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Mutations in the methyl-CpG binding protein 2 gene, Mecp2, affect primarily the brain and lead to a wide range of neuropsychiatrie disorders, most commonly Rett syndrome (RTT). Although the neuropathology of RTT is well understood, the cellular and molecular mechanism(s), which lead to the disease initiation and progression, has yet to be elucidated. RTT was initially attributed only to neuronal dysfunction, but our recent studies and those of others show that RTT is not exclusively neuronal but rather also involves interactions between neurons and glia. Importantly, studies have shown that MeCP2-restored astrocytes and microglia are able to attenuate the disease progression in otherwise MeCP2-null mice. Here we show that another type of glia, oligodendrocytes, and their progenitors are also involved in manifestation of specific RTT symptoms. Mice that lost MeCP2 specifically in the oligodendrocyte lineage cells, although overall normal, were more active and developed severe hindlimb clasping phenotypes. Inversely, restoration of MeCP2 in oligodendro-cyte lineage cells, in otherwise MeCP2-null mice, although only mildly prolonging their lifespan, significantly improved the locomotor deficits and hindlimb clasping phenotype, both in male and female mice, and fully restored the body weight in male mice. Finally, we found that the level of some myelin-related proteins was impaired in the MeCP2-null mice. Expression of MeCP2 in oligodendrocytes of these mice only partially restored their expression, suggesting that there is a non- cell-autonomous effect by other cell types in the brains on the expression of myelin-related proteins in oligodendrocytes. [ABSTRACT FROM AUTHOR]

Brain injury in the premature infant is associated with a high risk of neurodevelopmental disability. Previous small-animal models of brain injury attributable to extreme prematurity typically fail to generate a spectrum of pathology and behavior that closely resembles that observed in humans, although they provide initial answers to numerous cellular, molecular, and therapeutic questions. We tested the hypothesis that exposure of rats to repeated hypoxia from postnatal day 1 (PI) to P3 models the characteristic white matter neuropatho-logical injury, gray matter volume loss, and memory deficits seen in children born extremely prematurely. Male Sprague Dawley rats were exposed to repeated hypoxia or repeated normoxia from PI to P3. The absolute number of pre-oligodendrocytes and mature oligoden-drocytes, the surface area and g-ratio of myelin, the absolute volume of cerebral white and gray matter, and the absolute number of cerebral neurons were quantified stereologically. Spatial memory was investigated on a radial arm maze. Rats exposed to repeated hypoxia had a significant loss of (1) pre-oligodendrocytes at P4, (2) cerebral white matter volume and myelin at P14, (3) cerebral cortical and striatal gray matter volume without neuronal loss at P14, and (4) cerebral myelin and memory deficits in adulthood. Decreased myelin was correlated with increased attention deficit hyperactivity disorder-like hyperactivity. This new small-animal model of extreme prematurity generates a spectrum of short- and long-term pathology and behavior that closely resembles that observed in humans. This new rat model provides a clinically relevant tool to investigate numerous cellular, molecular, and therapeutic questions on brain injury attributable to extreme prematurity. [ABSTRACT FROM AUTHOR]

REST is a master repressor of neuronal genes; however, whether it has any role during nervous system development remains largely unknown. Here, we analyzed systematically the role of REST in embryonic stem cells and multipotent neural stem/progenitor (NS/P) cells, including neurogenic and gliogenic NS/P cells derived from embryonic stem (ES) cells or developing mouse embryos. We showed that REST-null ES cells remained pluripotent and generated teratomas consisting of the three germ layers. By contrast, multipotent NS/P cells lacking REST displayed significantly reduced self-renewal capacity owing to reduced cell cycle kinetics and precocious neuronal differentiation. Importantly, although early-born neurogenic NS/P cells that lack REST were capable of differentiating to neurons and glia, the neuronal and oligodendrocytic pools were significantly enlarged and the astrocytic pool was shrunken. However, gliogenic NS/P cells lacking REST were able to generate a normal astrocytic pool size, suggesting that the shrinkage of the astrocytic pool generated from neurogenic NS/P cells lacking REST probably occurs by default. Microarray profiling of early-born NS/P cells lacking REST showed upregulation of neuronal as well as oligodendrocytic genes, specifically those involved in myelination. Furthermore, chromatin immunoprecipitation analyses showed that some of the upregulated oligodendrocytic genes contain an RE1 motif and are direct REST targets. Together, our data support a central role for REST during neural development in promoting NS/P cell self-renewal while restricting the generation and maturation of neurons and oligodendrocytes [ABSTRACT FROM AUTHOR]

Pediatric traumatic brain injury (TBI) is a significant and underappreciated societal problem. Whereas many TBI studies have evaluated the mechanisms of cell death after TBI, fewer studies have evaluated the extent to which regeneration is occurring. Here we used a cryoinjury model to damage the somatosensory cortex of rats at postnatal day 6 (P6), P10 and P21. We evaluated the production of new neocortical neurons using a combination of 5-bromo-2-deoxyuridine (BrdU) labeling combined with staining for doublecortin (DCX). BrdU+/DCX+ bipolar cells were observed adjacent to the neocortical lesion, with their processes oriented perpendicular to the pial surface. As the animals aged, both the overall proliferative response as well as the production of neocortical neuroblasts diminished, with P6 animals responding most robustly, P10 animals less strongly, and P21 animals showing a very modest proliferative response and virtually no evidence of neocortical neurogenesis. When BrdU was administered at increasingly delayed intervals after the injury at P6, there was a clear difference in the number of new neuroblasts produced as a function of age, with the greatest number of new neocortical neurons produced between 4 and 7 days after the injury. These studies demonstrate that the immature brain has the capacity to produce neocortical neurons after traumatic injury, but this capacity diminishes as the brain continues to develop. Furthermore, in contrast to moderate hypoxic/ischemic brain damage in the P6 rat, where neurogenesis persists for at least 2 months, the response to cryoinjury is quite different as the neurogenic response diminishes over time. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: The most common behavioural disorder seen in children and adolescents born extremely prematurely is attention deficit hyperactivity disorder (ADHD). The hyperactive/impulsive sub-type of ADHD or the inattentive sub-type or the hyperactive/impulsive/inattentive sub-type can be evident. These sub-types of ADHD can persist into adulthood. The aim of this study was to investigate the relevance of a new immature rat model of repeated hypoxic exposure to these behavioural characteristics of extreme prematurity. More specifically, this study aimed to measure ADHD-like hyperactivity in response to delayed reward, and inattention, in repeated hypoxic versus repeated normoxic rats. Sprague-Dawley rats were exposed to either repeated hypoxia or repeated normoxia during postnatal days (PN) 1–3. The rat brain during PN1–3 is generally considered to be developmentally equivalent to the human brain during extreme prematurity. The rats were then behaviourally tested at 16 months-of-age on a multiple component fixed interval–extinction test. This test detects ADHD-like hyperactivity in response to delayed reward, as well as inattention. It was found that the repeated hypoxic rats exhibited ADHD-like hyperactivity in response to delayed reward, but no attention deficit, when compared to repeated normoxic rats. These findings provide a new animal model to investigate the biological mechanisms and treatment of ADHD-like hyperactivity due to repeated hypoxia during the equivalent of extreme prematurity. [Copyright &y& Elsevier]

Brain injuries, such as cerebral hypoxia-ischemia (H-I), induce a regenerative response from the neural stem/progenitors (NSPs) of the subventricular zone (SVZ); however, the mechanisms that regulate this expansion have not yet been fully elucidated. The Notch- Delta-Serrate-Lag2 (DSL) signaling pathway is considered essential for the maintenance of neural stem cells, but it is not known if it is necessary for the expansion of the NSPs subsequent to perinatal H-I injury. Therefore, the aim of this study was to investigate whether this pathway contributes to NSP expansion in the SVZ after H-I and, if so, to establish whether this pathway is directly induced by H-I or regulated by paracrine factors. Here we report that Notch1 receptor induction and one of its ligands, Delta-like 1, precedes NSP expansion after perinatal H-I in P6 rat pups and that this increase occurs specifically in the most medial cell layers of the SVZ where the stem cells reside. Pharmacologically inhibiting Notch signaling in vivo diminished NSP expansion. With an in vitro model of H-I, Notch1 was not induced directly by hypoxia, but was stimulated by soluble factors, specifically leukemia inhibitory factor, produced by astrocytes within the SVZ. These data confirm the importance both of the Notch-DSL signaling pathway in the expansion of NSPs after H-I and in the role of the support cells in their niche. They further support the body of evidence that indicates that leukemia inhibitory factor is a key injury-induced cytokine that is stimulating the regenerative response of the NSPs. © 2016 Wiley Periodicals, Inc., Competing Interests: The authors have no conflicts of interest to report., (© 2016 Wiley Periodicals, Inc.)

Mutations in the methyl-CpG binding protein 2 gene, Mecp2, affect primarily the brain and lead to a wide range of neuropsychiatric disorders, most commonly Rett syndrome (RTT). Although the neuropathology of RTT is well understood, the cellular and molecular mechanism(s), which lead to the disease initiation and progression, has yet to be elucidated. RTT was initially attributed only to neuronal dysfunction, but our recent studies and those of others show that RTT is not exclusively neuronal but rather also involves interactions between neurons and glia. Importantly, studies have shown that MeCP2-restored astrocytes and microglia are able to attenuate the disease progression in otherwise MeCP2-null mice. Here we show that another type of glia, oligodendrocytes, and their progenitors are also involved in manifestation of specific RTT symptoms. Mice that lost MeCP2 specifically in the oligodendrocyte lineage cells, although overall normal, were more active and developed severe hindlimb clasping phenotypes. Inversely, restoration of MeCP2 in oligodendrocyte lineage cells, in otherwise MeCP2-null mice, although only mildly prolonging their lifespan, significantly improved the locomotor deficits and hindlimb clasping phenotype, both in male and female mice, and fully restored the body weight in male mice. Finally, we found that the level of some myelin-related proteins was impaired in the MeCP2-null mice. Expression of MeCP2 in oligodendrocytes of these mice only partially restored their expression, suggesting that there is a non-cell-autonomous effect by other cell types in the brains on the expression of myelin-related proteins in oligodendrocytes.

Pediatric traumatic brain injury (TBI) is a significant and underappreciated societal problem. Whereas many TBI studies have evaluated the mechanisms of cell death after TBI, fewer studies have evaluated the extent to which regeneration is occurring. Here we used a cryoinjury model to damage the somatosensory cortex of rats at postnatal day 6 (P6), P10 and P21. We evaluated the production of new neocortical neurons using a combination of 5-bromo-2-deoxyuridine (BrdU) labeling combined with staining for doublecortin (DCX). BrdU+/DCX+ bipolar cells were observed adjacent to the neocortical lesion, with their processes oriented perpendicular to the pial surface. As the animals aged, both the overall proliferative response as well as the production of neocortical neuroblasts diminished, with P6 animals responding most robustly, P10 animals less strongly, and P21 animals showing a very modest proliferative response and virtually no evidence of neocortical neurogenesis. When BrdU was administered at increasingly delayed intervals after the injury at P6, there was a clear difference in the number of new neuroblasts produced as a function of age, with the greatest number of new neocortical neurons produced between 4 and 7 days after the injury. These studies demonstrate that the immature brain has the capacity to produce neocortical neurons after traumatic injury, but this capacity diminishes as the brain continues to develop. Furthermore, in contrast to moderate hypoxic/ischemic brain damage in the P6 rat, where neurogenesis persists for at least 2 months, the response to cryoinjury is quite different as the neurogenic response diminishes over time., (Copyright © 2010 S. Karger AG, Basel.)

Fundamental questions remain about the optimal temperature, duration, and mode of delivery that provide the best striatal neuroprotection from hypothermia after perinatal hypoxia-ischemia. This study used stereological methods to investigate whether a mild (i.e. 2 degrees C) or a moderate (5 degrees C) decrease in whole body temperature, for 6 h immediately postinsult, was neuroprotective for striatal medium-spiny neurons after perinatal hypoxia-ischemia in the rat. This study also investigated whether moderate hypothermia had any effect on normal striatal development. Hypoxia-ischemia or sham hypoxia-ischemia was induced on postnatal day (PN) 7. Pups were kept either normothermic, mildly hypothermic, or moderately hypothermic for 6 h immediately postinsult. The absolute number of striatal medium-spiny neurons was calculated using modern stereological methods. There was no significant difference in the absolute number of medium-spiny neurons in the right striatum after either mild hypothermia or moderate hypothermia. There was also no significant difference in the absolute number of medium-spiny neurons between the control normothermic and the control moderately hypothermic pups. The latter results suggest that moderate hypothermia for 6 h immediately postinsult may be a safe treatment for striatal medium-spiny neurons. Yet, neither mild nor moderate hypothermia alone for 6 h immediately posthypoxia-ischemia is neuroprotective for striatal medium-spiny neurons.

Objective: Neocortical neurons are sensitive to hypoxic-ischemic (H-I) injuries at term and their demise contributes to neurological disorders. Here we tested the hypothesis that the subventricular zone of the immature brain regenerates neocortical neurons, and that this response is sustained., Methods: Systemic injections of 5-bromo-2'-deoxyuridine (BrdU) and intraventricular injections of replication-deficient retroviruses were used to label newly born cells, and confocal microscopy after immunofluorescence was used to phenotype the new cells from several days to several months after perinatal H-I in the postnatal day 6 rat. Quantitative polymerase chain reaction was used to evaluate chemoattractants, growth factors, and receptors., Results: Robust production of new neocortical neurons after perinatal H-I occurs. These new neurons are descendants of the subventricular zone, and they colonize the cell-sparse columns produced by the injury to the neocortex. These columns are populated by reactive astrocytes and microglia. Surprisingly, this neuronogenesis is sustained for months. Molecular analyses demonstrated increased neocortical production of insulin-like growth factor-1 and monocyte chemoattractant factor-1 (but statistically insignificant production of erythropoietin, brain-derived neurotrophic factor, glial-derived neurotrophic factor, and transforming growth factor-alpha)., Interpretation: The young nervous system has long been known to possess a greater capacity to recover from injury than the adult system. Our data indicate that H-I injury in the neonatal brain initiates an enduring regenerative response from the subventricular zone. These data suggest that additional mechanisms than those previously surmised contribute to the remarkable ability of the immature brain to recover from injury.