Brain mechanisms of Pavlovian extinction

Abstract

The brain mechanisms that underlie the process of Pavlovian fear extinction are intricate, controversial, and of great interest to those that study learning and memory phenomena. Neural mechanisms of Pavlovian extinction were evaluated with fluorodeoxy-glucose metabolic mapping of mouse brain regions implicated in fear acquisition and extinction. Subjects were trained to show a conditioned response (CR), freezing, by pairing a tone conditioned stimulus (CS) with a footshock unconditioned stimulus (US) during acquisition, and received CS-alone presentations during extinction. Pavlov’s original hypothesis of inhibitory cortical mechanisms underlying extinction was supported by our finding that frontal cortical regions were hyperactive after extinction. Prefrontal activity was correlated with extinction retention behavior and showed evidence of inhibitory coupling with other regions after extinction. Changes in other regions may reflect elements of the original acquisition memory even after extinction, including the CS (auditory system), the US (external cuneate), CS-US contiguity (hippocampus), and expression of the CR (amygdala). Further behavioral experiments tested individual differences in extinction learning in congenitally helpless rats, a selectively bred strain which shows disruptions in the hypothalamic-pituitary-adrenal (HPA) axis and may model genetic susceptibility to posttraumatic stress disorder. The involvement of corticosterone in extinction learning was tested through the use of metyrapone, a corticosterone synthesis inhibitor. Both congenitally helpless rats and metyrapone-treated mice showed significant deficits in extinction behavior. We propose that a functional network of mutually interactive brain regions is formed after Pavlovian extinction training, composed of frontal regions, auditory regions, hippocampus, medial thalamus, and brainstem somatosensory systems. This network serves to inhibit the CR while preserving the original CS-US association, and the HPA axis may modulate this network, as evidenced by the extinction deficits seen in both metyrapone-treated and congenitally helpless subjects. This is the first time such a functional network has been demonstrated after Pavlovian extinction.