Chronic fluoxetine prevents fear memory generalization and enhances subsequent extinction by remodeling hippocampal dendritic spines and slowing down systems consolidation

Lizeth K Pedraza,Rodrigo O Sierra,Walquiria Nunes-Souza,Fernanda N Lotz,Marcelo Giachero,Lucas De Oliveira Alvares

doi:10.1038/s41398-019-0371-3

Abstract

Fear memory overgeneralization contributes to the genesis and persistence of anxiety disorders and is a central hallmark in the pathophysiology of post-traumatic stress disorder (PTSD). Recent findings suggest that fear generalization is closely related to hippocampal dependency during retrieval. The selective serotonin reuptake inhibitor (SSRI) fluoxetine has been used as a first-line treatment for PTSD; however, how it exerts its therapeutic effect remains a matter of debate. Here, using contextual fear conditioning in rats, we show that chronic fluoxetine treatment prevents fear generalization and enhances subsequent extinction. Moreover, fluoxetine treatment after extinction prevents spontaneous recovery. The mechanism through which fluoxetine affects generalization and extinction seems to be through the postponement of systems consolidation, thereby maintaining hippocampal involvement during retrieval. Such an effect relies on a remodeling of dendritic spines in the hippocampus, as well as the number of mature, mushroom-type spines promoted by fluoxetine treatment. In order to further investigate whether fear generalization is a potential predictor of extinction effectiveness, we categorized a large naive population according to their generalization rate. We found that discriminator rats showed a better extinction profile compared to generalizers, suggesting that the generalization rate predicts extinction effectiveness. Hence, we propose that the therapeutic strategy of choice should take into account the extension of memory generalization, in which therapies based on extinction could induce a better outcome in patients who present less fear overgeneralization. These results open new avenues for the development of interventions that prevent fear generalization by maintaining memory dependency of the hippocampus.

Highlights

Memory generalization allows animals to extend behavioral repertories to similar situations, contributing to cognitive flexibility
Chronic fluoxetine prevents fear memory generalization and enhances subsequent extinction First, in order to assess the effects of fluoxetine on fear generalization and subsequent extinction, animals were trained in Contextual fear conditioning (CFC) and received daily administration of fluoxetine or its vehicle i.p. for 21 days after training
The current study showed that chronic fluoxetine administration after training, but not citalopram, prevents fear generalization and enhances subsequent fear extinction (Fig. 1a–b)

Summary

Introduction

Memory generalization allows animals to extend behavioral repertories to similar situations, contributing to cognitive flexibility. Generalization can be considered a highly adaptive response, overgeneralization of fear memories contributes to pathological states such as post-traumatic stress disorder (PTSD). Fear overgeneralization is considered a hallmark of the diagnostic. Behavioral therapies and pharmacological treatments are the most common interventions to attenuate these pathological memories[4]. In exposure extinction-based therapies, traumatic reminders are repeatedly presented in a safe environment, leading to a progressive reduction in fear expression. Extinction does not erase the original memory but induces new learning that transiently inhibits fear expression. Fear memory eventually reemerges by the passage of time (spontaneous recovery)[5,6]

Methods

Results

Conclusion