Prenatal inflammation impairs adult neurogenesis and memory related behavior through persistent hippocampal TGFβ1 downregulation |
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| Authors: | Mariana Graciarena Amaicha M Depino Fernando J Pitossi |
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| Institution: | 1. Laboratory of Regenerative and Protective Therapies of the Nervous System, Foundation Leloir Institute, IIBBA-CONICET, 435 Av Patricias Argentinas, (1405) Buenos Aires, Argentina;2. Department of Physiology, Molecular and Cellular Biology, Faculty of Exact and Natural Sciences, University of Buenos Aires, (1428) Buenos Aires, Argentina;1. Division of Neonatology, Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA;2. Department of Pediatrics, Baystate Children’s Hospital, Springfield, MA 01199, USA;3. Department of Neurology, Children’s Hospital Boston, and Harvard Medical School, Boston, MA 02115, USA;4. Laboratory of Genital Tract Biology, Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA;5. Division of Pediatric Neurology, Department of Pediatrics, Boston University, Boston, MA 02118, USA;6. Department of Public Health and Community Medicine, Tufts University School of Medicine, Boston, MA 02111, USA;7. Perinatal Epidemiology Unit, Hannover Medical School, 30623 Hannover, Germany;1. Department of Psychology, National University of Ireland Maynooth, County Kildare, Ireland;2. Institute of Immunology, National University of Ireland Maynooth, County Kildare, Ireland;1. Sainte-Justine Hospital and Research Center, Department of Pediatrics, Université de Montréal, 3175 Chemin de la Côte-Sainte-Catherine, Montréal, Québec, Canada;2. Perinatal Center, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden;3. Montreal Heart Institute, 5000 Rue Bélanger, Montreal, Quebec, Canada;4. Department of Neuroscience, Université de Montréal, Montreal, Quebec, Canada;5. Departments of Ophtalmology, Université de Montréal, Montreal, Quebec, Canada;6. Departments of Pharmacology, Université de Montréal, Montreal, Quebec, Canada;1. Graduate Program in Neuroscience, Department of Psychology, University of Western Ontario, London, ON, Canada;2. The Kilee Patchell-Evans Autism Research Group, Department of Psychology, University of Western Ontario, London, ON, Canada;3. The Kilee Patchell-Evans Autism Research Group, Department of Psychology and Psychiatry, Division of Developmental Disabilities, University of Western Ontario, London, ON, Canada;1. Max-Delbrück-Center of Molecular Medicine, Cellular Neuroscience, 13125 Berlin, Germany;2. University Hospital, Clinic for Psychiatry and Psychotherapy, Experimental Psychiatry, 01307 Dresden, Germany;3. Department of Psychiatry and Psychotherapy, Charité – Universitätsmedizin Berlin, Charité Campus Mitte, 10117 Berlin, Germany |
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| Abstract: | Prenatal exposure to inflammatory stimuli is known to influence adult brain function. In addition, adult hippocampal neurogenesis is impaired by a local pro-inflammatory microenvironment. On this basis, we hypothesized that a pro-inflammatory insult during gestation would have negative effects on adult neurogenesis in the offspring. Pregnant Wistar rats received subcutaneous injections of lipopolysaccharide (LPS; 0.5 mg/kg) or saline every other day from gestational day 14 to 20. The adult offspring prenatally treated with LPS showed a decrease in the proliferating cells and the newborn neurons of the dentate gyrus. Furthermore, prenatal LPS treatment impaired performance in the neurogenesis-dependent novel object recognition test. Maternal care was impaired by prenatal LPS administration but did not contribute to the effects of prenatal LPS on adult neurogenesis. Persistent microglial activation and downregulated expression of transforming growth factor beta-1 (TGFβ1) occurred specifically in the adult hippocampus of animals treated prenatally with LPS. Importantly, chronic hippocampal TGFβ1 overexpression restored neurogenesis as well as recognition memory performance to control levels.These findings demonstrate that prenatal inflammation triggered by LPS impairs adult neurogenesis and recognition memory. Furthermore, we provide a model of reduced adult neurogenesis with long-lasting defined alterations in the neurogenic niche. Finally, we show that the expression of a single cytokine (TGFβ1) in the hippocampus can restore adult neurogenesis and its related behavior, highlighting the role of TGFβ1 in these processes. |
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