title: Towards a better preclinical model of PTSD: characterizing animals with weak extinction, maladaptive stress responses and low plasma corticosterone.
abstract: Most of the available preclinical models of PTSD have focused on isolated behavioural aspects and have not considered individual variations in response to stress. We employed behavioural criteria to identify and characterize a subpopulation of rats that present several features analogous to PTSD-like states after exposure to classical fear conditioning. Outbred Sprague-Dawley rats were segregated into weak- and strong-extinction groups on the basis of behavioural scores during extinction of conditioned fear responses. Animals were subsequently tested for anxiety-like behaviour in the open-field test (OFT), novelty suppressed feeding (NSF) and elevated plus maze (EPM). Baseline plasma corticosterone was measured prior to any behavioural manipulation. In a second experiment, rats underwent OFT, NSF and EPM prior to being subjected to fear conditioning to ascertain whether or not pre-stress levels of anxiety-like behaviours could predict extinction scores. We found that 25% of rats exhibit low extinction rates of conditioned fear, a feature that was associated with increased anxiety-like behaviour across multiple tests in comparison to rats showing strong extinction. In addition, weak-extinction animals showed low levels of corticosterone prior to fear conditioning, a variable that seemed to predict extinction recall scores. In a separate experiment, anxiety measures taken prior to fear conditioning were not predictive of a weak-extinction phenotype, suggesting that weak-extinction animals do not show detectable traits of anxiety in the absence of a stressful experience. These findings suggest that extinction impairment may be used to identify stress-vulnerable rats, thus providing a useful model for elucidating mechanisms and investigating potential treatments for PTSD.
authors.affiliation: Research Imaging Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
authors.forename: Roman
authors.initials: R
authors.lastname: Reznikov
authors.affiliation: Research Imaging Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada.
authors.forename: Mustansir
authors.initials: M
authors.lastname: Diwan
authors.affiliation: Research Imaging Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada.
authors.forename: José N
authors.initials: JN
authors.lastname: Nobrega
authors.affiliation: Research Imaging Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON, M5T 1R8, Canada; Institute of Medical Science, University of Toronto, Toronto, ON, Canada; Division of Neurosurgery, Toronto Western Hospital, 399 Bathurst Street, Toronto, ON, M5T 2S8, Canada. Electronic address: Clement.Hamani@camh.ca.
authors.forename: Clement
authors.initials: C
authors.lastname: Hamani
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D003214:Conditioning, Classical; D003345:Corticosterone / Q000097:blood*; D004195:Disease Models, Animal; D005108:Extinction, Psychological; D005239:Fear / Q000523:psychology; D008124:Locomotion; D008297:Male; D018782:Maze Learning; D051381:Rats; D017207:Rats, Sprague-Dawley; D013313:Stress Disorders, Post-Traumatic / Q000097:blood / Q000523:psychology*; D013315:Stress, Psychological / Q000097:blood / Q000523:psychology*
chemical_list: D003345:Corticosterone
keywords: Anxiety; Conditioning; Extinction; Fear; Post-traumatic stress disorder; Stress; Stress vulnerability