Modulation of PARP-1 Activity in a Broad Time Window Attenuates Memorizing Fear.

Einat Elharrar,Gal Yadid,Sapir Meninger-Mordechay,Yahav Dikshtein,Yehuda Lichtenstein

doi:10.3390/ijms22126170

Einat Elharrar, Gal Yadid + Show 3 more

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https://doi.org/10.3390/ijms22126170

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Abstract

The amygdala plays a critical role in the acquisition and consolidation of fear-related memories. Recent studies have demonstrated that ADP-ribosylation of histones, accelerated by PARPs, affects the chromatin structure and the binding of chromatin remodeling complexes with transcription factors. Inhibition of PARP-1 activity during the labile phase of re-consolidation may erase memory. Accordingly, we investigated the possibility of interfering with fear conditioning by PARP-1 inhibition. Herein, we demonstrate that injection of PARP-1 inhibitors, specifically into the CeA or i.p., in different time windows post-retrieval, attenuates freezing behavior. Moreover, the association of memory with pharmacokinetic timing of PARP inhibitor arrival to the brain enabled/achieved attenuation of a specific cue-associated memory of fear but did not hinder other memories (even traumatic events) associated with other cues. Our results suggest using PARP-1 inhibitors as a new avenue for future treatment of PTSD by disrupting specific traumatic memories in a broad time window, even long after the traumatic event. The safety of using these PARP inhibitors, that is, not interfering with other natural memories, is an added value.

Highlights

We demonstrated the effect of Poly(ADP-ribose) polymerases (PARPs)-1 activity in the central amygdala (CeA) on cocaine-associated memory and conditioned place preference (CPP) with cocaine
We demonstrated that inhibition of PARP-1 activity during cocaine-associated memory retrieval abolished CPP; compared to inhibition after memory retrieval, which did not affect the CPP reconsolidation process and subsequent retrievals [20]
Using cue based fear conditioning [25,27,28,30], we have found that pharmacological inhibition of PARP activity in situ, by injecting its inhibitor into the CeA or by applying it IP, obliterated the animal’s traumatic response to the fear-associated cue

Summary

Introduction

A neutral stimulus is paired with an aversive unconditioned stimulus to consolidate a new memory. This memory exists for a limited time in a labile state until stabilization-progress, namely, memory consolidation, and becomes a long-lasting memory [2]. Memories are inscribed as stable traces in the brain; once they are retrieved, they are rendered labile and can be modified during the progress of reconsolidation [3]. Disrupting or facilitating the reconsolidation of emotional memories by stress exposure has important implications for understanding anxiety disorders linked to traumatic memories, such as post-traumatic stress disorder (PTSD) [4]. Several studies indicate that by reconsolidation blocking, fear memories can be weakened [5]

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