title: Environmental Intervention as a Therapy for Adverse Programming by Ancestral Stress.
abstract: Ancestral stress can program stress sensitivity and health trajectories across multiple generations. While ancestral stress is uncontrollable to the filial generations, it is critical to identify therapies that overcome transgenerational programming. Here we report that prenatal stress in rats generates a transgenerationally heritable endocrine and epigenetic footprint and elevated stress sensitivity which can be alleviated by beneficial experiences in later life. Ancestral stress led to downregulated glucocorticoid receptor and prefrontal cortex neuronal densities along with precocious development of anxiety-like behaviours. Environmental enrichment (EE) during adolescence mitigated endocrine and neuronal markers of stress and improved miR-182 expression linked to brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) regulation in stressed lineages. Thus, EE may serve as a powerful intervention for adverse transgenerational programming through microRNA-mediated regulation of BDNF and NT-3 pathways. The identification of microRNAs that mediate the actions of EE highlights new therapeutic strategies for mental health conditions and psychiatric disease.
authors.affiliation: Canadian Centre for Behavioural Neuroscience, Department of Neuroscience, 4401 University Drive, Lethbridge, Alberta, Canada.
authors.forename: J Keiko
authors.initials: JK
authors.lastname: McCreary
authors.affiliation: Canadian Centre for Behavioural Neuroscience, Department of Neuroscience, 4401 University Drive, Lethbridge, Alberta, Canada.
authors.forename: Zachary T
authors.initials: ZT
authors.lastname: Erickson
authors.affiliation: Canadian Centre for Behavioural Neuroscience, Department of Neuroscience, 4401 University Drive, Lethbridge, Alberta, Canada.
authors.forename: YongXin
authors.initials: Y
authors.lastname: Hao
authors.affiliation: Department of Biology, University of Lethbridge, Lethbridge, AB T1K3M4 Canada.
authors.forename: Yaroslav
authors.initials: Y
authors.lastname: Ilnytskyy
authors.affiliation: Department of Biology, 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, 4401 University Drive, Lethbridge, Alberta, Canada.
authors.forename: Gerlinde A S
authors.initials: GA
authors.lastname: Metz
mesh_terms: D000293:Adolescent; D000818:Animals; D001007:Anxiety / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy; D015415:Biomarkers / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D004777:Environment; D044127:Epigenesis, Genetic / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000378:metabolism; D020933:Neurotrophin 3 / Q000378:metabolism; D017397:Prefrontal Cortex / Q000378:metabolism / Q000503:physiopathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism* / Q000628:therapy*; D051381:Rats; D020318:Rats, Long-Evans; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D013315:Stress, Psychological / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*
chemical_list: D015415:Biomarkers; D019208:Brain-Derived Neurotrophic Factor; D035683:MicroRNAs; D020933:Neurotrophin 3; D011965:Receptors, Glucocorticoid