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. Circadian rhythms: Maternal stress can disrupt adult offspring's biological clock When pregnant mothers are stressed, the fetus's circadian rhythms are reprogrammed, increasing the risk of health complications later in life. Stress during pregnancy was known to negatively affect the fetus, but how it affected circadian rhythms (day/night patterns of alertness) was poorly understood. Kyungjin Kim (Daegu Gyeongbuk Institute of Science and Technology) and Sooyoung Chung (Ewha Womans University, Seoul), both in South Korea, and co-workers stressed pregnant mice by confining them in small tubes, then measured the effects on their offspring. Pups of stressed mothers showed disturbed circadian rhythms, and the effects persisted into adulthood. Further analysis showed that the rhythms were disrupted because individual cells in the key brain region regulating circadian rhythms were poorly synchronized. These results suggest potential treatments to counteract the negative effects of prenatal stress on circadian rhythms.