Strain differences in responsiveness to chronic restraint stress affect remote contextual fear memory and blood transcriptomics

Fear memory regulation is thought to be similar between humans and animals, and the role of stress in altering remote memory is little explored. Since individual variation in stress reactivity exists, should stress alter remote memory, invividuals with differing stress-reactivity would affect it to various degree. We evaluate this question using two strains of rats with differing stress-reactivity. The Fisher 344 (F344) strain is known to have active coping style and represent normal stress-reactivity, while the Wistar–Kyoto (WKY) rat shows passive coping strategies and heightened stress-reactivity. Male animals were exposed contextual fear conditioning (CFC) and four weeks later, chronic restraint stress (CRS) or no stress (NS) was administered for two weeks. Remote memory, immediate stress response to a second CFC, and reinstated fear memory was measured. Both recent and reinstated fear memory were greater in F344s, regardless of the stress status, In contrast, remote memory was attenuated in F344 only, concurring with their increased immediate stress responsive behavior after CRS. To find if this strain-specific response to CRS can be mirrored by transcriptomic changes in the blood, RNA sequencing was carried out. Overlapping differentially expressed genes (DEGs) between NS vs. 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 unique DEGs than could be implicated as biomarkers stress-reactivity. Taken together, these results suggest that in some individuals, chronic or prolonged stress can attenuate prior fear memory and blood markers for stress-reactivity can be identified, which may be associated with fear memory forgetting.