Stress influences the dynamics of hippocampal structural remodeling associated with fear memory extinction

Abstract

Fear extinction is defined as a decline in fear-conditioned responses following non-reinforced exposure to a fear conditioned stimulus, therefore the conditioned stimulus gains new predictive properties. Patients with anxiety related disorders (e.g.: PTSD) subjected to extinction-like exposure treatments often experience a relapse of symptoms. Stress is a risk factor for those psychiatric disorders and a critical modulator of fear learning that turns the memory resistant to the extinction process. Dendritic spines are the anatomical sites where neuronal activity reshapes brain networks during learning and memory processes. Thus, we planned to characterize the dynamics of synaptic remodeling before and after contextual fear extinction in the dorsal hippocampus (DH), and how this process is affected by a previous stress experience. Animals with or without previous stress were contextually fear conditioned and one day later trained in an extinction paradigm. Rats were sacrificed one day after conditioning (pre-extinction) or one day after extinction for spine density analysis in the DH. We confirmed that stress exposure induced a deficit in extinction learning. Further, a higher density of dendritic spines, particularly mature ones, was observed in the DH of non-stressed conditioned animals at pre-extinction. Interestingly, after extinction, the spine levels returned to the control values. Conversely, stressed animals did not show such spines boost (pre-extinction) or any other change (post-extinction). In contrast, such standard dynamics of dendritic changes as well as the behavioral extinction was recovered when stressed animals received an intra-basolateral amygdala infusion of midazolam prior to stress. Altogether, these findings suggest that stress hinders the normal dynamic of dendritic remodeling after fear extinction and this could be part of the neurobiological substrate that makes those memories resistant to be extinguished.