Stress Enables Reinforcement-Elicited Serotonergic Consolidation of Fear Memory

Michael V. Baratta, Suhasa B. Kodandaramaiah, Patrick E. Monahan, Junmei Yao, Michael D. Weber, Pei Ann Lin, Barbara Gisabella, Natalie Petrossian, Jose Amat, Kyungman Kim, Aimei Yang, Craig R. Forest, Edward S. Boyden, Ki A. Goosens

Research output: Contribution to journalArticlepeer-review

50 Scopus citations


Background Prior exposure to stress is a risk factor for developing posttraumatic stress disorder (PTSD) in response to trauma, yet the mechanisms by which this occurs are unclear. Using a rodent model of stress-based susceptibility to PTSD, we investigated the role of serotonin in this phenomenon. Methods Adult mice were exposed to repeated immobilization stress or handling, and the role of serotonin in subsequent fear learning was assessed using pharmacologic manipulation and western blot detection of serotonin receptors, measurements of serotonin, high-speed optogenetic silencing, and behavior. Results Both dorsal raphe serotonergic activity during aversive reinforcement and amygdala serotonin 2C receptor (5-HT2CR) activity during memory consolidation were necessary for stress enhancement of fear memory, but neither process affected fear memory in unstressed mice. Additionally, prior stress increased amygdala sensitivity to serotonin by promoting surface expression of 5-HT2CR without affecting tissue levels of serotonin in the amygdala. We also showed that the serotonin that drives stress enhancement of associative cued fear memory can arise from paired or unpaired footshock, an effect not predicted by theoretical models of associative learning. Conclusions Stress bolsters the consequences of aversive reinforcement, not by simply enhancing the neurobiological signals used to encode fear in unstressed animals, but rather by engaging distinct mechanistic pathways. These results reveal that predictions from classical associative learning models do not always hold for stressed animals and suggest that 5-HT2CR blockade may represent a promising therapeutic target for psychiatric disorders characterized by excessive fear responses such as that observed in PTSD.

Original languageEnglish (US)
Pages (from-to)814-822
Number of pages9
JournalBiological psychiatry
Issue number10
StatePublished - May 15 2016

Bibliographical note

Funding Information:
ESB acknowledges funding by Jerry and Marge Burnett; Department of Defense Congressionally Directed Medical Research Programs Posttraumatic Stress Disorder Program; Human Frontiers Science Program; Massachusetts Institute of Technology (MIT) Intelligence Initiative; MIT McGovern Institute and McGovern Institute Neurotechnology Program; MIT Media Lab; MIT Mind-Machine Project; National Alliance for Research on Schizophrenia and Depression; National Institutes of Health Director’s New Innovator Award (1DP2OD002002); National Institutes of Health Grant Nos. 1R01DA029639, 1R43NS070453, and 1RC1MH088182; and the Alfred P. Sloan Foundation. KAG acknowledges funding by National Institute of Mental Health R01 MH084966 and the U.S. Army Research Laboratory and the U.S. Army Research Officer under Grant No. 58076-LS-DRP.

Publisher Copyright:
© 2016 Society of Biological Psychiatry.


  • 5-HT2C receptor
  • Amygdala
  • Fear
  • Optogenetics
  • PTSD
  • Serotonin


Dive into the research topics of 'Stress Enables Reinforcement-Elicited Serotonergic Consolidation of Fear Memory'. Together they form a unique fingerprint.

Cite this