The role of stress in altering fear memory is not well understood. Since individual variations in stress reactivity exist, and stress alters fear memory, exposing individuals with differing stress-reactivity to repeated stress would affect their fear memory to various degrees. We explored this question using the average stress-reactive Fisher 344 (F344) rat strain and the Wistar–Kyoto (WKY) strain with its heightened stress-reactivity. Male F344 and WKY rats were exposed to the contextual fear conditioning (CFC) paradigm and then chronic restraint stress (CRS) or no stress (NS) was administered for two weeks before a second CFC. Both recent and reinstated fear memory were greater in F344s than WKYs, regardless of the stress status. In contrast, remote memory was attenuated only in F344s after CRS. In determining whether this strain-specific response to CRS was mirrored by transcriptomic changes in the blood, RNA sequencing was carried out. Overlapping differentially expressed genes (DEGs) between NS and CRS in the blood of F344 and WKY suggest a convergence of stress-related molecular mechanisms, independent of stress-reactivity. In contrast, DEGs unique to the F344 and the WKY stress responses are divergent in their functionality and networks, beyond that of strain differences in their non-stressed state.

These results suggest that in some individuals chronic or repeated stress, different from the original fear memory-provoking stress, can attenuate prior fear memory. Furthermore, the novel blood DEGs can report on the general state of stress of the individual, or can be associated with individual variation in stress-responsiveness.

压力在改变恐惧记忆中的作用尚不清楚。由于存在压力反应性的个体差异，并且压力会改变恐惧记忆，因此，将具有不同压力反应性的个体暴露于重复的压力会在不同程度上影响他们的恐惧记忆。我们使用平均应力反应性Fisher 344（F344）大鼠菌株和Wistar-Kyoto（WKY）菌株（其应力反应性更高）探讨了这个问题。将雄性F344和WKY大鼠暴露于情境恐惧调节（CFC）范式，然后在第二次CFC之前的两周内进行慢性束缚应激（CRS）或无应激（NS）给药。无论压力状态如何，F344中最近和恢复的恐惧记忆都比WKY大。相反，远程记忆仅在CRS后的F344中衰减。在确定这种对CRS的菌株特异性反应是否通过血液中的转录组变化反映出来时，进行了RNA测序。F344和WKY血液中NS和CRS之间重叠的差异表达基因（DEG）暗示了与压力相关的分子机制的收敛，而与压力反应性无关。相比之下，F344和WKY应力响应所特有的DEG在其功能和网络方面存在差异，其非应力状态下的应变差异除外。

这些结果表明，在某些个体中，与原始的引起恐惧记忆的压力不同，长期或反复的压力可以减弱先前的恐惧记忆。此外，新型血液DEG可以报告个体的一般应激状态，或者可以与个体应激反应的变化相关。