Delayed neural network degeneration after neonatal hypoxia-ischemia.
OBJECTIVE
Clinical magnetic resonance studies show delayed and ongoing neurodegeneration after neonatal hypoxia-ischemia (HI), but the mechanisms and timing of this neurodegeneration remain unclear. We used ex vivo diffusion tensor imaging (DTI) and brain neuropathology to determine whether selective injury to white matter tracts occurs after neonatal HI in mice resulting in neural system-associated attrition in remote regions and at delayed times.


METHODS
The Rice-Vannucci model (unilateral carotid ligation + 45 minutes of hypoxia FiO(2) = 0.08) was used to cause brain injury in postnatal day 7 (p7) C57BL6 mice, and ex vivo DTI and correlative neuropathology were performed at p8, p11, p15, p21, p28, and p42.


RESULTS
DTI provides excellent contrast visualization of unmyelinated white matter in the immature mouse brain. Severe ipsilateral injury to the hippocampus is seen with both histopathology and diffusion-weighted magnetic resonance imaging 24 hours after injury. Injury to axons is evident 24 hours after HI in the hippocampal alveus. By p11 and continuing until p28, the ipsilateral fimbria fornix degenerates. At p15, there is injury and loss of axons entering the ipsilateral septal nucleus followed by ipsilateral septal atrophy. Volume loss in the hippocampus is rapid and severe, but is subacute and significantly slower in the ipsilateral septum. Neonatal HI also interrupts the normal developmental increase in fractional anisotropy in the ipsilateral fimbria but not in the contralateral fimbria from p8 to p42.


CONCLUSIONS
In neonatal brain, there is progressive systems-preferential injury after HI. DTI allows unparalleled visualization of this neural network-associated attrition so that it can be followed longitudinally in developing brain.
Stone
Brian S
BS
Department of Pediatrics, Eudowood Neonatal Pulmonary Division, Neonatal Research Laboratory, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Zhang
Jiangyang
J
Mack
Devin W
DW
Mori
Susumu
S
Martin
Lee J
LJ
Northington
Frances J
FJ
D000818:Animals; D000831:Animals, Newborn; D016880:Anisotropy; D001921:Brain / Q000254:growth & development / Q000473:pathology* / Q000503:physiopathology; D001931:Brain Mapping / Q000379:methods; D038524:Diffusion Magnetic Resonance Imaging / Q000379:methods*; D004195:Disease Models, Animal; D018450:Disease Progression; D020712:Fornix, Brain / Q000473:pathology / Q000503:physiopathology; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology; D020925:Hypoxia-Ischemia, Brain / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009413:Nerve Fibers, Myelinated / Q000473:pathology*; D009415:Nerve Net / Q000254:growth & development / Q000473:pathology* / Q000503:physiopathology; D009434:Neural Pathways / Q000473:pathology / Q000503:physiopathology; D012686:Septal Nuclei / Q000473:pathology / Q000503:physiopathology; D013997:Time Factors; D014855:Wallerian Degeneration / Q000473:pathology / Q000503:physiopathology