Serotonin modulates neural dynamics in a subspace orthogonal to the choice space

Serotonin (5-HT) is a central neuromodulator which is implicated in, amongst other functions, cognitive flexibility. 5-HT is released from the dorsal raphe nucleus (DRN) throughout nearly the entire forebrain. Little is known, however, about how serotonin affects downstream populations of neurons and how this modulation might support its cognitive functions. Here, we optogenetically stimulated serotonergic neurons in the DRN while recording large parts of the brain with Neuropixels during quiet wakefulness and performance of a perceptual decision-making task. During quiet wakefulness, 5-HT stimulation induced a rapid switch in internal state, as indicated by dilation of the pupil, suppression of hippocampal sharp wave ripples, and increased exploratory behaviors, such as whisking. To elucidate the brain-wide effect of serotonin release we performed acute Neuropixel recordings in seven target locations, a total of 7,478 neurons were recorded across 17 mice. We found that 5-HT stimulation significantly modulated neural activity in all the recorded brain regions, both during quiet wakefulness and task performance. During task performance, however, we observed no change in behavior when stimulating 5-HT. We found that the 5-HT modulation of high-dimensional neural dynamics is confined to a subspace which is orthogonal relative to the choice axis. These observations describe a possible mechanism for the induction of state-dependent stimulus representations, suggesting a neural basis for neuromodulatory effects on brain-wide circuits to flexible decision-making.