Sex-specific effects of early life stress exposure on memory performance and medial prefrontal cortex transcriptomic pattern of adolescent mice

Abstract Early life stress (ELS) is considered a risk factor for the development of cognitive and executive disfunctions throughout development. The medial portion of the prefrontal cortex (mPFC) is directly implicated with short-term and 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 ELS on PFC-dependent memory as well as mPFC transcriptomic profile. From postnatal day (PND) 2 to PND 15 BALB/cJ mice were exposed to maternal separation for 3h per day combined with limited bedding (ELS group) or left undisturbed (CT group). During the period of stress, maternal behavior observations were recorded pre-MS and post-MS. During adolescence (PND45 to PND47), male and female 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 showed impairments in the OIP, while only females performed worse in the Y-maze. Regarding the mPFC transcriptome, we identified 13 differently expressed genes in the females, with significant influence of chaperon-mediated protein folding processes, while 4 genes were altered in males. In conclusion, we showed that ELS alters maternal behavior and leads to more extensive impairments in memory function and transcriptomic alterations in females compared to males.