TY - JOUR
T1 - Sex-Specific Effects of Early-Life Stress Exposure on Memory Performance and the Medial Prefrontal Cortex Transcriptomic Pattern in Adolescent Mice
AU - Orso, Rodrigo
AU - Viola, Thiago Wendt
AU - Heberle, Bernardo Aguzzoli
AU - Creutzberg, Kerstin Camile
AU - Lumertz, Francisco Sindermann
AU - Grassi-Oliveira, Rodrigo
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025
Y1 - 2025
N2 - 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.
AB - 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.
KW - Limited Bedding
KW - Maternal Separation
KW - RNA-seq
KW - Short-Term Memory
KW - Working Memory
UR - http://www.scopus.com/inward/record.url?scp=86000341711&partnerID=8YFLogxK
U2 - 10.1007/s12035-025-04803-x
DO - 10.1007/s12035-025-04803-x
M3 - Journal article
C2 - 40038196
AN - SCOPUS:86000341711
SN - 0893-7648
JO - Molecular Neurobiology
JF - Molecular Neurobiology
ER -