Serotonin induces DOWN states across the anesthetized mouse forebrain

Serotonergic neurons in the dorsal raphe nucleus (DRN) project extensively throughout the forebrain, yet their influence on global network states remains controversial. Serotonin is implicated in regulating slow-oscillations, so-called UP and DOWN states, which occur during sleep and light anesthesia. While optogenetic fMRI suggests that serotonin (5-HT) suppresses brain-wide activity, classical electrical stimulation studies report the induction of cortical UP states. To resolve this discrepancy, we combined optogenetic 5-HT stimulation with large-scale Neuropixel recordings across the forebrain of lightly anesthetized mice. We demonstrate that selective 5-HT release consistently induces DOWN states across the cortex and striatum, while leaving midbrain dynamics largely unaffected. A multi-area computational model constrained by biologically plausible connectivity, indicates that in certain regions the transitions arises from network-level synchronization rather than direct DRN input.