Abstract

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.