title: Impaired extinction of learned fear in rats selectively bred for high anxiety--evidence of altered neuronal processing in prefrontal-amygdala pathways.
abstract: The impaired extinction of acquired fear is a core symptom of anxiety disorders, such as post-traumatic stress disorder, phobias or panic disorder, and is known to be particularly resistant to existing pharmacotherapy. We provide here evidence that a similar relationship between trait anxiety and resistance to extinction of fear memory can be mimicked in a psychopathologic animal model. Wistar rat lines selectively bred for high (HAB) or low (LAB) anxiety-related behaviour were tested in a classical cued fear conditioning task utilizing freezing responses as a measure of fear. Fear acquisition was similar in both lines. In the extinction trial, however, HAB rats showed a marked deficit in the attenuation of freezing responses to repeated auditory conditioned stimulus presentations as compared with LAB rats, which exhibited rapid extinction. To gain information concerning the putatively altered neuronal processing associated with the differential behavioural response between HAB and LAB rats, c-Fos expression was investigated in the main prefrontal-amygdala pathways important for cued fear extinction. HAB compared to LAB rats showed an attenuated c-Fos response to repeated conditioned stimulus presentations in infralimbic and cingulate cortices, as well as in the lateral amygdala, but facilitated the c-Fos response in the medial part of the central amygdala. In conclusion, the present results support the notion that impaired extinction in high anxiety rats is accompanied by an aberrant activation profile in extinction-relevant prefrontal-amygdala circuits. Thus, HAB rats may represent a clinically relevant model to study the mechanisms and potential targets to accelerate delayed extinction processes in subjects with enhanced trait anxiety.
authors.affiliation: Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Peter-Mayer-Strasse 1, A-6020 Innsbruck, Austria.
authors.forename: Patrik
authors.initials: P
authors.lastname: Muigg
authors.forename: Alfred
authors.initials: A
authors.lastname: Hetzenauer
authors.forename: Gabriele
authors.initials: G
authors.lastname: Hauer
authors.forename: Markus
authors.initials: M
authors.lastname: Hauschild
authors.forename: Stefano
authors.initials: S
authors.lastname: Gaburro
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Frank
authors.forename: Rainer
authors.initials: R
authors.lastname: Landgraf
authors.forename: Nicolas
authors.initials: N
authors.lastname: Singewald
mesh_terms: D000679:Amygdala / Q000503:physiopathology*; D000818:Animals; D001008:Anxiety Disorders / Q000235:genetics / Q000503:physiopathology*; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D003213:Conditioning, Psychological / Q000502:physiology; D003463:Cues; D004195:Disease Models, Animal; D005108:Extinction, Psychological / Q000502:physiology*; D005239:Fear / Q000502:physiology*; D006179:Gyrus Cinguli / Q000503:physiopathology; D007858:Learning / Q000502:physiology*; D008297:Male; D009434:Neural Pathways / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism; D009483:Neuropsychological Tests; D017397:Prefrontal Cortex / Q000503:physiopathology*; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis / Q000378:metabolism; D019655:Quantitative Trait, Heritable; D051381:Rats
chemical_list: D015415:Biomarkers; D016760:Proto-Oncogene Proteins c-fos