The Pharmacology and Circuitry Underlying Stress Enhanced Fear Learning in an Animal Model of Post-traumatic Stress Disorder

Post-traumatic stress disorder (PTSD) is a debilitating anxiety disorder that profoundly affects the lives of men and women worldwide. PTSD is characterized by exposure to an acute or traumatic stress that precipitates a number of psychological and physiological symptoms. There are many challenges that hinder the development of effective preventative and palliative treatments for PTSD such as co-morbidity with other anxiety disorders, major depression and substance abuse. Although brain regions associated with fear learning and memory have been implicated in PTSD, the neurobiological mechanisms by which normal fear learning becomes pathological is yet unresolved. Here we describe a stress sensitization model of PTSD in rodents that recapitulates several aspects of PTSD such as its resistance to extinction (the animal analog of cognitive/behavior therapy), resistance to pharmaco-therapy, long-term effects, and maladaptive fear response. Stress-enhanced Fear Learning (SEFL) is a model of PTSD that examines how normally adaptive fear learning becomes maladaptive. The SEFL model uses un-signaled, unpredictable foot-shocks to mimic and induce traumatic stress rather than tone-shock pairings used in typical Pavlovian conditioning procedures. The SEFL procedure consists of a 15 foot-shock traumatic experience followed 24 (or more) hours later by a single shock in a novel environment. Fear memory, indexed by freezing behavior, is tested in a novel environment on the following day where animals received the single foot-shock. When animals are tested for contextual fear memory of the novel environment they show a disproportionate amount of new fear to the single shock context. This enhancement of new fear learning is the primary characteristic of SEFL and defines the phenomena. Thus, SEFL models non-associative sensitization of fear that occurs subsequent to the initial trauma, demonstrating how prior experience of trauma modulates later fear learning. Using the behavioral phenomenon of SEFL as a measure of maladaptive fear we examine the effects of behavioral and pharmacological manipulations as well as begin to define the contributions of the dorsal hippocampus (DH) and the basolateral amygdala (BLA). Our findings suggest that SEFL is mediated by the BLA; functional inactivation of this region during trauma prevents SEFL. Furthermore, we demonstrate that DH normally contributes to SEFL but is not necessary for the phenomenon to occur. Finally, we show that SEFL is a robust behavioral effect that appears to be refractory to extinction of trauma-associated fear and pharmacological treatments used to treat anxiety and PTSD.