The cellular basis of myelin deficits detected by neuroimaging in long-term survivors of periventricular leukomalacia (PVL) is poorly understood. We tested the hypothesis that oligodendrocyte lineage (OL) cell density is reduced in PVL, thereby contributing to subsequent myelin deficits. Using computer-based methods, we determined OL cell density in sections from 18 PVL and 18 age-adjusted control cases, immunostained with the OL-lineage marker Olig2. Myelination was assessed with myelin basic protein (MBP) immunostaining. We found no significant difference between PVL and control cases in Olig2 cell density in the periventricular or intragyral white matter. We did find, however, a significant increase in Olig2 cell density at the necrotic foci, compared with distant areas. Although no significant difference was found in the degree of MBP immunostaining, we observed qualitative abnormalities of MBP immunostaining in both the diffuse and necrotic components of PVL. Abnormal MBP immunostaining in PVL despite preserved Olig2 cell density may be secondary to arrested OL maturation, damage to OL processes, and/or impaired axonal-OL signaling. OL migration toward the "core" of injury may occur to replenish OL cell number. This study provides new insight into the cellular basis of the myelin deficits observed in survivors of PVL.

Myelin abnormalities without oligodendrocyte loss in periventricular leukomalacia.

Neural cell cycle dysregulation and central nervous system diseases

Hypoxic-ischemic encephalopathy : Biochemical and physiological aspects

Objective
Although 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 pre-oligodendrocytes (preOLs). We determined whether ex vivo MRI can distinguish distinct microglial and astroglial responses related to WMI progression and arrested preOL differentiation.

Histopathological correlates of magnetic resonance imaging–defined chronic perinatal white matter injury

Microglia exist in different morphological forms in the developing brain. They show a small cell body with scanty cytoplasm with many branching processes in the grey matter of the developing brain. However, in the white matter such as the corpus callosum where the unmyelinated axons are loosely organized, they appear in an amoeboid form having a round cell body endowed with copious cytoplasm rich in organelles. The amoeboid cells eventually transform into ramified microglia in the second postnatal week when the tissue becomes more compact with the onset of myelination. Microglia serve as immunocompetent macrophages that act as neuropathology sensors to detect and respond swiftly to subtle changes in the brain tissues in pathological conditions. Microglial functions are broadly considered as protective in the normal brain development as they phagocytose dead cells and sculpt neuronal connections by pruning excess axons and synapses. They also secrete a number of trophic factors such as insulin-like growth factor-1 and transforming growth factor-β among many others that are involved in neuronal and oligodendrocyte survival. On the other hand, microglial cells when activated produce a plethora of molecules such as proinflammatory cytokines, chemokines, reactive oxygen species, and nitric oxide that are implicated in the pathogenesis of many pathological conditions such as epilepsy, cerebral palsy, autism, and perinatal hypoxic-ischemic brain injury. Although many studies have investigated the origin and functions of the microglia in the developing brain, in-depth in vivo studies along with analysis of their transcriptome and epigenetic changes need to be undertaken to elucidate their full potential be it protective or neurotoxic. This would lead to a better understanding of their roles in the healthy and diseased developing brain and advancement of therapeutic strategies to target microglia-mediated neurotoxicity.

Biology of Microglia in the Developing Brain.

This study examines cell death and proliferation in the white matter after neonatal stroke. In post-natal day 7 injured rat, there was a marked reduction in myelin basic protein (MBP) immunostaining mainly corresponding to numerous pyknotic immature oligodendrocytes and TUNEL-positive astrocytes in the ipsilateral external capsule. In contrast, a substantial restoration of MBP, as indicated by the MBP ratio of left-toright, occurred in the cingulum at 48 (1.27 +- 0.12) and 72 (1.30 +- 0.18, p<0.05) hours of recovery as compared to age-matched controls (1.03 +- 0.14). Ki-67 immunostaining revealed a first peak of newly-generated cells in the dorsolateral hippocampal subventricular zone and cingulum at 72 hours after reperfusion. Double immunofluorescence revealed that most of the Ki-67-positive cells were astrocytes at 48 hours and NG2 pre-oligodendrocytes at 72 hours of recovery. Microglia infiltration occurs over several days in the cingulum and a huge quantity of macrophages reached the subcortical white matter where they engulfed immature oligodendrocytes. The overall results suggest that the persistent activation of microglia involves a chronic component of immunoinflammation, which overwhelms repair processes and contributes to cystic growth in the developing brain.

Glial activation in white matter following ischemia in the neonatal P7 rat brain

Glial activation in white matter following ischemia in the neonatal P7 rat brain.

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Glial activation in white matter following ischemia in the neonatal P7 rat brain

Glial activation in white matter following ischemia in the neonatal P7 rat brain.