Sex-Specific Effects of Early-Life Stress Exposure on Memory Performance and the Medial Prefrontal Cortex Transcriptomic Pattern in Adolescent Mice

Early life stress (ELS) is considered a risk factor for the development of cognitive and executive dysfunctions throughout development. The medial portion of the prefrontal cortex (mPFC) is directly implicated in short-term working memory. Furthermore, due to its late development compared to other brain regions, the mPFC is considered a vulnerable brain region to ELS exposure. Here, we investigated the effects of the ELS on PFC-dependent memory and mPFC transcriptomic profiles. From postnatal day (PND) 2 to PND 15, BALB/cJ mice were exposed to maternal separation (MS) for 3 h per day combined with limited bedding (ELS group) or left undisturbed (CT group). During the period of stress, maternal behavior was recorded pre-MS and post-MS. From PND 45 to PND 47, males and females were tested for working memory performance in the Y-maze and short-term recognition memory in the object in place task (OIP). Later, we assessed mRNA level alterations in the mPFC by RNA-seq. Here, we showed that ELS increases maternal care post-MS and the number of nest exits pre-MS and post-MS. Furthermore, males and females exposed to ELS exhibited impairments in the OIP, while only females performed worse in the Y-maze. With respect to the mPFC transcriptome, we identified 13 DEGs in the females, which were significantly influenced by chaperone-mediated protein folding processes, while 4 genes were altered in males. In conclusion, we showed that, compared with male sex, ELS alters maternal behavior and leads to more extensive impairments in memory function and transcriptomic alterations in females.