title: Altered brain morphology and functional connectivity reflect a vulnerable affective state after cumulative multigenerational stress in rats.
abstract: Prenatal stress is a risk factor for abnormal neuroanatomical, cognitive, behavioral and mental health outcomes with potentially transgenerational consequences. Females in general seem more resilient to the effects of prenatal stress than males. Here, we examined if repeated stress across generations may diminish stress resiliency and cumulatively enhance the susceptibility for adverse health outcomes in females. Pregnant female rats of three successive generations were exposed to stress from gestational days 12-18 to generate multigenerational prenatal stress (MPS) in the maternal lineage. Stress response was measured by plasma corticosterone levels and open-field exploration in each generation. Neuromorphological consequences of MPS were investigated in the F3 generation using in vivo manganese-enhanced magnetic resonance imaging (MEMRI), T2-relaxometry, and cytoarchitectonics in relation to candidate gene expression involved in brain plasticity and mental health. Each additional generation of prenatal stress incrementally elevated hypothalamic-pituitary-adrenal axis activation, anxiety-like and aversive behaviors in adult female offspring. Elevated stress responses in the MPS F3 generation were accompanied by reduced neural density in prefrontal cortex, hippocampus and whole brain along with altered brain activation patterns in in vivo MEMRI. MPS increased ephrin receptor A5 (Epha5), neuronal growth regulator (Negr1) and synaptosomal-associated protein 25 (Snap25) gene expression and reduced fibroblast growth factor 12 (Fgf12) in prefrontal cortex. These genes regulate neuronal maturation, arborization and synaptic plasticity and may explain altered brain cytoarchitectonics and connectivity. These findings emphasize that recurrent stress across generations may cumulatively increase stress vulnerability and the risk of adverse health outcomes through perinatal programing in females.
authors.affiliation: Canadian Centre for Behavioural Neuroscience, Department of Neuroscience, University of Lethbridge, Lethbridge, AB T1K3M4, Canada.
authors.forename: J Keiko
authors.initials: JK
authors.lastname: McCreary
authors.affiliation: Canadian Centre for Behavioural Neuroscience, Department of Neuroscience, University of Lethbridge, Lethbridge, AB T1K3M4, Canada.
authors.forename: L Sorina
authors.initials: LS
authors.lastname: Truica
authors.affiliation: Canadian Centre for Behavioural Neuroscience, Department of Neuroscience, University of Lethbridge, Lethbridge, AB T1K3M4, Canada.
authors.forename: Becky
authors.initials: B
authors.lastname: Friesen
authors.affiliation: Canadian Centre for Behavioural Neuroscience, Department of Neuroscience, University of Lethbridge, Lethbridge, AB T1K3M4, Canada; Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K3M4, Canada.
authors.forename: Youli
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Department of Obstetrics & Gynecology, University of Alberta, Edmonton, AB T6G2S2, Canada; Department of Pediatrics, University of Alberta, Edmonton, AB T6G2S2, Canada; Department of Physiology, University of Alberta, Edmonton, AB T6G2S2, Canada.
authors.forename: David M
authors.initials: DM
authors.lastname: Olson
authors.affiliation: Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K3M4, Canada.
authors.forename: Igor
authors.initials: I
authors.lastname: Kovalchuk
authors.affiliation: Canadian Centre for Behavioural Neuroscience, Department of Neuroscience, University of Lethbridge, Lethbridge, AB T1K3M4, Canada; Department of Physics and Astronomy, University of Lethbridge, Lethbridge, AB T1K3M4, Canada.
authors.forename: Albert R
authors.initials: AR
authors.lastname: Cross
authors.affiliation: Canadian Centre for Behavioural Neuroscience, Department of Neuroscience, University of Lethbridge, Lethbridge, AB T1K3M4, Canada. Electronic address: gerlinde.metz@uleth.ca.
authors.forename: Gerlinde A S
authors.initials: GA
authors.lastname: Metz
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000254:growth & development / Q000473:pathology* / Q000503:physiopathology*; D002452:Cell Count; D003287:Contrast Media; D003345:Corticosterone / Q000097:blood; D004195:Disease Models, Animal; D004644:Emotions / Q000502:physiology*; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D008279:Magnetic Resonance Imaging; D008345:Manganese; D009434:Neural Pathways / Q000000981:diagnostic imaging / Q000254:growth & development / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000473:pathology / Q000502:physiology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D020318:Rats, Long-Evans; D036123:Receptor, EphA5 / Q000378:metabolism; D055500:Resilience, Psychological; D013315:Stress, Psychological / Q000503:physiopathology; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism
chemical_list: D003287:Contrast Media; C494210:Snap25 protein, rat; D050825:Synaptosomal-Associated Protein 25; C000604599:fibroblast growth factor 12, rat; D008345:Manganese; D005346:Fibroblast Growth Factors; C084437:Epha5 protein, rat; D036123:Receptor, EphA5; D003345:Corticosterone
keywords: HPA axis; T(2)-relaxometry; gene expression; manganese-enhanced magnetic resonance imaging; multigenerational prenatal stress; stress resilience