title: Central Ghrelin Resistance Permits the Overconsolidation of Fear Memory.
abstract: There are many contradictory findings about the role of the hormone ghrelin in aversive processing, with studies suggesting that ghrelin signaling can both inhibit and enhance aversion. Here, we characterize and reconcile the paradoxical role of ghrelin in the acquisition of fearful memories.
  
  
  
  We used enzyme-linked immunosorbent assay to measure endogenous acyl-ghrelin and corticosterone at time points surrounding auditory fear learning. We used pharmacological (systemic and intra-amygdala) manipulations of ghrelin signaling and examined several aversive and appetitive behaviors. We also used biotin-labeled ghrelin to visualize ghrelin binding sites in coronal brain sections of amygdala. All work was performed in rats.
  
  
  
  In unstressed rodents, endogenous peripheral acyl-ghrelin robustly inhibits fear memory consolidation through actions in the amygdala and accounts for virtually all interindividual variability in long-term fear memory strength. Higher levels of endogenous ghrelin after fear learning were associated with weaker long-term fear memories, and pharmacological agonism of the ghrelin receptor during the memory consolidation period reduced fear memory strength. These fear-inhibitory effects cannot be explained by changes in appetitive behavior. In contrast, we show that chronic stress, which increases both circulating endogenous acyl-ghrelin and fear memory formation, promotes profound loss of ghrelin binding sites in the amygdala and behavioral insensitivity to ghrelin receptor agonism.
  
  
  
  These studies provide a new link between stress, a novel type of metabolic resistance, and vulnerability to excessive fear memory formation and reveal that ghrelin can regulate negative emotionality in unstressed animals without altering appetite.
authors.affiliation: McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge.
authors.forename: Elia S
authors.initials: ES
authors.lastname: Harmatz
authors.affiliation: McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge.
authors.forename: Lauren
authors.initials: L
authors.lastname: Stone
authors.affiliation: McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge; Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, Massachusetts.
authors.forename: Seh Hong
authors.initials: SH
authors.lastname: Lim
authors.affiliation: McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge.
authors.forename: Graham
authors.initials: G
authors.lastname: Lee
authors.affiliation: McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge.
authors.forename: Anna
authors.initials: A
authors.lastname: McGrath
authors.affiliation: McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge.
authors.forename: Barbara
authors.initials: B
authors.lastname: Gisabella
authors.affiliation: McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Peng
authors.affiliation: McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge.
authors.forename: Eliza
authors.initials: E
authors.lastname: Kosoy
authors.affiliation: McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge.
authors.forename: Junmei
authors.initials: J
authors.lastname: Yao
authors.affiliation: McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Liu
authors.affiliation: McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge; Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Nuno J
authors.initials: NJ
authors.lastname: Machado
authors.affiliation: McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge.
authors.forename: Veronica S
authors.initials: VS
authors.lastname: Weiner
authors.affiliation: McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge.
authors.forename: Warren
authors.initials: W
authors.lastname: Slocum
authors.affiliation: Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Cunha
authors.affiliation: McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge. 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; D003214:Conditioning, Classical / Q000502:physiology; D003345:Corticosterone / Q000097:blood; D004435:Eating / Q000502:physiology; D005239:Fear / Q000187:drug effects / Q000502:physiology*; D054439:Ghrelin / Q000097:blood / Q000502:physiology*; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D000069077:Memory Consolidation / Q000502:physiology*; D051381:Rats; D054440:Receptors, Ghrelin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D013141:Spiro Compounds / Q000494:pharmacology; D013315:Stress, Psychological / Q000378:metabolism
chemical_list: D054439:Ghrelin; D007211:Indoles; D054440:Receptors, Ghrelin; D013141:Spiro Compounds; C094817:ibutamoren mesylate; D003345:Corticosterone
keywords: Amygdala; Chronic stress; Corticosterone; Fear; Ghrelin; Hunger