Objective Recently, we reported that the neocortex displays impaired growth after transient cerebral hypoxia–ischemia (HI) at preterm gestation that is unrelated to neuronal death but is associated with decreased dendritic arbor complexity of cortical projection neurons. We hypothesized that these morphological changes constituted part of a more widespread neuronal dysmaturation response to HI in the caudate nucleus (CN), which contributes to motor and cognitive disability in preterm survivors. Methods Ex vivo magnetic resonance imaging (MRI), immunohistochemistry, and Golgi staining defined CN growth, cell death, proliferation, and dendritic maturation in preterm fetal sheep 4 weeks after HI. Patch‐clamp recording was used to analyze glutamatergic synaptic currents in CN neurons. Results MRI‐defined growth of the CN was reduced after ischemia compared to controls. However, no significant acute or delayed neuronal death was seen in the CN or white matter. Nor was there significant loss of calbindin‐positive medium spiny projection neurons (MSNs) or CN interneurons expressing somatostatin, calretinin, parvalbumin, or tyrosine hydroxylase. Morphologically, ischemic MSNs showed a markedly immature dendritic arbor, with fewer dendritic branches, nodes, endings, and spines. The magnitude and kinetics of synaptic currents, and the relative contribution of glutamate receptor subtypes in the CN were significantly altered. Interpretation The marked MSN dendritic and functional abnormalities after preterm cerebral HI, despite the marked resistance of immature CN neurons to cell death, are consistent with widespread susceptibility of projection neurons to HI‐induced dysmaturation. These global disturbances in dendritic maturation and glutamatergic synaptic transmission suggest a new mechanism for long‐term motor and behavioral disabilities in preterm survivors via widespread disruption of neuronal connectivity. Ann Neurol 2014;75:508–524

Children who survive preterm birth exhibit persistent unexplained disturbances in cerebral cortical growth with associated cognitive and learning disabilities. The mechanisms underlying these deficits remain elusive. We used ex vivo diffusion magnetic resonance imaging to demonstrate in a preterm large-animal model that cerebral ischemia impairs cortical growth and the normal maturational decline in cortical fractional anisotropy (FA). Analysis of pyramidal neurons revealed that cortical deficits were associated with impaired expansion of the dendritic arbor and reduced synaptic density. Together, these findings suggest a link between abnormal cortical FA and disturbances of neuronal morphological development. To experimentally investigate this possibility, we measured the orientation distribution of dendritic branches and observed that it corresponds with the theoretically predicted pattern of increased anisotropy within cases that exhibited elevated cortical FA after ischemia. We conclude that cortical growth impairments are associated with diffuse disturbances in the dendritic arbor and synapse formation of cortical neurons, which may underlie the cognitive and learning disabilities in survivors of preterm birth. Further, measurement of cortical FA may be useful for noninvasively detecting neurological disorders affecting cortical development.

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.

Editor's Summary neural stem cell transplantation in PMD and other dysmyelination disorders. transplantation region in three of the four patients. These results support further study of potential clinical benefits of derived myelination in the − were used to assess myelination. The imaging results were consistent with donor cell tolerated. Magnetic resonance imaging techniques, performed before transplant and five times in the following year, Human neural stem cells were transplanted directly into the brain; the procedure and transplantation were well Pelizaeus-Merzbacher disease (PMD), a rare X-linked condition in which oligodendrocytes cannot myelinate axons.. then tested the safety and efficacy of such cells in four young boys with a severe, fatal form of et al Gupta which ensheathed axons and improved nerve conduction in both categories of mice. In an open-label phase 1 study, dysmyelination. These transplanted cells preferentially differentiated into oligodendrocytes that generated myelin, newborn mice were asymptomatic, the juvenile mice were already symptomatic and displayed advanced mice. Whereas the Shi stem cells, which had been expanded and banked, into the brains of newborn and juvenile. transplanted human neural et al) mice, a hypomyelination model, could prolong survival. In the new work, Uchida Shi (shiverer disorders. Previous work showed that transplantation of human oligodendrocyte progenitors into newborn as a potential treatment for such −− which can differentiate into myelin-producing oligodendrocytes −− stem cells. now investigate the use of neural et al. and Gupta et al nervous system cause severe neurological decline. Uchida the rapid transmission of nerve impulses and in axon integrity, mutations that affect myelin formation in the central can have destructive effects. Because of myelin's crucial roles in promoting −− the myelin sheath −− around nerve fibers Faulty insulation around household wiring is an electric shock and fire hazard; likewise, defects in the insulation Bringing Insulation Up to Code

Although magnetic resonance imaging (MRI) is the optimal imaging modality to define cerebral white‐matter injury (WMI) in preterm survivors, the histopathological features of MRI‐defined chronic lesions are poorly defined. We hypothesized that chronic WMI is related to a combination of delayed oligodendrocyte (OL) lineage cell death and arrested maturation of preoligodendrocytes (preOLs). We determined whether ex vivo MRI can distinguish distinct microglial and astroglial responses related to WMI progression and arrested preOL differentiation.