Abstract
Using a rodent paradigm of early life stress, infant maternal separation (IMS), we examined whether IMS-triggered behavioral and epigenetic phenotypes of the stress-susceptible mouse strain Balb/c are propagated across generations. These phenotypes include impaired emotional behavior and deficits in executive cognitive functions in adulthood, and they are associated with increased acetylation of histone H4K12 protein (acH4K12) in the forebrain neocortex. These behavioral and epigenetic phenotypes are transmitted to the first progeny of IMS Balb/c mothers, but not fathers, and cross-fostering experiments revealed that this transmission is triggered by maternal behavior and modulated by the genetic background of the pups. In the continued absence of the original stressor, this transmission fades in later progenies. An adolescent treatment that lowers the levels of acH4K12 in IMS Balb/c mice augments their emotional abnormality but abolishes their cognitive deficits. Conversely, a treatment that further elevates the levels of acH4K12 improved the emotional phenotype but had no effects on the cognitive deficits. Moreover, treatments that prevent the emergence of either emotional or cognitive deficits in the mother also prevent the establishment of such deficits in her offspring, indicating that trans-generational effects of early life stress can be prevented.
Highlights
Using a rodent paradigm of early life stress, infant maternal separation (IMS), we examined whether IMS-triggered behavioral and epigenetic phenotypes of the stress-susceptible mouse strain Balb/c are propagated across generations
Adult male and female Balb/c mice that were exposed to the IMS paradigm were mated with non-stressed, standard facility reared (SRF)
This includes anxiety- and depressionlike behaviors in the Elevated Plus Maze (EPM) and Forced Swim Test (FST), deficits in spatial working memory and extradimensional attention set-shifting, and increased enrichment of acetylation of histone H4K12 protein (acH4K12) and RNA Polymerase II at the Gaq gene promotor leading to increased transcription of the Gaq gene
Summary
Using a rodent paradigm of early life stress, infant maternal separation (IMS), we examined whether IMS-triggered behavioral and epigenetic phenotypes of the stress-susceptible mouse strain Balb/c are propagated across generations These phenotypes include impaired emotional behavior and deficits in executive cognitive functions in adulthood, and they are associated with increased acetylation of histone H4K12 protein (acH4K12) in the forebrain neocortex. Studies on the inbred mouse strains Balb/c, for example, showed that a powerful rodent paradigm of early life stress, infant maternal separation (IMS; a daily 3 hour separation of mothers from their 2 to 15 day-old pups), triggers persistent changes in emotional and cognitive behavior as well as changes in forebrain neocortical gene expression that are not found in the genetically different inbred strain C57Bl/65–8. We found evidence for a germline-independent transmission of behavioral and epigenetic marks of early life stress that is mediated by maternal behavior during postnatal care of her pups, modulated by the genetic background of pups, and susceptible to intervention during adolescent development of future mothers
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