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Programming effects of maternal stress on the circadian system of adult offspring.

ABSTRACT: Maternal stress has long-lasting influences on the brain functions of offspring, and several brain regions have been proposed to mediate such programming. Although perinatal programming of crosstalk between the circadian and stress systems has been proposed, the functional consequences of prenatal stress on the circadian system and the underlying mechanisms remain largely unknown. Therefore, we investigated whether exposing pregnant mice to chronic restraint stress had prolonged effects on the suprachiasmatic nucleus (SCN), which bears the central pacemaker for mammalian circadian rhythms, of offspring. SCN explants from maternally stressed mice exhibited altered cyclic expression patterns of a luciferase reporter under control of the mouse Per1 promoter (mPer1::LUC), which manifested as a decreased amplitude and impaired stability of the rhythm. Bioluminescence imaging at the single-cell level subsequently revealed that impaired synchrony among individual cells was responsible for the impaired rhythmicity. These intrinsic defects appeared to persist during adulthood. Adult male offspring from stressed mothers showed advanced-phase behavioral rhythms with impaired stability as well as altered clock gene expression in the SCN. In addition to affecting the central rhythm, maternal stress also had prolonged influences on the circadian characteristics of the adrenal gland and liver, as determined by circulating corticosterone levels and hepatic glycogen content, and on canonical clock gene mRNA expression in those tissues. Taken together, our findings suggest that the SCN is a key target of the programming effects of maternal stress. The widespread effects of circadian disruptions caused by a misprogrammed clock may have further impacts on metabolic and mental health in later life.

SUBMITTER: Yun S

PROVIDER: S-EPMC7156466 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Programming effects of maternal stress on the circadian system of adult offspring.

Yun Seongsik S Lee Eun Jeong EJ Choe Han Kyoung HK Son Gi Hoon GH Kim Kyungjin K Chung Sooyoung S

Experimental & molecular medicine 20200311 3

Maternal stress has long-lasting influences on the brain functions of offspring, and several brain regions have been proposed to mediate such programming. Although perinatal programming of crosstalk between the circadian and stress systems has been proposed, the functional consequences of prenatal stress on the circadian system and the underlying mechanisms remain largely unknown. Therefore, we investigated whether exposing pregnant mice to chronic restraint stress had prolonged effects on the s ...[more]

PMID: 32161397

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Project description:The risk of obesity in adulthood is subject to programming beginning at conception. In animal models, exposure to maternal obesity and high fat diets influences the risk of obesity in the offspring. Among other long-term changes, offspring from obese rats develop hyperinsulinemia, hepatic steatosis, and lipogenic gene expression in the liver at weaning. However, the precise underlying mechanisms leading to metabolic dysregulation in the offspring remains unclear. Using a rat model of overfeeding-induced obesity, we previously demonstrated that exposure to maternal obesity from pre-conception to birth, is sufficient to program increased obesity risk in the offspring. Offspring of obese rat dams gain greater body weight and fat mass when fed high fat diet (HFD) as compared to lean dam. Since, disruptions of diurnal circadian rhythm are known to detrimentally impact metabolically active tissues such as liver, we examined the hypothesis that maternal obesity leads to perturbations of core clock components and thus energy metabolism in offspring liver. Offspring from lean and obese dams were examined at post-natal day 35, following a short (2 wk) HFD challenge. Hepatic mRNA expression of circadian (CLOCK, BMAL1, REV-ERBα, CRY, PER) and metabolic (PPARα, SIRT1) genes were strongly suppressed in offspring exposed to both maternal obesity and HFD. Using a mathematical model, we identified two distinct biological mechanisms that modulate PPARα mRNA expression: i) decreased mRNA synthesis rates; and ii) increased non-specific mRNA degradation rate. Moreover, our findings demonstrate that changes in PPARα transcription were associated with epigenomic alterations in H3K4me3 and H3K27me3 histone marks near the PPARα transcription start site. Our findings indicated that offspring from obese rat dams have detrimental alternations to circadian machinery that may contribute to impaired liver metabolism in response to HFD, specifically via reduced PPARα expression prior to obesity development.

Project description:Adverse experiences during pregnancy induce placental programming, affecting the fetus and its developmental trajectory. However, the influence of 'positive' maternal experiences on the placenta and fetus remain unclear. In animal models of early life stress, environmental enrichment (EE) has ameliorated and even prevented associated impairments in brain and behavior. Here, using a maternal immune activation (MIA) model in rats, we test whether EE attenuates maternal, placental and/or fetal responses to an inflammatory challenge, thereby offering a mechanism by which fetal programming may be prevented. Moreover, we evaluate life-long EE exposure on offspring development and examine a constellation of genes and epigenetic writers that may protect against MIA challenges. In our model, maternal plasma corticosterone and interleukin-1? were elevated 3?h after MIA, validating the maternal inflammatory response. Evidence for developmental programming was demonstrated by a simultaneous decrease in the placental enzymes Hsd11b2 and Hsd11b2/Hsd11b1, suggesting disturbances in glucocorticoid metabolism. Reductions of Hsd11b2 in response to challenge is thought to result in excess glucocorticoid exposure to the fetus and altered glucocorticoid receptor expression, increasing susceptibility to behavioral impairments later in life. The placental, but not maternal, glucocorticoid implications of MIA were attenuated by EE. There were also sustained changes in epigenetic writers in both placenta and fetal brain as a consequence of environmental experience and sex. Following MIA, both male and female juvenile animals were impaired in social discrimination ability. Life-long EE mitigated these impairments, in addition to the sex specific MIA associated disruptions in central Fkbp5 and Oprm1. These data provide the first evidence that EE protects placental functioning during stressor exposure, underscoring the importance of addressing maternal health and well-being throughout pregnancy. Future work must evaluate critical periods of EE use to determine if postnatal EE experience is necessary, or if prenatal exposure alone is sufficient to confer protection.

Dataset Information

Programming effects of maternal stress on the circadian system of adult offspring.

Publications

Programming effects of maternal stress on the circadian system of adult offspring.

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