title: Chronic neonatal hypoxia leads to long term decreases in the volume and cell number of the rat cerebral cortex.
abstract: Preterm birth results in significant neurodevelopmental disability. The neonatal rodent model of chronic sublethal hypoxia faithfully mimics the effect of preterm birth on the developing brain. We employed this model to test the hypothesis that the hypoxia that accompanies preterm birth results in inappropriate signaling of apoptotic mechanisms in developing brain. We performed cortical cell counts, determinations of neuronal size and Western analyses of the apoptosis related proteins, Bcl-2 and Bax, in rat pups who were raised in chronic hypoxia (FiO2 9.5%) beginning on postnatal day 3 (P3) and extending for either 10 (P13) or 30 (P33) days. A third group of animals was exposed to 30 days of hypoxia followed by an additional 30 days in a normoxic environment (P63) to assess the potential for recovery from the initial effects of hypoxia. Age matched control pups were raised in room air throughout the experimental time period. Assessment of cortical cell number revealed a 25% reduction (P < 0.01) in total cell number following 30 days of hypoxic rearing. Glia were significantly reduced by 34% and 41% after 10 and 30 days of hypoxia, respectively, while neuron numbers were only significantly reduced (14%) after 30 days of hypoxia. Animals exposed to a hypoxic environment for 30 days followed by 30 days in a normoxic environment revealed some recovery of glial cell numbers, but no significant recovery of neuronal cell numbers. Measurement of cell size at both P13 and P33 revealed that neurons of layer III were significantly smaller in cross-sectional area in hypoxic compared with control rats (P < 0.01). However, no significant difference was noted in neuronal size following 30 days of normoxic recovery. Western blot analyses of Bcl-2 and Bax protein levels demonstrated a ratio favorable to Bax at multiple time points during the period of hypoxic exposure. These data suggest that chronic exposure to hypoxia during the perinatal period alters the production and maintenance of glial and neuronal cells and that glia and neurons demonstrate differential patterns of vulnerability and recovery following subsequent periods of normoxic exposure. It is hypothesized that the mechanisms responsible for these alterations in cortical cell number may depend on the state of differentiation of the different cell types at the time of hypoxic exposure.
authors.affiliation: Department of Neurobiology, Yale University School of Medicine, New Haven, CT 06510, USA. michael.schwartz@yale.edu
authors.forename: Michael L
authors.initials: ML
authors.lastname: Schwartz
authors.forename: Flora
authors.initials: F
authors.lastname: Vaccarino
authors.forename: Monica
authors.initials: M
authors.lastname: Chacon
authors.forename: Wei Li
authors.initials: WL
authors.lastname: Yan
authors.forename: Laura R
authors.initials: LR
authors.lastname: Ment
authors.forename: William B
authors.initials: WB
authors.lastname: Stewart
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology; D049108:Cell Enlargement; D049109:Cell Proliferation; D002540:Cerebral Cortex / Q000503:physiopathology*; D002908:Chronic Disease; D000860:Hypoxia / Q000503:physiopathology*; D023421:Models, Animal; D009416:Nerve Regeneration / Q000502:physiology; D009457:Neuroglia / Q000502:physiology; D009474:Neurons / Q000502:physiology; D051381:Rats; D015398:Signal Transduction