title: Dysfunction in amygdala-prefrontal plasticity and extinction-resistant avoidance: A model for anxiety disorder vulnerability.
abstract: Individuals exhibiting an anxiety disorder are believed to possess an innate vulnerability that makes them susceptible to the disorder. Anxiety disorders are also associated with abnormalities in the interconnected brain regions of the amygdala and prefrontal cortex (PFC). However, the link between anxiety vulnerability and amygdala-PFC dysfunction is currently unclear. Accordingly, the present study sought to determine if innate dysfunction within the amygdala to PFC projection underlies the susceptibility to develop anxiety-like behavior, using an anxiety vulnerable rodent model. The inbred Wistar Kyoto (WKY) rat was used to model vulnerability, as this strain naturally expresses extinction-resistant avoidance; a behavior that models the symptom of avoidance present in anxiety disorders. Synaptic plasticity was assessed within the projection from the basolateral nucleus of the amygdala (BLA) to the prelimbic cortical subdivision of the PFC in WKY and Sprague Dawley (SD) rats. While WKY rats exhibited normal paired-pulse plasticity, they did not maintain long-term potentiation (LTP) as SD rats. Thus, impaired plasticity within the BLA-PL cortex projection may contribute to extinction resistant avoidance of WKY, as lesions of the PL cortex in SD rats impaired extinction of avoidance similar to WKY rats. Treatment with d-cycloserine to reverse the impaired LTP in WKY rats was unsuccessful. The lack of LTP in WKY rats was associated with a significant reduction of NMDA receptors containing NR2A subunits in the PL cortex. Thus, dysfunction in amygdala-PFC plasticity is innate in anxiety vulnerable rats and may promote extinction-resistant avoidance by disrupting communication between the amygdala and prefrontal cortex.
authors.affiliation: Neurobehavioral Research Laboratory, Research Service, VA New Jersey Heath Care System, East Orange, NJ 07018, USA; Graduate School of Biomedical Sciences, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA.
authors.forename: Jennifer E C
authors.initials: JE
authors.lastname: Fragale
authors.affiliation: Graduate School of Biomedical Sciences, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA; Reynolds Family Spine Laboratory, Department of Neurological Surgery, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark 07103, USA.
authors.forename: Veronika
authors.initials: V
authors.lastname: Khariv
authors.affiliation: Graduate School of Biomedical Sciences, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Gregor
authors.affiliation: Neurobehavioral Research Laboratory, Research Service, VA New Jersey Heath Care System, East Orange, NJ 07018, USA; Veterans Biomedical Research Institute, East Orange, NJ, 07018, USA.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Smith
authors.affiliation: Neurobehavioral Research Laboratory, Research Service, VA New Jersey Heath Care System, East Orange, NJ 07018, USA; Veterans Biomedical Research Institute, East Orange, NJ, 07018, USA.
authors.forename: Xilu
authors.initials: X
authors.lastname: Jiao
authors.affiliation: Graduate School of Biomedical Sciences, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA; Reynolds Family Spine Laboratory, Department of Neurological Surgery, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark 07103, USA.
authors.forename: Stella
authors.initials: S
authors.lastname: Elkabes
authors.affiliation: Graduate School of Biomedical Sciences, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA; Syracuse VA Medical Center, Syracuse, NY 13210, USA; Department of Pharmacology, Physiology, & Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Servatius
authors.affiliation: Neurobehavioral Research Laboratory, Research Service, VA New Jersey Heath Care System, East Orange, NJ 07018, USA; Graduate School of Biomedical Sciences, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA; Department of Pharmacology, Physiology, & Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA.
authors.forename: Kevin C H
authors.initials: KC
authors.lastname: Pang
authors.affiliation: Neurobehavioral Research Laboratory, Research Service, VA New Jersey Heath Care System, East Orange, NJ 07018, USA; Graduate School of Biomedical Sciences, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA; Department of Pharmacology, Physiology, & Neuroscience, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ 07103, USA. Electronic address: beckkd@njms.rutgers.edu.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Beck
mesh_terms: D000679:Amygdala / Q000503:physiopathology*; D000818:Animals; D001008:Anxiety Disorders / Q000503:physiopathology*; D001362:Avoidance Learning / Q000502:physiology; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D005108:Extinction, Psychological / Q000502:physiology; D008297:Male; D009434:Neural Pathways / Q000503:physiopathology; D009473:Neuronal Plasticity / Q000502:physiology*; D017397:Prefrontal Cortex / Q000503:physiopathology*; D051381:Rats; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley
keywords: Anxiety vulnerability; Avoidance; Long-term potentiation; NMDA; NR2A; Wistar Kyoto rat