Inhibition of Protein Synthesis Attenuates Formation of Traumatic Memory and Normalizes Fear-induced c-Fos Expression in a Mouse Model of Posttraumatic Stress Disorder

Abstract

Posttraumatic stress disorder (PTSD) is a debilitating psychosomatic condition characterized by impairment of brain fear circuits and persistence of exceptionally strong associative memories notoriously resistant to extinction. In this study, we investigated the neural and behavioral consequences of inhibiting protein synthesis, a process known to suppress the formation of conventional aversive memories, in an established animal model of PTSD based on contextual fear conditioning in mice. Control animals were subjected to the conventional fear conditioning task to evaluate the differential impact of protein synthesis inhibition on traumatic versus normal aversive memories. Utilizing c-Fos neural activity mapping, we found that the retrieval of PTSD and normal aversive memories produced activation of overlapping set of brain structures, though several specific areas, such as the infralimbic cortex and the paraventricular nucleus of the thalamus, exhibited heightened activation during induction of PTSD. Administration of protein synthesis inhibitor cycloheximide prior to PTSD induction disrupted the formation of traumatic memories, resulting in behavior that matched the behavior of mice with usual aversive memory. Concomitant with this behavioral shift was a normalization of brain c-Fos activation pattern matching the one observed in usual fear memory. Our findings demonstrate that inhibiting protein synthesis during traumatic experiences significantly impairs the development of PTSD in a mouse model. These data provide insights into the neural underpinnings of protein synthesis-dependent traumatic memory formation and open prospects for the development of new therapeutic strategies for prevention of PTSD.