title: Vulnerability versus resilience to prenatal stress in male and female rats; implications from gene expression profiles in the hippocampus and frontal cortex.
abstract: Adverse life events during pregnancy may impact upon the developing fetus, predisposing prenatally stressed offspring to the development of psychopathology. In the present study, we examined the effects of prenatal restraint stress (PS) on anxiety- and depression-related behavior in both male and female adult Sprague-Dawley rats. In addition, gene expression profiles within the hippocampus and frontal cortex (FC) were examined in order to gain more insight into the molecular mechanisms that mediate the behavioral effects of PS exposure. PS significantly increased anxiety-related behavior in male, but not female offspring. Likewise, depression-related behavior was increased in male PS rats only. Further, male PS offspring showed increased basal plasma corticosterone levels in adulthood, whereas both PS males and females had lower stress-induced corticosterone levels when compared to controls. Microarray-based profiling of the hippocampus and FC showed distinct sex-dependent changes in gene expression after PS. Biological processes and/or signal transduction cascades affected by PS included glutamatergic and GABAergic neurotransmission, mitogen-activated protein kinase (MAPK) signaling, neurotrophic factor signaling, phosphodiesterase (PDE)/ cyclic nucleotide signaling, glycogen synthase kinase 3 (GSK3) signaling, and insulin signaling. Further, the data indicated that epigenetic regulation is affected differentially in male and female PS offspring. These sex-specific alterations may, at least in part, explain the behavioral differences observed between both sexes, i.e. relative vulnerability versus resilience to PS in male versus female rats, respectively. These data reveal novel potential targets for antidepressant and mood stabilizing drug treatments including PDE inhibitors and histone deacetylase (HDAC) inhibitors.
authors.affiliation: Department of Neuroscience, School for Mental Health and Neuroscience (MHeNS), Maastricht University, European Graduate School of Neuroscience (EURON), Universiteitssingel 50, P.O. Box 616, 6200 MD, Maastricht, The Netherlands; Molecular Psychiatry, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Fuechsleinstrasse 15, 97080 Wuerzburg, Germany. Electronic address: d.vandenhove@maastrichtuniversity.nl.
authors.forename: D L A
authors.initials: DL
authors.lastname: Van den Hove
authors.forename: G
authors.initials: G
authors.lastname: Kenis
authors.forename: A
authors.initials: A
authors.lastname: Brass
authors.forename: R
authors.initials: R
authors.lastname: Opstelten
authors.forename: B P F
authors.initials: BP
authors.lastname: Rutten
authors.forename: M
authors.initials: M
authors.lastname: Bruschettini
authors.forename: C E
authors.initials: CE
authors.lastname: Blanco
authors.forename: K P
authors.initials: KP
authors.lastname: Lesch
authors.forename: H W M
authors.initials: HW
authors.lastname: Steinbusch
authors.forename: J
authors.initials: J
authors.lastname: Prickaerts
mesh_terms: D000818:Animals; D001007:Anxiety / Q000097:blood / Q000209:etiology / Q000378:metabolism; D001522:Behavior, Animal; D003345:Corticosterone / Q000097:blood; D003863:Depression / Q000097:blood / Q000209:etiology / Q000378:metabolism; D004198:Disease Susceptibility; D044127:Epigenesis, Genetic; D005260:Female; D005625:Frontal Lobe / Q000201:enzymology / Q000378:metabolism*; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000201:enzymology / Q000378:metabolism; D011247:Pregnancy; D011248:Pregnancy Complications / Q000503:physiopathology*; D011297:Prenatal Exposure Delayed Effects / Q000097:blood / Q000209:etiology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012149:Restraint, Physical; D012727:Sex Characteristics; D015398:Signal Transduction; D013312:Stress, Physiological; D013315:Stress, Psychological / Q000503:physiopathology*
chemical_list: D009419:Nerve Tissue Proteins; D003345:Corticosterone