Phasic Activation of Dorsal Raphe Serotonergic Neurons Increases Pupil Size

Curr Biol. 2021 Jan 11;31(1):192-197.e4. doi: 10.1016/j.cub.2020.09.090. Epub 2020 Nov 12.


Transient variations in pupil size (PS) under constant luminance are coupled to rapid changes in arousal state,1-3 which have been interpreted as vigilance,4 salience,5 or a surprise signal.6-8 Neural control of such fluctuations presumably involves multiple brain regions5,9-11 and neuromodulatory systems,3,12,13 but it is often associated with phasic activity of the noradrenergic system.9,12,14,15 Serotonin (5-HT), a neuromodulator also implicated in aspects of arousal16 such as sleep-wake transitions,17 motivational state regulation,18 and signaling of unexpected events,19 seems to affect PS,20-24 but these effects have not been investigated in detail. Here we show that phasic 5-HT neuron stimulation causes transient PS changes. We used optogenetic activation of 5-HT neurons in the dorsal raphe nucleus (DRN) of head-fixed mice performing a foraging task. 5-HT-driven modulations of PS were maintained throughout the photostimulation period and sustained for a few seconds after the end of stimulation. We found no evidence that the increase in PS with activation of 5-HT neurons resulted from interactions of photostimulation with behavioral variables, such as locomotion or licking. Furthermore, we observed that the effect of 5-HT on PS depended on the level of environmental uncertainty, consistent with the idea that 5-HT could report a surprise signal.19 These results advance our understanding of the neuromodulatory control of PS, revealing a tight relationship between phasic activation of 5-HT neurons and changes in PS.

Keywords: arousal; behavioral states; dorsal raphe; foraging; mouse; neuromodulation; optogenetics; pupil; serotonin; uncertainty.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arousal / physiology
  • Dorsal Raphe Nucleus / cytology
  • Dorsal Raphe Nucleus / physiology*
  • Female
  • Lasers
  • Light
  • Male
  • Mice
  • Mice, Transgenic
  • Models, Animal
  • Optogenetics
  • Photic Stimulation / instrumentation
  • Pupil / physiology*
  • Pupil / radiation effects
  • Serotonergic Neurons / metabolism*
  • Serotonin / metabolism*
  • Serotonin Plasma Membrane Transport Proteins / genetics
  • Serotonin Plasma Membrane Transport Proteins / metabolism
  • Uncertainty


  • Serotonin Plasma Membrane Transport Proteins
  • Slc6a4 protein, mouse
  • Serotonin