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.

Transcranial direct current stimulation may modulate extinction memory in posttraumatic stress disorder

“…The core deficit in PTSD has been conceptualized as pathological fear conditioning with a failure to recall extinction (Pitman, 1988; VanElzakker, Dahlgren, Davis, Dubois, & Shin, 2014). Animal models and human studies of PTSD have highlighted aberrations in neural circuitry including hyperactivity in the amygdala and dorsal anterior cingulate cortex, regions that promote fear responses, alongside hypoactivity in the ventromedial prefrontal cortex (vmPFC), a region that is thought to suppress fear responses (Milad & Quirk, 2012; Quirk, Garcia, & González‐Lima, 2006; VanElzakker et al., 2014).…”

“…The core deficit in PTSD has been conceptualized as pathological fear conditioning with a failure to recall extinction (Pitman, 1988; VanElzakker, Dahlgren, Davis, Dubois, & Shin, 2014). Animal models and human studies of PTSD have highlighted aberrations in neural circuitry including hyperactivity in the amygdala and dorsal anterior cingulate cortex, regions that promote fear responses, alongside hypoactivity in the ventromedial prefrontal cortex (vmPFC), a region that is thought to suppress fear responses (Milad & Quirk, 2012; Quirk, Garcia, & González‐Lima, 2006; VanElzakker et al., 2014). More specifically, vmPFC engagement during extinction learning predicts extinction success and is associated with “top‐down” modulation of amygdala‐driven fear expression (Do‐Monte, Manzano‐Nieves, Quiñones‐Laracuente, Ramos‐Medina, & Quirk, 2015; Lebrón, Milad, & Quirk, 2004; Milad et al., 2005, 2007; Phelps, Delgado, Nearing, & LeDoux, 2004; Quirk, Likhtik, Pelletier, & Paré, 2003; Rosenkranz, Moore, & Grace, 2003).…”

Dexamethasone Treatment Leads to Enhanced Fear Extinction and Dynamic Fkbp5 Regulation in Amygdala

“…A growing body of translational research has identified the interaction of several neurobiological mechanisms underlying the mammalian response to traumatic stress (for recent review, see (VanElzakker et al, 2014). For example, in rodents, activation of the hypothalamicpituitary-adrenal (HPA) axis invokes stress-induced plasticity in limbic structures such as the amygdala (Roozendaal et al, 2009).…”

Modeling fear‐conditioned bradycardia in humans

“…It is often seen as a laboratory model of phobia or posttraumatic stress disorder (VanElzakker, Dahlgren, Davis, Dubois, & Shin, 2014). This is why ongoing research programs seek to elucidate the neural microcircuits supporting this type of learning (Bach, Weiskopf, & Dolan, 2011; Ciocchi et al, 2010) and possibilities to prevent (Grillon, Cordova, Morgan, Charney, & Davis, 2004; Reist, Duffy, Fujimoto, & Cahill, 2001), or even erase (Kroes et al, 2014; Schiller et al, 2010) fear memory.…”