Chronic Mild Stress during Gestation Worsens Neonatal Brain Lesions in Mice

Abstract

Cerebral palsy remains a public health priority. Recognition of factors of susceptibility to perinatal brain lesions is key for the prevention of cerebral palsy. In most cases, the pathophysiology of these lesions is thought to involve prior exposure to predisposing factors that make the developing brain more vulnerable to perinatal events. The present study tested the hypothesis that exposure to chronic minimal stress throughout gestation would sensitize the offspring to neonatal excitotoxic brain lesions, which mimic lesions observed in cerebral palsy. Pregnant mice were exposed to chronic, ultramild stress, applied throughout gestation. Neonatal brain lesions were induced by intracerebral injection of glutamate analogs. Excitotoxic lesions were significantly worsened in pups exposed to gestational stress. Stress induced a significant rise of circulating corticosterone levels both in pregnant mothers and in newborn pups. The deleterious effects of stress on excitotoxicity were totally suppressed in mice with reduced levels of glucocorticoid receptors. Stress induced a significant increase of neopallial NMDA binding sites in the offspring. At adulthood, animals exposed to stress and neonatal excitotoxic challenge showed a significant impairment in the Morris water maze test when compared with animals exposed to the excitotoxic challenge but not the gestational stress. These findings suggest that stress during gestation, which may mimic low-level stress in human pregnancy, could be a novel risk factor for cerebral palsy.

Early Sensitivity Training for Parents of Preterm Infants: Impact on the Developing Brain

“…We speculate that stress exposure in the immature brain has an adverse effect on cerebral injury and/or development such that reduction in stress via MITP-type intervention enhances cerebral white matter development as measured by ADC and anisotropy. This is supported by recent experimental data in the immature brain that has emphasized the capacity of mild chronic stress to worsen brain injury (29). In addition, stress exposure increases hypothalamic-pituitary-adrenal (HPA) hormonal reactions resulting in altered cerebral white matter development (30).…”

Inflammation‐induced sensitization of the brain in term infants

“…71 We have shown that mild chronic stress during murine gestation sensitizes the neonatal brain to excitotoxic lesions in a manner comparable to systemic injection with cytokines. 18 Preliminary data show that administration of RU486, a glucocorticoid and progesterone receptor blocker, completely prevents the sensitizing effect of systemic IL-1b (Fig. 2), suggesting an involvement of the hypothalamo-pituitary-adrenal axis (and/or progesterone receptors) in the sensitizing effect of systemic inflammation.…”

“…Substantial numbers of preclinical studies have demonstrated the sensitizing effects of gestational or neonatal systemic inflammation, gestational chronic mild maternal stress, and gestational hypoxia on perinatal excitotoxic or hypoxic-ischaemic lesions. [16][17][18][19][20][21] Genetic factors have also been shown to influence the developing brain's response to sensitizing factors. 22,23 Robust epidemiological studies, performed in preterm and term-born neonates, support a role for inflammation as a sensitizer.…”

Effects of Antenatal Uteroplacental Hypoperfusion on Neonatal Microvascularisation and Excitotoxin Sensitivity in Mice

“…Quantification of mRNAs for NMDA receptor subunits showed no significant alterations in the expression of these receptors. Thus, changes in these receptors cannot explain the increased NMDA agonist toxicity, in contrast for instance to data from neonates born to dams subjected to chronic mild stress during pregnancy (24). This finding suggests that AUVL may alter NMDA receptor function downstream from receptor expression.…”