measurements revealed that DOI increased both thalamo-cortical and long-range cortico-cortical influence onto the AL domain. We speculate that these increases in functional influence are driving the DOI-induced increase in the coupling between cortical domains. Our results provide a mouse correlate of the network reorganization seen under psychedelics in human neuroimaging and identify thalamo-cortical and cortico-cortical changes as candidate circuit mechanisms for this reorganization.