Chronic stress enhanced fear memories are associated with increased amygdala zif268 mRNA expression and are resistant to reconsolidation.
The chronically stressed brain may present a vulnerability to develop maladaptive fear-related behaviors in response to a traumatic event. In rodents, chronic stress leads to amygdala hyperresponsivity and dendritic hypertrophy and produces a post traumatic stress disorder (PTSD)-like phenotype that includes exaggerated fear learning following Pavlovian fear conditioning and resistance to extinction. It is unknown whether chronic stress-induced enhanced fear memories are vulnerable to disruption via reconsolidation blockade, as a novel therapeutic approach for attenuating exaggerated fear memories. We used a chronic stress procedure in a rat model (wire mesh restraint for 6h/d/21d) to create a vulnerable brain that leads to a PTSD-like phenotype. We then examined freezing behavior during acquisition, reactivation and after post-reactivation rapamycin administration (i.p., 40mg/kg) in a Pavlovian fear conditioning paradigm to determine its effects on reconsolidation as well as the subsequent functional activation of limbic structures using zif268 mRNA. Chronic stress increased amygdala zif268 mRNA during fear memory retrieval at reactivation. Moreover, these enhanced fear memories were unaffected by post reactivation rapamycin to disrupt long-term fear memory. Also, post-reactivation long term memory processing was also associated with increased amygdala (LA and BA), and decreased hippocampal CA1 zif268 mRNA expression. These results suggest potential challenges for reconsolidation blockade as an effective approach in treating exaggerated fear memories, as in PTSD. Our findings also support chronic stress manipulations combined with fear conditioning as a useful preclinical approach to study a PTSD-like phenotype.
Department of Psychology, Arizona State University, Tempe, AZ 85287-1104, United States; Department of Neurosurgery, University of California Los Angeles, Los Angeles, CA 90095, United States.
Ann N
AN
Hoffman
Neuroscience Program, Arizona State University, Tempe, AZ 85287, United States; Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, AZ 85004, United States.
Alejandro
A
Parga
Department of Psychology, Arizona State University, Tempe, AZ 85287-1104, United States.
Pooja R
PR
Paode
Department of Psychology, Arizona State University, Tempe, AZ 85287-1104, United States.
Lucas R
LR
Watterson
Neuroscience Program, Arizona State University, Tempe, AZ 85287, United States; Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, AZ 85004, United States.
Ella M
EM
Nikulina
Neuroscience Program, Arizona State University, Tempe, AZ 85287, United States; Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, AZ 85004, United States.
Ronald P
RP
Hammer
Department of Psychology, Arizona State University, Tempe, AZ 85287-1104, United States; Neuroscience Program, Arizona State University, Tempe, AZ 85287, United States. Electronic address: conradc@asu.edu.
Cheryl D
CD
Conrad
D000679:Amygdala / Q000737:chemistry / Q000502:physiology*; D000818:Animals; D003214:Conditioning, Classical; D051766:Early Growth Response Protein 1 / Q000032:analysis / Q000502:physiology*; D005239:Fear / Q000502:physiology*; D017403:In Situ Hybridization; D008297:Male; D008568:Memory / Q000502:physiology*; D000069077:Memory Consolidation / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013315:Stress, Psychological / Q000503:physiopathology*
D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D012333:RNA, Messenger
Amygdala; Chronic stress; Fear conditioning; Hippocampus; PTSD; Rapamycin; Reconsolidation; mTOR