Non-injurious neonatal hypoxia confers resistance to brain senescence in aged male rats.

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.

Conditioning-like brief neonatal hypoxia improves cognitive function and brain tissue properties with marked gender dimorphism in adult rats.

Although recent studies have documented compensatory generation of neurons in adult brains in response to various insults, a noninjurious short episode of hypoxia in rat neonates has been shown to trigger neurogenesis within the ensuing weeks, without apparent brain lesions. Very little is known of the long-term consequences. We therefore investigated the effects of such a conditioning-like hypoxia (100% N(2), 5 min) on the brain and the cognitive outcomes of rats at 40 to 100 days of age. Control and posthypoxic rats developed similar learning capacities over postnatal days 14 to 18, but hypoxia was associated with enhanced scores in a test used to evaluate memory retrieval between 40 and 100 days. A striking sexual dimorphism was observed, with an earlier functional gain observed in female (40 days) compared with male (100 days) rats; gains were associated with matching structural changes in areas involved in cognition, including the hippocampus and frontal cortex. Therefore, it is proposed that brief neonatal hypoxia may exert long-term beneficial effects through neurogenesis stimulation.

Regional brain metabolism with cytochrome c oxidase histochemistry in a PS1/A246E mouse model of autosomal dominant Alzheimer's disease: correlations with behavior and oxidative stress.

Mitochondrial dysfunction and brain metabolic alteration are early neurofunctional aspects in Alzheimer's disease (AD). Regional brain metabolism was analyzed by cytochrome c oxidase (COX) histochemistry in PS1-A246E mouse mutants, a model of autosomal dominant AD overexpressing beta-amyloid (Abeta) peptide without amyloidosis or cell degeneration. Immunohistochemical samples were analyzed on adjacent sections for regional Abeta1-42 levels, as well as DNA oxidative damage with 8-hydroxy-2-deoxyguanosine (8-OHdG). COX activity increased in the basal forebrain nuclear complex, specific parts of the amygdala and hippocampus, as well as in striatum and connected regions. On the contrary, a hypometabolism was observed in midline thalamic, interpeduncular, and pedonculopontine nuclei. The integration of these regions in circuitries subserving emotions, arousal, and cognitive functions may explain why neurochemical alterations in specific brain regions were linearly correlated with psychomotor slowing and disinhibition previously reported in the mutant. As the PS1-A246E model appears to mimick prodromal AD, the results support the existence of mitochondrial abnormalities prior to AD-related cognitive deficits. However, since affected PS1-A246E brain regions were not primarily those altered in AD-associated histopathological features and did not systematically display either Abeta overexpression or higher 8-OHdG immunolabelling, the hypermetabolism observed seems to comprise a compensatory reaction to early mitochondrial abnormalities; furthermore, neuronal synaptic function should be considered as particularly relevant in COX activity changes.