title: Stress Enables Reinforcement-Elicited Serotonergic Consolidation of Fear Memory.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; MIT Media Lab, Massachusetts Institute of Technology, Cambridge, Massachusetts; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Baratta
authors.affiliation: MIT Media Lab, Massachusetts Institute of Technology, Cambridge, Massachusetts; The George W. Woodruff School of Mechanical Engineering (SBK, CRF), Georgia Institute of Technology, Atlanta, Georgia.
authors.forename: Suhasa B
authors.initials: SB
authors.lastname: Kodandaramaiah
authors.affiliation: MIT Media Lab, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Patrick E
authors.initials: PE
authors.lastname: Monahan
authors.affiliation: McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Junmei
authors.initials: J
authors.lastname: Yao
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, Colorado.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Weber
authors.affiliation: MIT Media Lab, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Pei-Ann
authors.initials: PA
authors.lastname: Lin
authors.affiliation: McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Barbara
authors.initials: B
authors.lastname: Gisabella
authors.affiliation: McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Natalie
authors.initials: N
authors.lastname: Petrossian
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, Colorado.
authors.forename: Jose
authors.initials: J
authors.lastname: Amat
authors.affiliation: MIT Media Lab, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Kyungman
authors.initials: K
authors.lastname: Kim
authors.affiliation: MIT Media Lab, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Aimei
authors.initials: A
authors.lastname: Yang
authors.affiliation: The George W. Woodruff School of Mechanical Engineering (SBK, CRF), Georgia Institute of Technology, Atlanta, Georgia.
authors.forename: Craig R
authors.initials: CR
authors.lastname: Forest
authors.affiliation: McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts; MIT Media Lab, Massachusetts Institute of Technology, Cambridge, Massachusetts; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Edward S
authors.initials: ES
authors.lastname: Boyden
authors.affiliation: McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts. Electronic address: kgoosens@mit.edu.
authors.forename: Ki A
authors.initials: KA
authors.lastname: Goosens
mesh_terms: D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001245:Association Learning / Q000187:drug effects / Q000502:physiology; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D065847:Dorsal Raphe Nucleus / Q000378:metabolism; D004597:Electroshock; D005239:Fear / Q000187:drug effects / Q000502:physiology*; D008297:Male; D000069077:Memory Consolidation / Q000187:drug effects / Q000502:physiology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008959:Models, Neurological; D008960:Models, Psychological; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D062308:Optogenetics; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism*; D012149:Restraint, Physical; D012701:Serotonin / Q000378:metabolism*; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D013313:Stress Disorders, Post-Traumatic / Q000378:metabolism; D013315:Stress, Psychological / Q000503:physiopathology*
chemical_list: C000599853:5-hydroxytryptamine2C receptor, mouse; D044405:Receptor, Serotonin, 5-HT2C; D058830:Serotonin 5-HT2 Receptor Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D012701:Serotonin
keywords: 5-HT2C receptor; Amygdala; Fear; Optogenetics; PTSD; Serotonin