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.

Prefrontal circuits signaling active avoidance retrieval and extinction

“…While not associated with extinction of conditioned fear (Rosas-Vidal et al 2014; Sierra-Mercado et al 2011), PL has recently been implicated in extinction of avoidance. PL lesions have been shown to impair extinction of lever-press avoidance (Fragale et al 2016), and blocking BDNF in PL impairs retrieval of extinction in this avoidance task (Rosas-Vidal et al 2018). The involvement of PL in extinction of avoidance, but not extinction of fear conditioning, suggests that PL may regulate strategy switching and behavioral flexibility, especially when avoidance decisions compete with food-seeking (Dalley et al 2004; Floresco et al 2008; Kesner and Churchwell 2011; Oualian and Gisquet-Verrier 2010; Rich and Shapiro 2009).…”

The Stress Acceleration Hypothesis: effects of early-life adversity on emotion circuits and behavior

“…This adaptation, may increase the vulnerability of the individual to developing fear-related psychopathology in adulthood. Indeed, decreased plasticity in adulthood between amygdala and prefrontal regions has recently been shown to increase the risk for an anxious phenotype in a rodent model [44]. Taken together, the argument follows that prematurely terminating the plasticity afforded by a developmental sensitive period for emotional behaviors may have significant consequences on emotion regulation abilities in adulthood.…”

Human extinction learning is accelerated by an angiotensin antagonist via ventromedial prefrontal cortex and its connections with basolateral amygdala

“…The vmPFC is critically engaged in the reduction of threat expression during extinction 2,7,11 and governs the amygdala inhibition of conditioned threat response 6,8 . Translational disorder models suggest that dysfunctions in amygdala-prefrontal plasticity (at least partly) contribute to the extinction-failure in anxiety disorders 12 . Converging evidence come from clinical research suggesting that anxiety disorders are characterized by deficient extinction, hypoactivation within the vmPFC and attenuated vmPFCamygdala functional connectivity 5,6,10,11,13 .…”