title: Ovarian steroids regulate gene expression in the dorsal raphe of old female macaques.
abstract: With extended life spans in modern humans, menopause has become a significant risk factor for depression, anxiety, loss of cognitive functions, weight gain, metabolic disease, osteoporosis, cardiovascular disease, and neurodegenerative diseases. Clinical studies have found beneficial neural effects of ovarian steroid hormone therapy (HT) during the menopausal transition and data are emerging that it can be continued long term. To further understand molecular underpinnings of the clinical studies, we used quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) to examine gene expression in the serotonergic dorsal raphe of old (>18 years) rhesus macaques, focusing on genes related to depression, cellular resilience, and neurodegenerative diseases. The animals were ovariectomized (Ovx, surgically menopausal) and subjected to either estradiol or estradiol plus progesterone HT, or to placebo, starting 2 months after Ovx and continuing for ∼ 4 years. Significant changes were observed in 36 of 48 genes examined that encode proteins supporting serotonin neurotransmission, synapse assembly, glutamate neurotransmission, DNA repair, chaperones, ubiquinases and transport motors, as well as genes encoding proteins that have potential to delay the onset of neuropathologies. The data reveal important gene targets for chronic HT that contribute to neural health. Alternatively, the loss of ovarian steroids may lead to loss of functions at the gene level that contribute to many of the observable neural deficits after menopause.
authors.affiliation: Division of Reproductive Sciences, Oregon National Primate Research Center, Beaverton, OR, USA; Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR, USA; Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR, USA. Electronic address: betheac@ohsu.edu.
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Bethea
authors.affiliation: Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Kohama
authors.affiliation: Division of Reproductive Sciences, Oregon National Primate Research Center, Beaverton, OR, USA; Department of Internal Medicine, Texas Tech Health Science Center, Lubbock, TX, USA.
authors.forename: Arubala P
authors.initials: AP
authors.lastname: Reddy
authors.affiliation: Division of Reproductive Sciences, Oregon National Primate Research Center, Beaverton, OR, USA; Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR, USA; Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Henryk F
authors.initials: HF
authors.lastname: Urbanski
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D003863:Depression / Q000235:genetics; D065847:Dorsal Raphe Nucleus / Q000378:metabolism*; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology*; D015914:Estrogen Replacement Therapy; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D018698:Glutamic Acid / Q000502:physiology; D008253:Macaca mulatta; D018832:Molecular Chaperones / Q000235:genetics; D019636:Neurodegenerative Diseases / Q000235:genetics; D010052:Ovariectomy; D011374:Progesterone / Q000008:administration & dosage / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012701:Serotonin / Q000502:physiology; D013569:Synapses; D009435:Synaptic Transmission / Q000235:genetics; D013997:Time Factors
chemical_list: D018832:Molecular Chaperones; D012701:Serotonin; D018698:Glutamic Acid; D011374:Progesterone; D004958:Estradiol
keywords: Chaperones; DNA repair; Dorsal raphe; Estrogen; Glutamate; Macaques; Neurodegeneration; Progesterone; Serotonin; Synapse; Transport; Ubiquinases