Dynorphins Regulate Fear Memory: from Mice to Men

Reexposure to trauma reminders is an integral element of trauma-focused cognitive behavioral therapy (Roberts et al., 2009), but little is known about the physiological processes underlying the therapeutic progress. While it is well established that amygdala, prefrontal cortex and hippocampus are key brain structures in fear memory processing (McGaugh, 2004; Herry et al., 2008; Likhtik et al., 2008), it is not well known which neurotransmitters or neuromodulators are involved. Here with a translational approach we investigated the role of dynorphins in the formation and extinction of fear memories in mice and in humans. Mice lacking dynorphin showed an enhanced cue-dependent fear conditioning, as well as delayed extinction in contextual conditioning/extinction paradigms. The pharmacological blockade of kappa-opioid receptors before the extinction trials but not before or after the conditioning produced a similar effect. Analysis of neuronal activity, using the immediate early gene c-fos, demonstrated a reduced neuronal activity in key limbic structures during extinction in the absence of dynorphin. Translating these findings into the human domain, fear conditioning and extinction, coupled with functional MRI was then performed in volunteers preselected for a functionally relevant polymorphism in the dynorphin gene. Human volunteers bearing the (T) allele of PDYN (prodynorphin) at rs1997794 showed reduced fear extinction and a significantly diminished functional connectivity between amygdala and ventromedial prefrontal cortex. Our findings establish a role of dynorphin kappa-opioid receptor signaling in fear extinction.