title: 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.
authors.affiliation: Inserm, Unité 676, 75019 Paris, France.
authors.forename: Claire-Marie
authors.initials: CM
authors.lastname: Rangon
authors.forename: Silvia
authors.initials: S
authors.lastname: Fortes
authors.forename: Vincent
authors.initials: V
authors.lastname: Lelièvre
authors.forename: Philippe
authors.initials: P
authors.lastname: Leroux
authors.forename: Frank
authors.initials: F
authors.lastname: Plaisant
authors.forename: Chantal
authors.initials: C
authors.lastname: Joubert
authors.forename: Laurence
authors.initials: L
authors.lastname: Lanfumey
authors.forename: Charles
authors.initials: C
authors.lastname: Cohen-Salmon
authors.forename: Pierre
authors.initials: P
authors.lastname: Gressens
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000097:blood / Q000378:metabolism / Q000523:psychology; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D001927:Brain Diseases / Q000139:chemically induced / Q000150:complications / Q000401:mortality / Q000473:pathology*; D002908:Chronic Disease; D003345:Corticosterone / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D004827:Epilepsy / Q000209:etiology; D005260:Female; D007051:Ibotenic Acid; D007274:Injections, Intraperitoneal; D018782:Maze Learning; D051379:Mice; D008815:Mice, Inbred Strains; D009498:Neurotoxins; D011247:Pregnancy; D011248:Pregnancy Complications / Q000097:blood / Q000503:physiopathology*; D011297:Prenatal Exposure Delayed Effects; D017470:Receptors, Glutamate / Q000172:deficiency / Q000378:metabolism; D013312:Stress, Physiological / Q000097:blood / Q000503:physiopathology*; D013997:Time Factors
chemical_list: D009498:Neurotoxins; D017470:Receptors, Glutamate; D007051:Ibotenic Acid; D003345:Corticosterone