title: Mild Transient Hypercapnia as a Novel Fear Conditioning Stimulus Allowing Re-Exposure during Sleep.
abstract: Studies suggest that sleep plays a role in traumatic memories and that treatment of sleep disorders may help alleviate symptoms of posttraumatic stress disorder. Fear-conditioning paradigms in rodents are used to investigate causal mechanisms of fear acquisition and the relationship between sleep and posttraumatic behaviors. We developed a novel conditioning stimulus (CS) that evoked fear and was subsequently used to study re-exposure to the CS during sleep.
  
  
  
  Experiment 1 assessed physiological responses to a conditioned stimulus (mild transient hypercapnia, mtHC; 3.0% CO2; n = 17)+footshock for the purpose of establishing a novel CS in male FVB/J mice. Responses to the novel CS were compared to tone+footshock (n = 18) and control groups of tone alone (n = 17) and mild transient hypercapnia alone (n = 10). A second proof of principle experiment re-exposed animals during sleep to mild transient hypercapnia or air (control) to study sleep processes related to the CS.
  
  
  
  Footshock elicited a response of acute tachycardia (30-40 bpm) and increased plasma epinephrine. When tone predicted footshock it elicited mild hypertension (1-2 mmHg) and a three-fold increase in plasma epinephrine. When mtHC predicted footshock it also induced mild hypertension, but additionally elicited a conditioned bradycardia and a smaller increase in plasma epinephrine. The overall mean 24 hour sleep-wake profile was unaffected immediately after fear conditioning.
  
  
  
  Our study demonstrates the efficacy of mtHC as a conditioning stimulus that is perceptible but innocuous (relative to tone) and applicable during sleep. This novel model will allow future studies to explore sleep-dependent mechanisms underlying maladaptive fear responses, as well as elucidate the moderators of the relationship between fear responses and sleep.
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Angela L
authors.initials: AL
authors.lastname: McDowell
authors.forename: Ashlee B
authors.initials: AB
authors.lastname: Filippone
authors.forename: Alex
authors.initials: A
authors.lastname: Balbir
authors.forename: Anne
authors.initials: A
authors.lastname: Germain
authors.forename: Christopher P
authors.initials: CP
authors.lastname: O'Donnell
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D003213:Conditioning, Psychological / Q000502:physiology*; D004569:Electroencephalography; D005239:Fear / Q000502:physiology*; D006339:Heart Rate; D006935:Hypercapnia / Q000503:physiopathology*; D008297:Male; D051379:Mice; D012890:Sleep / Q000502:physiology*