From Pavlov to PTSD: the extinction of conditioned fear in rodents, humans, and anxiety disorders

Abstract

Nearly 100 years ago, Ivan Pavlov demonstrated that dogs could learn to use a neutral cue to predict a biologically relevant event: after repeated predictive pairings, Pavlov's dogs were conditioned to anticipate food at the sound of a bell, which caused them to salivate. Like sustenance, danger is biologically relevant, and neutral cues can take on great salience when they predict a threat to survival. In anxiety disorders such as posttraumatic stress disorder (PTSD), this type of conditioned fear fails to extinguish, and reminders of traumatic events can cause pathological conditioned fear responses for decades after danger has passed. In this review, we use fear conditioning and extinction studies to draw a direct line from Pavlov to PTSD and other anxiety disorders. We explain how rodent studies have informed neuroimaging studies of healthy humans and humans with PTSD. We describe several genes that have been linked to both PTSD and fear conditioning and extinction and explain how abnormalities in fear conditioning or extinction may reflect a general biomarker of anxiety disorders. Finally, we explore drug and neuromodulation treatments that may enhance therapeutic extinction in anxiety disorders.

Keywords: Amygdala; Anxiety; Fear conditioning; Fear extinction; Posttraumatic stress disorder; Prefrontal cortex; Treatment.

FIGURE 1

A simplified schematic of fear neurocircuitry, showing functional homology of rat and human brain regions. PL in rat and dACC in human are homologues, both project to the lateral nucleus of the amygdala. IL in rat and vmPFC in human are homologues, both project to the basal nucleus and to intercalated cells of the amygdala. The circuitry within the amygdala is shared among species. Arrowheads represent excitatory projections and circle-endings represent inhibitory projections. Within the amygdala, green shapes represent glutamatergic (excitatory) cells and red shapes represent GABAergic (inhibitory) cells. Projections from lateral nucleus to CeL, from basal nucleus to CeM, and some other connections are not shown. FIGURE ABBREVIATIONS: CeL = centrolateral subdivision; CeM = centromedial subdivision; dACC = dorsal anterior cingulate cortex; H = hippocampus; IL = infralimbic cortex; ITC = intercalated neurons; PL = prelimbic cortex; SC = somatosensory cortex; T = thalamus