title: Differential vulnerability of adult neurogenesis by adult and prenatal inflammation: role of TGF-β1.
abstract: Peripheral inflammation, both during the prenatal period and in adulthood, impairs adult neurogenesis. We hypothesized that, similar to other programming effects of prenatal treatments, only prenatal inflammation causes long-term consequences in adult neurogenesis and its neurogenic niche. To test this, pregnant Wistar rats were subcutaneously injected with lipopolysaccharide (LPS; 0.5 mg/kg) or saline solution every other day from gestational/embryonic day (GD) 14-20. In addition adult animals were injected with a single intraperitoneal saline or LPS injection (1 mg/kg) and the effects on neurogenesis were assessed 7 days later. Alternatively, to evaluate long-term consequences of adult LPS injections, LPS (1 mg/kg) was administered peripherally to adult rats four times every other day, and the effects on neurogenesis were assessed 60 days later. Prenatal and adult LPS treatments reduced adult neurogenesis and provoked specific microglial (but not astroglial) activation in the dentate gyrus (DG). However, only prenatal inflammation-mediated effects were long-lasting (at least 60 days). Moreover, these effects were specific to the DG since the Subventricular Zone (SVZ) and the Rostral Migratory Stream (RMS) were not affected. In addition, these stimuli caused differential effects on the molecular components of the neurogenic niche; only prenatal LPS treatment reduced the local levels of TGF-β1 mRNA in the DG. Finally, TGF-β1 exerted its pro-neurogenic effects via the Smad 2/3 pathway in a neural stem cell culture. Taken together, these data add evidence to the duration, regional specificity and dramatic consequences of prenatal immune programming on CNS physiology, compared with the limited response observed in the adult brain.
authors.affiliation: Leloir Institute Foundation, Institute for Biochemical Investigations of Buenos Aires - CONICET, 1405 Buenos Aires, Argentina.
authors.forename: Mariana
authors.initials: M
authors.lastname: Graciarena
authors.forename: Valeria
authors.initials: V
authors.lastname: Roca
authors.forename: Patricia
authors.initials: P
authors.lastname: Mathieu
authors.forename: Amaicha M
authors.initials: AM
authors.lastname: Depino
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Pitossi
mesh_terms: D000367:Age Factors; D000818:Animals; D001253:Astrocytes / Q000166:cytology; D018891:Dentate Gyrus / Q000166:cytology* / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D005260:Female; D007249:Inflammation / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D017628:Microglia / Q000166:cytology; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D008070:Lipopolysaccharides; D053773:Transforming Growth Factor beta1
keywords: Adult neurogenesis; Inflammation; Microglial activation; Neurogenic niche; Prenatal programming; TGF-β1