期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：28
页码：E3729-E3737
DOI：10.1073/pnas.1500682112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificancePosttraumatic stress disorder is characterized by a resistance to extinction learning and dysregulated signaling of the neurotransmitter norepinephrine. Previous research suggested the prelimbic and infralimbic subdivisions of the medial prefrontal cortex (mPFC) regulate fear expression and suppression, respectively. However, noradrenergic signaling in response to psychological stress may disrupt mPFC function, contributing to extinction deficits. Here we show, for the first time to our knowledge, that footshock stress dysregulates mPFC spike firing; this can be stabilized by propranolol, a {beta}-noradrenergic receptor blocking drug, which in turn facilitates extinction when it normally fails. These findings suggest that propranolol may be a particularly effective adjunct to behavioral therapy soon after trauma, when stress is high, at least in part by normalizing prefrontal cortical function. Stress-induced impairments in extinction learning are believed to sustain posttraumatic stress disorder (PTSD). Noradrenergic signaling may contribute to extinction impairments by modulating medial prefrontal cortex (mPFC) circuits involved in fear regulation. Here we demonstrate that aversive fear conditioning rapidly and persistently alters spontaneous single-unit activity in the prelimbic and infralimbic subdivisions of the mPFC in behaving rats. These conditioning-induced changes in mPFC firing were mitigated by systemic administration of propranolol (10 mg/kg, i.p.), a {beta}-noradrenergic receptor antagonist. Moreover, propranolol administration dampened the stress-induced impairment in extinction observed when extinction training is delivered shortly after fear conditioning. These findings suggest that {beta}-adrenoceptors mediate stress-induced changes in mPFC spike firing that contribute to extinction impairments. Propranolol may be a helpful adjunct to behavioral therapy for PTSD, particularly in patients who have recently experienced trauma.
关键词：fear ; extinction ; propranolol ; prefrontal cortex ; rat
