Explore the vast range of titles available.

Oligodendrogenesis is essential for replacing worn-out oligodendrocytes, promoting myelin plasticity, and for myelin repair following a demyelinating injury in the adult mammalian brain. Neural stem cells are an important source of oligodendrocytes in the adult brain; however, there are considerable differences in oligodendrogenesis from neural stem cells residing in different areas of the adult brain. Amongst the distinct niches containing neural stem cells, the subventricular zone lining the lateral ventricles and the subgranular zone in the dentate gyrus of the hippocampus are considered the principle areas of adult neurogenesis. In addition to these areas, radial glia-like cells, which are the precursors of neural stem cells, are found in the lining of the third ventricle, where they are called tanycytes, and in the cerebellum, where they are called Bergmann glia. In this review, we will describe the contribution and regulation of each of these niches in adult oligodendrogenesis.

Background: Inherited white matter (WM) disorders of the central nervous systems (CNS), or leukodystrophies, are devastating diseases that primarily affect children, many of whom die early in life or suffer from long-term disability. Methods: q-Space diffusion MR imaging (QSI) and diffusion tensor MR imaging (DTI) with the same resolution and timing parameters were used to study the spinal cords (SCs) of two myelin mutants that are experimental models of WM diseases of different severity, namely the 28-day-old taiep and Long–Evans Shaker (les) rats. The aim was to verify if and which of the diffusion methodologies used is more suitable for early detection of the milder taiep pathology and to characterize its early phase. We also aimed to compare the diffusion MRI results with quantitative electron microscopy (EM) findings. Results: We found that at this early age (28 days), both QSI and DTI were able to detect the severe les WM pathology, while the milder WM pathology in the SC of the taiep rats was detected only by QSI. An increase in the mean radial displacement (RaDis), representing the MRI axon diameter (AD), and a decrease in the probability for zero displacement (PZD) were observed in the dorsal column (ROI 1) of the taiep SCs. In other WM areas, the same trends were observed but the differences were not of statistical significance. In DTI, we found some lower fractional anisotropy (FA) values in the taiep SCs compared to the controls; however, these differences were not statistically significant. For the more severe les pathology, we observed a dramatic increase in the RaDis values and a large decrease in PZD values in all ROIs examined. There, even the FA values were lower than that of the control SCs in all ROIs, albeit with much smaller statistical significance. These MRI results, which show a higher detectability of WM pathology with heavier diffusion weighting, followed histological findings that showed significant myelin deficiency in the dorsal column in the taiep SCs and a practically complete myelin loss in all WM areas in the les SCs. This study also revealed that, under the experimental conditions used here, the apparent increase in RaDis agrees better with myelin thickness and not with average AD extracted form EM, probably reflecting the effect of water exchange. Conclusions: These results, corroborated by diffusion time-dependent QSI, also imply that while diffusion MRI in general and QSI in particular provide acceptable apparent axon diameter estimations in heathy and mature WM, this appears not to be the case in severely damaged WM where exchange appears to play a more important role.

Despite concerted efforts over decades, the etiology of multiple sclerosis (MS) remains unclear. Autoimmunity, environmental-challenges, molecular mimicry and viral hypotheses have proven equivocal because early-stage disease is typically presymptomatic. Indeed, most animal models of MS also lack defined etiologies. We have developed a novel adult-onset oligodendrogliopathy using a delineated metabolic stress etiology in myelinating cells, and our central question is, “how much of the pathobiology of MS can be recapitulated in this model?” The analyses described herein demonstrate that innate immune activation, glial scarring, cortical and hippocampal damage with accompanying electrophysiological, behavioral and memory deficits naturally emerge from disease progression. Molecular analyses reveal neurofilament changes in normal-appearing gray matter that parallel those in cortical samples from MS patients with progressive disease. Finally, axon initial segments of deep layer pyramidal neurons are perturbed in entorhinal/frontal cortex and hippocampus from OBiden mice, and computational modeling provides insight into vulnerabilities of action potential generation during demyelination and early remyelination. We integrate these findings into a working model of corticohippocampal circuit dysfunction to predict how myelin damage might eventually lead to cognitive decline.

Wobbly hedgehog syndrome (WHS) has been long considered to be a myelin disease primarily affecting the four-toed hedgehog. In this study, we have shown for the first time that demyelination is accompanied by extensive remyelination in WHS. However, remyelination is not enough to compensate for the axonal degeneration and neuronal loss, resulting in a progressive neurodegenerative disease reminiscent of progressive forms of multiple sclerosis (MS) in humans. Thus, understanding the pathological features of WHS may shed light on the disease progression in progressive MS and ultimately help to develop therapeutic strategies for both diseases.Wobbly hedgehog syndrome (WHS) has been long considered to be a myelin disease primarily affecting the four-toed hedgehog. In this study, we have shown for the first time that demyelination is accompanied by extensive remyelination in WHS. However, remyelination is not enough to compensate for the axonal degeneration and neuronal loss, resulting in a progressive neurodegenerative disease reminiscent of progressive forms of multiple sclerosis (MS) in humans. Thus, understanding the pathological features of WHS may shed light on the disease progression in progressive MS and ultimately help to develop therapeutic strategies for both diseases.Wobbly hedgehog syndrome (WHS) is a progressive neurodegenerative disease.Spongy degeneration of the brain and spinal cord is the diagnostic feature of WHS.WHS affected brain and spinal cord show extensive demyelination and remyelination.Axonal degeneration is accompanied by loss of neurons in WHS.HighlightsWobbly hedgehog syndrome (WHS) is a progressive neurodegenerative disease.Spongy degeneration of the brain and spinal cord is the diagnostic feature of WHS.WHS affected brain and spinal cord show extensive demyelination and remyelination.Axonal degeneration is accompanied by loss of neurons in WHS.

Enhancing repair of myelin is an important therapeutic goal in many neurological disorders characterized by demyelination. In the healthy adult brain, ventral neural stem cells in the sub-ventricular zone are marked by Gli1 expression and do not generate oligodendrocytes. However, in response to demyelination they migrate to lesions and differentiate into oligodendrocytes. Inhibition of Gli1 further increases their contribution to remyelination. Gli1 and Gli2 are both transcriptional effectors of the Sonic Hedgehog pathway with highly conserved domains but the role of Gli2 in remyelination by ventral neural stem cells is not clear. Here we show that while genetic ablation of Gli1 in the ventral neural stem cells increases remyelination, loss of Gli2 in these cells decreases their migration to the white matter lesion and reduces their differentiation into mature oligodendrocytes. These studies indicate Gli1 and Gli2 have distinct, non-redundant functions in NSCs, including that Gli2 is essential for the enhanced remyelination mediated by Gli1 inhibition. They highlight the importance of designing specific Gli1 inhibitors that do not inhibit Gli2 as a strategy for therapies targeting the Shh pathway.

Gli1 expressing neural stem cells, in the subventricular zone of the adult mammalian brain, respond to demyelination injury by differentiating into oligodendrocytes. We have identified Gpnmb as a novel regulator of oligodendrogenesis in Gli1 neural stem cells, whose expression is induced by TGFβ1 signaling via Gli1, in response to a demyelinating injury. Upregulation of Gpnmb further activates the TGFβ1 pathway by increasing the expression of the TGFβ1 binding receptor subunit, TGFβR2. Thus the TGFβ1→Gli1→Gpnmb→TGFβR2 signaling pathway forms a feed forward loop for sustained activation of TGFβ1 signaling in Gli1 neural stem cells, resulting in inhibition of their differentiation into mature oligodendrocytes following demyelination.