Prenatal Bystander Stress Alters Brain, Behavior, and the Epigenome of Developing Rat Offspring

Abstract

The prenatal environment, including prenatal stress, has been extensively studied in laboratory animals and humans. However, studies of the prenatal environment usually directly stress pregnant females, but stress may come ‘indirectly’, through stress to a cage-mate. The current study used indirect prenatal bystander stress and investigated the effects on the gross morphology, pre-weaning behavior, and epigenome of rat offspring. Pregnant Long-Evans rats were housed with another female rat that underwent elevated platform stress from gestational days 12 to 16. We found that ultrasonic vocalizations of female cage-mates were disrupted following the stress procedure. After birth, offspring were tested on two behavioral tasks and sacrificed at postnatal day 21 (p21). Frontal cortex and hippocampal tissue was used to measure global DNA methylation and gene expression changes. At p21, bystander-stressed female offspring exhibited increased body weight. Offspring behavior on the negative geotaxis task was altered by prenatal bystander stress, and locomotor behavior was reduced in female offspring. Global DNA methylation increased in the frontal cortex and hippocampus of bystander-stressed offspring. Microarray analysis revealed significant gene expression level changes in 558 different genes, of which only 10 exhibited overlap between males and females or brain areas. These alterations in gene expression were associated with overrepresentation of 36 biological processes and 34 canonical pathways. Prenatal stress thus does not have to be experienced by the mother herself to influence offspring brain development. Furthermore, this type of ‘indirect’ prenatal stress alters offspring DNA methylation patterns, gene expression profiles, and behavior.

Prenatal Stress Produces Sexually Dimorphic and Regionally Specific Changes in Gene Expression in Hippocampus and Frontal Cortex of Developing Rat Offspring

“…Studies need to be conducted to determine what effects changes to postnatal maternal care alone have on the epigenome, in order to assert that these changes are unrelated to the prenatal stress paradigm. Therefore, because prenatal stress has previously been associated with gene expression changes in the brain [19,20,43,51], and the prenatal period is characterized by extreme plasticity, we believe the changes we identified in gene expression were likely induced by the exposure to prenatal stress. …”

“…The plethora of epigenetic changes support fetal programming and developmental plasticity theories confirming offspring change in response to the prenatal environment. Future studies should look to further correlate the epigenetic changes to behavioural and neuroanatomical outcomes, such as those in our earlier studies [11,19,20]. We recognize the study is limited by the possibility that the prenatal stress paradigm altered maternal care, and the altered maternal care was responsible for the genetic changes identified.…”

“…The purpose of the current study was to examine the changes in gene expression that occur in the frontal cortex and hippocampus of offspring exposed to stress during gestation. We have previously demonstrated that stress during gestation alters offspring behaviour prior to weaning [19,20], and in adulthood [11]. These studies also identified changes in global methylation patterns in the hippocampus and frontal cortex, along with neuroanatomical modifications in the frontal cortex and nucleus accumbens.…”

Experience and the developing prefrontal cortex

“…It appears, however, that early stress can be quite subtle. Mychasiuk et al (46) housed two pregnant dams together throughout their pregnancies. One dam was given mild prenatal stress as in the earlier studies, whereas the other dam was not.…”

Preconception paternal stress in rats alters dendritic morphology and connectivity in the brain of developing male and female offspring

“…Numerous studies within our lab have examined the effects of gestational stress on these specific brain areas (Mychasiuk et al, 2011aMuhammad et al, 2012). Recently, we found that PPS significantly influenced early behavior, and had a significant effect on DNA global methylation levels in the prefrontal cortex (PFC) (Mychasiuk et al, 2013a,b).…”