Lateral habenula neurocircuits mediate the maternal disruptive effect of maternal stress: A hypothesis

Up to 20%of women experience stress-related disorders during the postpartum period;however,little is known about the specific neural circuitry by which maternal stress exerts its negative impacts on mental health and maternal caregiving behavior.Theoretically,such a circuitry should serve as an interface between the stress response system and maternal neural network,transmitting stress signals to the neural circuitry that mediates maternal behavior.In this paper,I propose that the lateral habenula(LHb)serves this interface function.Evidence shows that the LHb plays a key role in encoding stress-induced effects and in the pathophysiology of major depression and stressrelated anxiety,and thus may play a role in maternal behavior as part of the maternal brain network.I hypothesize that maternal stress acts upon the LHb and two of its major downstream targets,i.e.,ventral tegmental area(VTA)and dorsal raphe nucleus(DRN),compromising the maternal care and contributing to postpartum mental disorders.This hypothesis makes three predictions:(1)maternal stress enhances LHb neuronal activity;(2)activation of DRN-and VTA-projecting neurons in the LHb mimics the detrimental effects of maternal stress on maternal behavior;and(3)suppression of DRN-and VTA-projecting neurons in the LHb attenuates the detrimental effects of maternal stress on maternal care in stressed mothers.Confirmation of this hypothesis is expected to enhance our understanding of the neurocircuit mechanisms mediating stress effects on maternal behavior.

Ovine hippocampal mRNA expression in offspring from dams supplemented with fishmeal and stress challenged in late pregnancy with endotoxin

Previous research has shown that adulthood disease can be attributed to stress events that occur during gestation. The objective of the present study was to determine whether maternal stress during late pregnancy, using a bacterial endotoxemia model, causes changes in hippocampal mRNA expression of candidate genes related to hypothalamic-pituitary-adrenal axis(HPAA) regulation in sheep. This study also sought to investigate whether maternal diets supplemented with fishmeal(FM) rich in omega-3 polyunsaturated fatty acids(PUFAs) offer protection to the fetus when subjected to maternal endotoxin stress. Using RT-qPCR, relative mRNA expression was assessed in both fetal lambs and 6-month-old lambs from dams supplemented with soybean meal(SM) or FM and challenged with either endotoxin or saline. From this it was found that fetal mineralocorticoid receptor(MR) gene expression had a tendency to be altered during endotoxin challenge, however, in the 6-month-old offspring, MR and glucocorticoid receptor(GR) gene expression were differently altered across treatment groups. These results suggest that gene regulation within the hippocampus is altered into adulthood by maternal endotoxin stress and that dietary supplementation affects outcome.

Embryonic exposure to hyper glucocorticoids suppresses brown fat development and thermogenesis via REDD1

Maternal stress during pregnancy is prevailing worldwide, which exposes fetuses to intrauterine hyper glucocorticoids(GC), programming offspring to obesity and metabolic diseases. Despite the importance of brown adipose tissue(BAT) in maintaining long-term metabolic health, impacts of prenatal hyper GC on postnatal BAT thermogenesis and underlying regulations remain poorly defined. Pregnant mice were administrated with synthetic GC dexamethasone(DEX) at levels comparable to fetal GC exposure of stressed mothers. Prenatal GC exposure dose-dependently reduced BAT thermogenic activity, contributing to lower body temperature and higher mortality of neonates;such difference was abolished under thermoneutrality, underscoring BAT deficiency was the major contributor to adverse changes in postnatal thermogenesis due to excessive GC. Prenatal GC exposure highly activated Redd1 expression and reduced Ppargc1 a transcription from the alternative promoter(Ppargc1 a-AP) in neonatal BAT. During brown adipocyte differentiation, ectopic Redd1 expression reduced Ppargc1 a-AP expression and mitochondrial biogenesis;and the inhibitory effects of GC on mitochondrial biogenesis and Ppargc1 a-AP expression were blocked by Redd1 ablation. Redd1 reduced protein kinase A phosphorylation and suppressed cyclic adenosine monophosphate(c AMP)-responsive element-binding protein(CREB) binding to the c AMP regulatory element(CRE) in Ppargc1 a-AP promoter, leading to Ppargc1 a-AP inactivation. In summary, excessive maternal GC exposure during pregnancy dysregulates Redd1-Ppargc1 a-AP axis, which impairs fetal BAT development, hampering postnatal thermogenic adaptation and metabolic health of offspring.