Journal
BIOLOGICAL PSYCHIATRY
Volume 79, Issue 10, Pages 814-822Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2015.06.025
Keywords
Amygdala; Fear; 5-HT2C receptor; Optogenetics; PTSD; Serotonin
Categories
Funding
- 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
- McGovern Institute Neurotechnology Program
- MIT Media Lab
- MIT Mind-Machine Project
- National Alliance for Research on Schizophrenia and Depression
- National Institutes of Health [1DP2OD002002, 1R01DA029639, 1R43NS070453, 1RC1MH088182]
- Alfred P. Sloan Foundation
- National Institute of Mental Health [R01 MH084966]
- U.S. Army Research Laboratory
- U.S. Army Research Officer [58076-LS-DRP]
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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.
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