Research Projects


mechanisms of axonal pathology following oligodendrocyte apoptosis

A principal goal of our research seeks to understand the pathological consequences of oligodendrocyte apoptosis, a process thought to initiate the development of new multiple sclerosis lesions. We have demonstrated that the loss of key symbiotic interactions between the oligodendrocyte and the axons they ensheath has profound functional consequences that occur prior to the removal of the myelin membrane, that is, in the absence of demyelination. Our findings illustrate that the genesis of axonal pathology in the absence of demyelination in recent onset disease could be induced by oligodendrocyte death or dysfunction.

 

 

Following demyelination, neural progenitor cells (NPCs) produce myelin of normal thickness, whereas oligodendrocyte progenitor cells (OPCs) produce thin myelin. b) Immunogold electron microscopy reveals that progenitor identity determines the thickness of the myelin that they regenerate following demyelination (Xing et al, 2014; J Neurosci). c) Schematic of coronal section of adult mouse brain: NPC-derived oligodendrocytes remyelinate the region of the CC proximal to the SVZ, whereas OPC-derived oligodendrocytes remyelinate the medial and lateral regions of the CC. CC, corpus callosum; LV, lateral ventricle; SVZ, subventricular zone. Scalebar = 1µm.

Contribution of neural stem cells to remyelination

We recently demonstrated that the quality of myelin that is regenerated in the adult brain depends on the type of progenitor cell that is recruited to produce new oligodendrocytes. Whilst both neural progenitor cells (NPCs) and oligodendrocyte progenitor cells (OPCs) can regenerate oligodendrocytes after demyelination, only oligodendrocytes that derive from NPCs can restore myelin to a control/normal level; OPC-derived oligodendrocytes only produce thin myelin after demyelination, whereas NPCs produce myelin of similar thickness to that seen in myelinated controls

 

 

Role of electrical activity in regulating myelination

Mounting evidence suggests that neuronal activity influences myelination, potentially allowing for experience-driven modulation of neural circuitry. The degree to which neuronal activity is capable of regulating myelination at the individual axon level is unclear, however. We have recently shown that stimulation of somatosensory axons in the mouse brain increases proliferation and differentiation of oligodendrocyte progenitor cells (OPCs) within the underlying white matter. Stimulated axons show an increased probability of being myelinated compared to neighbouring non-stimulated axons, in addition to being ensheathed with thicker myelin. Conversely, attenuating neuronal firing lessens the myelination of axons with reduced activity, also in a selective manner. Our findings reveal that the process of selecting axons for myelination is strongly influenced by the relative activity of individual axons within a population. These observed cellular changes are consistent with the emerging concept that adaptive myelination is a key mechanism for the fine-tuning of neuronal circuitry in the mammalian CNS.

 

Newly-generated oligodendrocytes preferentially target axons with higher levels of activity. Representative images of the corpus callosum of PdgfRα-CreERT2: Tau-mGFP mice that had undergone one week of treatment with either CNO or saline. Coronal sections were immunolabeled with antibodies against GFP (green), neurofilament (magenta) and mCherry (red). The number of internodes generated by newly-differentiated cortical oligodendrocytes that aligned with mCherry+/hM3Dq+ axons was more than two-fold higher in CNO-administered mice than in saline controls (12.1±1.3 versus 27.6±1.5 for saline and CNO-administered mice, respectively; Fig. 8h; P = 0.003, n = 4, Welch’s corrected t-test). Scale bar = 20 µm.

Newly-generated oligodendrocytes preferentially target axons with higher levels of activity. Representative images of the corpus callosum of PdgfRα-CreERT2: Tau-mGFP mice that had undergone one week of treatment with either CNO or saline. Coronal sections were immunolabeled with antibodies against GFP (green), neurofilament (magenta) and mCherry (red). The number of internodes generated by newly-differentiated cortical oligodendrocytes that aligned with mCherry+/hM3Dq+ axons was more than two-fold higher in CNO-administered mice than in saline controls (12.1±1.3 versus 27.6±1.5 for saline and CNO-administered mice, respectively; Fig. 8h; P = 0.003, n = 4, Welch’s corrected t-test). Scale bar = 20 µm.