Limited contextual memory and transcriptional dysregulation in the medial prefrontal cortex of mice exposed to early protein malnutrition are intergenerationally transmitted

Abstract

Memory contextualization is vital for the subsequent retrieval of relevant memories in specific situations and is a critical dimension of social cognition. The inability to properly contextualize information has been described as characteristic of psychiatric disorders like autism spectrum disorders, schizophrenia, and post-traumatic stress disorder. The exposure to early-life adversities, such as nutritional deficiency, increases the risk to trigger alterations in different domains of cognition related to those observed in mental diseases. In this work, we explored the consequences of exposure to perinatal protein malnutrition on contextual memory in a mouse model and assessed whether these consequences are transmitted to the next generation. Female mice were fed with a normal or hypoproteic diet during pregnancy and lactation. To evaluate contextual memory, the object-context mismatch test was performed in both sexes of F1 offspring and in the subsequent F2 generation. We observed that contextual memory was altered in mice of both sexes that had been subjected to maternal protein malnutrition and that the deficit in contextual memory was transmitted to the next generation. The basis of this alteration seems to be a transcriptional dysregulation of genes involved in the excitatory and inhibitory balance and immediate-early genes within the medial prefrontal cortex (mPFC) of both generations. The expression of genes encoding enzymes that regulate H3K27me3 levels was altered in the mPFC and partially in sperm of F1 malnourished mice. These results support the hypothesis that early nutritional deficiency represents a risk factor for the emergence of symptoms associated with mental disorders.