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1.
J Neurosci ; 26(11): 3045-55, 2006 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-16540583

RESUMEN

Although periventricular white matter injury (PWMI) is the leading cause of chronic neurological disability and cerebral palsy in survivors of premature birth, the cellular-molecular mechanisms by which ischemia-reperfusion contributes to the pathogenesis of PWMI are not well defined. To define pathophysiologic relationships among ischemia, acute cerebral white matter damage, and vulnerable target populations, we used a global cerebral ischemia-reperfusion model in the instrumented 0.65 gestation fetal sheep. We developed a novel method to make repeated measurements of cerebral blood flow using fluorescently labeled microspheres to resolve the spatial heterogeneity of flow in situ in three-dimensional space. Basal flow in the periventricular white matter (PVWM) was significantly lower than in the cerebral cortex. During global cerebral ischemia induced by carotid occlusion, flow to all regions was reduced by nearly 90%. Ischemia of 30 or 37 min duration generated selective graded injury to frontal and parietal PVWM, two regions of predilection for human PWMI. Injury was proportional to the duration of ischemia and increased markedly with 45 min of ischemia to extensively damage cortical and subcortical gray matter. Surprisingly, the distribution of PVWM damage was not uniform and not explained by heterogeneity in the degree of white matter ischemia. Rather, the extent of white matter damage coincided with the presence of a susceptible population of late oligodendrocyte progenitors. These data support that although ischemia is necessary to generate PWMI, the presence of susceptible populations of oligodendrocyte progenitors underlies regional predilection to injury.


Asunto(s)
Hipoxia Fetal/patología , Leucomalacia Periventricular/etiología , Oligodendroglía/patología , Animales , Apoptosis , Barrera Hematoencefálica , Linaje de la Célula , Circulación Cerebrovascular , Susceptibilidad a Enfermedades , Femenino , Hipoxia Fetal/fisiopatología , Edad Gestacional , Humanos , Hipoxia-Isquemia Encefálica/embriología , Hipoxia-Isquemia Encefálica/patología , Imagenología Tridimensional , Recién Nacido , Leucomalacia Periventricular/patología , Leucomalacia Periventricular/fisiopatología , Imagen por Resonancia Magnética , Microesferas , Modelos Animales , Embarazo , Daño por Reperfusión/embriología , Daño por Reperfusión/patología , Ovinos
2.
J Neurosci ; 25(25): 5988-97, 2005 Jun 22.
Artículo en Inglés | MEDLINE | ID: mdl-15976088

RESUMEN

Disruption of oligodendrocyte lineage progression is implicated in the white-matter injury that occurs in cerebral palsy. We have previously published a model in rabbits consistent with cerebral palsy. Little is known of normal white-matter development in perinatal rabbits. Using a multidimensional approach, we defined the relationship of oligodendrocyte lineage progression and functional maturation of axons to structural development of selected cerebral white-matter tracts as determined by diffusion tensor imaging (DTI). Immunohistochemical studies showed that late oligodendrocyte progenitors appear at gestational age 22 [embryonic day 22 (E22)], whereas immature oligodendrocytes appear at E25, and both increase rapidly with time (approximately 13 cells/mm2/d) until the onset of myelination. Myelination began at postnatal day 5 (P5) (E36) in the internal capsule (IC) and at P11 in the medial corpus callosum (CC), as determined by localization of sodium channels and myelin basic protein. DTI of the CC and IC showed that fractional anisotropy (FA) increased rapidly between E25 and P1 (E32) (11% per day) and plateaued (<5% per day) after the onset of myelination. Postnatal maturation of the compound action potential (CAP) showed a developmental pattern similar to FA, with a rapid rise between E29 and P5 (in the CC, 18% per day) and a slower rise from P5 to P11 (in the CC, <5% per day). The development of immature oligodendrocytes after E29 coincides with changes in FA and CAP area in both the CC and IC. These findings suggest that developmental expansion of immature oligodendrocytes during the premyelination period may be important in defining structural and functional maturation of the white matter.


Asunto(s)
Potenciales de Acción/fisiología , Envejecimiento/fisiología , Encéfalo/crecimiento & desarrollo , Cuerpo Calloso/anatomía & histología , Cuerpo Calloso/crecimiento & desarrollo , Oligodendroglía/fisiología , Animales , Femenino , Imagen por Resonancia Magnética , Modelos Animales , Oligodendroglía/citología , Conejos
3.
J Neurosci ; 24(1): 24-34, 2004 Jan 07.
Artículo en Inglés | MEDLINE | ID: mdl-14715934

RESUMEN

Prenatal hypoxia-ischemia to the developing brain has been strongly implicated in the subsequent development of the hypertonic motor deficits of cerebral palsy (CP) in premature and full-term infants who present with neonatal encephalopathy. Despite the enormous impact of CP, there is no animal model that reproduces the hypertonia and motor disturbances of this disorder. We report a rabbit model of in utero placental insufficiency, in which hypertonia is accompanied by marked abnormalities in motor control. Preterm fetuses (67-70% gestation) were subjected to sustained global hypoxia. The dams survived and gave spontaneous birth. At postnatal day 1, the pups that survived were subjected to a battery of neurobehavioral tests developed specifically for these animals, and the tests were videotaped and scored in a masked manner. Newborn pups of hypoxic groups displayed significant impairment in multiple tests of spontaneous locomotion, reflex motor activity, and the coordination of suck and swallow. Increased tone of the limbs at rest and with active flexion and extension were observed in the survivors of the preterm insult. Histopathological studies identified a distinct pattern of acute injury to subcortical motor pathways that involved the basal ganglia and thalamus. Persistent injury to the caudate putamen and thalamus at P1 was significantly correlated with hypertonic motor deficits in the hypoxic group. Antenatal hypoxia-ischemia at preterm gestation results in hypertonia and abnormalities in motor control. These findings provide a unique behavioral model to define mechanisms and sequelae of perinatal brain injury from antenatal hypoxia-ischemia.


Asunto(s)
Parálisis Cerebral/etiología , Modelos Animales de Enfermedad , Hipoxia-Isquemia Encefálica/complicaciones , Trastornos de la Destreza Motora/etiología , Hipertonía Muscular/congénito , Conejos , Animales , Animales Recién Nacidos , Conducta Animal , Encéfalo/patología , Femenino , Enfermedades Fetales/etiología , Humanos , Actividad Motora , Corteza Motora/patología , Destreza Motora , Trastornos de la Destreza Motora/diagnóstico , Trastornos de la Destreza Motora/patología , Hipertonía Muscular/etiología , Hipertonía Muscular/patología , Embarazo , Resultado del Embarazo
4.
Sci Transl Med ; 4(155): 155ra136, 2012 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-23052293

RESUMEN

Shiverer-immunodeficient (Shi-id) mice demonstrate defective myelination in the central nervous system (CNS) and significant ataxia by 2 to 3 weeks of life. Expanded, banked human neural stem cells (HuCNS-SCs) were transplanted into three sites in the brains of neonatal or juvenile Shi-id mice, which were asymptomatic or showed advanced hypomyelination, respectively. In both groups of mice, HuCNS-SCs engrafted and underwent preferential differentiation into oligodendrocytes. These oligodendrocytes generated compact myelin with normalized nodal organization, ultrastructure, and axon conduction velocities. Myelination was equivalent in neonatal and juvenile mice by quantitative histopathology and high-field ex vivo magnetic resonance imaging, which, through fractional anisotropy, revealed CNS myelination 5 to 7 weeks after HuCNS-SC transplantation. Transplanted HuCNS-SCs generated functional myelin in the CNS, even in animals with severe symptomatic hypomyelination, suggesting that this strategy may be useful for treating dysmyelinating diseases.


Asunto(s)
Enfermedades Desmielinizantes/terapia , Vaina de Mielina/metabolismo , Células-Madre Neurales/citología , Animales , Encéfalo/citología , Encéfalo/metabolismo , Encéfalo/patología , Sistema Nervioso Central/citología , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , Humanos , Inmunohistoquímica , Imagen por Resonancia Magnética , Ratones , Células-Madre Neurales/fisiología , Trasplante de Células Madre
5.
Exp Neurol ; 181(2): 231-40, 2003 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-12781996

RESUMEN

The development of a rodent model in the perinatal rat or mouse that reproduces the principal features of human perinatal white matter injury (periventricular leukomalacia) has been hampered by uncertainty about the developmental window in the rodent that coincides temporally with cerebral white matter development in the premature infant. We recently determined oligodendrocyte (OL) lineage progression in human cerebral white matter and found that the late OL progenitor (preOL) predominates throughout the high-risk period for periventricular leukomalacia [J. Neurosci. 21(2001), 1302-1312]. Here, we determined in the perinatal rat and mouse when each species displays a distribution of OL stages that is similar to the premature human cerebral white matter. PreOLs are abundant in the rat and mouse at P2. By P7, extensive OL maturation occurs in both species and coincides with the onset of early myelination. PreOLs and immature OLs mature in the P2 white matter along a medial to lateral gradient. This may provide an explanation for regional variation in the susceptibility of perinatal white matter to injury. We propose that the sequence of OL lineage progression is a useful means to estimate developmental windows of white matter maturation in perinatal rodents that coincide with those of developing human cerebral white matter. These studies support that the vulnerable period for white matter injury in the rodent is centered around P2 and should decline thereafter, coincident with the onset of myelination.


Asunto(s)
Encéfalo/citología , Diferenciación Celular/fisiología , Oligodendroglía/citología , Células Madre/citología , Animales , Animales Recién Nacidos , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Recuento de Células , Linaje de la Célula/fisiología , Técnica del Anticuerpo Fluorescente , Humanos , Inmunohistoquímica , Ratones , Ratones Endogámicos C57BL , Vaina de Mielina/metabolismo , Oligodendroglía/metabolismo , Ratas , Ratas Sprague-Dawley , Especificidad de la Especie , Células Madre/metabolismo , Factores de Tiempo
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