title: Non-injurious neonatal hypoxia confers resistance to brain senescence in aged male rats.
abstract: Whereas brief acute or intermittent episodes of hypoxia have been shown to exert a protective role in the central nervous system and to stimulate neurogenesis, other studies suggest that early hypoxia may constitute a risk factor that influences the future development of mental disorders. We therefore investigated the effects of a neonatal "conditioning-like" hypoxia (100% N₂, 5 min) on the brain and the cognitive outcomes of rats until 720 days of age (physiologic senescence). We confirmed that such a short hypoxia led to brain neurogenesis within the ensuing weeks, along with reduced apoptosis in the hippocampus involving activation of Erk1/2 and repression of p38 and death-associated protein (DAP) kinase. At 21 days of age, increased thicknesses and cell densities were recorded in various subregions, with strong synapsin activation. During aging, previous exposure to neonatal hypoxia was associated with enhanced memory retrieval scores specifically in males, better preservation of their brain integrity than controls, reduced age-related apoptosis, larger hippocampal cell layers, and higher expression of glutamatergic and GABAergic markers. These changes were accompanied with a marked expression of synapsin proteins, mainly of their phosphorylated active forms which constitute major players of synapse function and plasticity, and with increases of their key regulators, i.e. Erk1/2, the transcription factor EGR-1/Zif-268 and Src kinase. Moreover, the significantly higher interactions between PSD-95 scaffolding protein and NMDA receptors measured in the hippocampus of 720-day-old male animals strengthen the conclusion of increased synaptic functional activity and plasticity associated with neonatal hypoxia. Thus, early non-injurious hypoxia may trigger beneficial long term effects conferring higher resistance to senescence in aged male rats, with a better preservation of cognitive functions.
authors.affiliation: Inserm U954, Vandoeuvre-lès-Nancy, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Martin
authors.forename: Carine
authors.initials: C
authors.lastname: Bossenmeyer-Pourié
authors.forename: Violette
authors.initials: V
authors.lastname: Koziel
authors.forename: Rozat
authors.initials: R
authors.lastname: Jazi
authors.forename: Sandra
authors.initials: S
authors.lastname: Audonnet
authors.forename: Paul
authors.initials: P
authors.lastname: Vert
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Guéant
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Daval
authors.forename: Grégory
authors.initials: G
authors.lastname: Pourié
mesh_terms: D000375:Aging / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D001784:Blood Gas Analysis; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D016923:Cell Death; D049109:Cell Proliferation; D002470:Cell Survival; D005260:Female; D000860:Hypoxia / Q000097:blood / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008124:Locomotion / Q000502:physiology; D008297:Male; D008568:Memory / Q000502:physiology; D055495:Neurogenesis; D009473:Neuronal Plasticity / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D013569:Synapses / Q000378:metabolism