A Discrete Dorsal Raphe to Basal Amygdala 5-HT Circuit Calibrates Aversive Memory

Neuron. 2019 Aug 7;103(3):489-505.e7. doi: 10.1016/j.neuron.2019.05.029. Epub 2019 Jun 13.


Despite a wealth of clinical and preclinical data implicating the serotonin (5-HT) system in fear-related affective disorders, a precise definition of this neuromodulator's role in fear remains elusive. Using convergent anatomical and functional approaches, we interrogate the contribution to fear of basal amygdala (BA) 5-HT inputs from the dorsal raphe nucleus (DRN). We show the DRN→BA 5-HT pathway is engaged during fear memory formation and retrieval, and activity of these projections facilitates fear and impairs extinction. The DRN→BA 5-HT pathway amplifies fear-associated BA neuronal firing and theta power and phase-locking. Although fear recruits 5-HT and VGluT3 co-expressing DRN neurons, the fear-potentiating influence of the DRN→BA 5-HT pathway requires signaling at BA 5-HT1A/2A receptors. Input-output mapping illustrates how the DRN→BA 5-HT pathway is anatomically distinct and connected with other brain regions that mediate fear. These findings reveal how a discrete 5-HT circuit orchestrates a broader neural network to calibrate aversive memory.

Keywords: 5-HT; basal amygdala; dorsal raphe nucleus; fear conditioning; fear extinction; nucleus accumbens; serotonin.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Amygdala / physiology*
  • Animals
  • Avoidance Learning / physiology*
  • Conditioning, Classical / physiology
  • Dorsal Raphe Nucleus / physiology*
  • Extinction, Psychological
  • Fear / physiology
  • Female
  • Genes, Reporter
  • Immobility Response, Tonic / physiology
  • Male
  • Mental Recall / physiology
  • Mice
  • Mice, Inbred C57BL
  • Neural Pathways / physiology*
  • Optogenetics
  • Serotonin / physiology*
  • Synaptophysin / administration & dosage
  • Synaptophysin / analysis
  • Theta Rhythm / physiology


  • Synaptophysin
  • Serotonin