A Matter of State: Diversity in Oligodendrocyte Lineage Cells.

Oligodendrocyte precursor cells (OPCs) give rise to oligodendrocytes which myelinate axons in the central nervous system. Although classically thought to be a homogeneous population, OPCs are reported to have different developmental origins and display regional and temporal diversity in their transcriptome, response to growth factors, and physiological properties. Similarly, evidence is accumulating that myelinating oligodendrocytes display transcriptional heterogeneity. Analyzing this reported heterogeneity suggests that OPCs, and perhaps also myelinating oligodendrocytes, may exist in different functional cell states. Here, we review the evidence indicating that OPCs and oligodendrocytes are diverse, and we discuss the implications of functional OPC states for myelination in the adult brain and for myelin repair.

Nutritional regulation of oligodendrocyte differentiation regulates perineuronal net remodeling in the median eminence.

The mediobasal hypothalamus (MBH; arcuate nucleus of the hypothalamus [ARH] and median eminence [ME]) is a key nutrient sensing site for the production of the complex homeostatic feedback responses required for the maintenance of energy balance. Here, we show that refeeding after an overnight fast rapidly triggers proliferation and differentiation of oligodendrocyte progenitors, leading to the production of new oligodendrocytes in the ME specifically. During this nutritional paradigm, ME perineuronal nets (PNNs), emerging regulators of ARH metabolic functions, are rapidly remodeled, and this process requires myelin regulatory factor (Myrf) in oligodendrocyte progenitors. In genetically obese ob/ob mice, nutritional regulations of ME oligodendrocyte differentiation and PNN remodeling are blunted, and enzymatic digestion of local PNN increases food intake and weight gain. We conclude that MBH PNNs are required for the maintenance of energy balance in lean mice and are remodeled in the adult ME by the nutritional control of oligodendrocyte differentiation.

Neuronal activity-dependent myelin repair after stroke.

Brain tissue undergoes substantial activity-dependent reorganisation after stroke due to neuronal plasticity, leading to partial functional recovery in patients. Concurrent myelin repair is crucial for proper neuronal network function and reorganisation. Myelin repair after stroke might occur as myelin plasticity or as remyelination through the recruitment and differentiation of oligodendrocyte precursor cells (OPCs), which become myelin-forming oligodendrocytes (OLs). These two processes might share a similar guiding mechanism, which is postulated to depend on neuronal activity and glutamate signaling to OPCs. However, with ageing, the ability of OPCs to differentiate into myelinating OLs decreases due to changes in their ion channel and neurotransmitter receptor expression profile, rendering them less sensitive to neuronal activity. Because of their unique ability to replace damaged OLs, OPCs represent a potential therapeutic target for myelin repair in the context of stroke.

Neuronal Activity-Dependent Control of Postnatal Neurogenesis and Gliogenesis.

The addition of new neurons and oligodendroglia in the postnatal and adult mammalian brain presents distinct forms of gray and white matter plasticity. Substantial effort has been devoted to understanding the cellular and molecular mechanisms controlling postnatal neurogenesis and gliogenesis, revealing important parallels to principles governing the embryonic stages. While during central nervous system development, scripted temporal and spatial patterns of neural and glial progenitor proliferation and differentiation are necessary to create the nervous system architecture, it remains unclear what driving forces maintain and sustain postnatal neural stem cell (NSC) and oligodendrocyte progenitor cell (OPC) production of new neurons and glia. In recent years, neuronal activity has been identified as an important modulator of these processes. Using the distinct properties of neurotransmitter ionotropic and metabotropic channels to signal downstream cellular events, NSCs and OPCs share common features in their readout of neuronal activity patterns. Here we review the current evidence for neuronal activity-dependent control of NSC/OPC proliferation and differentiation in the postnatal brain, highlight some potential mechanisms used by the two progenitor populations, and discuss future studies that might advance these research areas further.

Surpassing light-induced cell damage in vitro with novel cell culture media.

Light is extensively used to study cells in real time (live cell imaging), separate cells using fluorescence activated cell sorting (FACS) and control cellular functions with light sensitive proteins (Optogenetics). However, photo-sensitive molecules inside cells and in standard cell culture media generate toxic by-products that interfere with cellular functions and cell viability when exposed to light. Here we show that primary cells from the rat central nervous system respond differently to photo-toxicity, in that astrocytes and microglia undergo morphological changes, while in developing neurons and oligodendrocyte progenitor cells (OPCs) it induces cellular death. To prevent photo-toxicity and to allow for long-term photo-stimulation without causing cellular damage, we formulated new photo-inert media called MEMO and NEUMO, and an antioxidant rich and serum free supplement called SOS. These new media reduced the detrimental effects caused by light and allowed cells to endure up to twenty times more light exposure without adverse effects, thus bypassing the optical constraints previously limiting experiments.

Glutamate signalling: A multifaceted modulator of oligodendrocyte lineage cells in health and disease.

Myelin is essential for the mammalian brain to function efficiently. Whilst many factors have been associated with regulating the differentiation of oligodendroglia and myelination, glutamate signalling might be particularly important for learning-dependent myelination. The majority of myelinated projection neurons are glutamatergic. Oligodendrocyte precursor cells receive glutamatergic synaptic inputs from unmyelinated axons and oligodendrocyte lineage cells express glutamate receptors which enable them to monitor and respond to changes in neuronal activity. Yet, what role glutamate plays for oligodendroglia is not fully understood. Here, we review glutamate signalling and its effects on oligodendrocyte lineage cells, and myelination in health and disease. Furthermore, we discuss whether glutamate signalling between neurons and oligodendroglia might lay the foundation to activity-dependent white matter plasticity. This article is part of the Special Issue entitled 'Oligodendrocytes in Health and Disease'.

Neuronal activity regulates remyelination via glutamate signalling to oligodendrocyte progenitors.

Myelin regeneration can occur spontaneously in demyelinating diseases such as multiple sclerosis (MS). However, the underlying mechanisms and causes of its frequent failure remain incompletely understood. Here we show, using an in-vivo remyelination model, that demyelinated axons are electrically active and generate de novo synapses with recruited oligodendrocyte progenitor cells (OPCs), which, early after lesion induction, sense neuronal activity by expressing AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)/kainate receptors. Blocking neuronal activity, axonal vesicular release or AMPA receptors in demyelinated lesions results in reduced remyelination. In the absence of neuronal activity there is a ∼6-fold increase in OPC number within the lesions and a reduced proportion of differentiated oligodendrocytes. These findings reveal that neuronal activity and release of glutamate instruct OPCs to differentiate into new myelinating oligodendrocytes that recover lost function. Co-localization of OPCs with the presynaptic protein VGluT2 in MS lesions implies that this mechanism may provide novel targets to therapeutically enhance remyelination.

Aberrant methylation of tRNAs links cellular stress to neuro-developmental disorders.

Mutations in the cytosine-5 RNA methyltransferase NSun2 cause microcephaly and other neurological abnormalities in mice and human. How post-transcriptional methylation contributes to the human disease is currently unknown. By comparing gene expression data with global cytosine-5 RNA methylomes in patient fibroblasts and NSun2-deficient mice, we find that loss of cytosine-5 RNA methylation increases the angiogenin-mediated endonucleolytic cleavage of transfer RNAs (tRNA) leading to an accumulation of 5' tRNA-derived small RNA fragments. Accumulation of 5' tRNA fragments in the absence of NSun2 reduces protein translation rates and activates stress pathways leading to reduced cell size and increased apoptosis of cortical, hippocampal and striatal neurons. Mechanistically, we demonstrate that angiogenin binds with higher affinity to tRNAs lacking site-specific NSun2-mediated methylation and that the presence of 5' tRNA fragments is sufficient and required to trigger cellular stress responses. Furthermore, the enhanced sensitivity of NSun2-deficient brains to oxidative stress can be rescued through inhibition of angiogenin during embryogenesis. In conclusion, failure in NSun2-mediated tRNA methylation contributes to human diseases via stress-induced RNA cleavage.

Astrocyte response to motor neuron injury promotes structural synaptic plasticity via STAT3-regulated TSP-1 expression.

The role of remote astrocyte (AC) reaction to central or peripheral axonal insult is not clearly understood. Here we use a transgenic approach to compare the direct influence of normal with diminished AC reactivity on neuronal integrity and synapse recovery following extracranial facial nerve transection in mice. Our model allows straightforward interpretations of AC-neuron signalling by reducing confounding effects imposed by inflammatory cells. We show direct evidence that perineuronal reactive ACs play a major role in maintaining neuronal circuitry following distant axotomy. We reveal a novel function of astrocytic signal transducer and activator of transcription-3 (STAT3). STAT3 regulates perineuronal astrocytic process formation and re-expression of a synaptogenic molecule, thrombospondin-1 (TSP-1), apart from supporting neuronal integrity. We demonstrate that, through this new pathway, TSP-1 is responsible for the remote AC-mediated recovery of excitatory synapses onto axotomized motor neurons in adult mice. These data provide new targets for neuroprotective therapies via optimizing AC-driven plasticity.

Neuregulin and BDNF induce a switch to NMDA receptor-dependent myelination by oligodendrocytes.

Myelination is essential for rapid impulse conduction in the CNS, but what determines whether an individual axon becomes myelinated remains unknown. Here we show, using a myelinating coculture system, that there are two distinct modes of myelination, one that is independent of neuronal activity and glutamate release and another that depends on neuronal action potentials releasing glutamate to activate NMDA receptors on oligodendrocyte lineage cells. Neuregulin switches oligodendrocytes from the activity-independent to the activity-dependent mode of myelination by increasing NMDA receptor currents in oligodendrocyte lineage cells 6-fold. With neuregulin present myelination is accelerated and increased, and NMDA receptor block reduces myelination to far below its level without neuregulin. Thus, a neuregulin-controlled switch enhances the myelination of active axons. In vivo, we demonstrate that remyelination after white matter damage is NMDA receptor-dependent. These data resolve controversies over the signalling regulating myelination and suggest novel roles for neuregulin in schizophrenia and in remyelination after white matter damage.

Mechanical difference between white and gray matter in the rat cerebellum measured by scanning force microscopy.

The mechanical properties of tissues are increasingly recognized as important cues for cell physiology and pathology. Nevertheless, there is a sparsity of quantitative, high-resolution data on mechanical properties of specific tissues. This is especially true for the central nervous system (CNS), which poses particular difficulties in terms of preparation and measurement. We have prepared thin slices of brain tissue suited for indentation measurements on the micrometer scale in a near-native state. Using a scanning force microscope with a spherical indenter of radius ∼20µm we have mapped the effective elastic modulus of rat cerebellum with a spatial resolution of 100µm. We found significant differences between white and gray matter, having effective elastic moduli of K=294±74 and 454±53Pa, respectively, at 3µm indentation depth (n(g)=245, n(w)=150 in four animals, p<0.05; errors are SD). In contrast to many other measurements on larger length scales, our results were constant for indentation depths of 2-4µm indicating a regime of linear effective elastic modulus. These data, assessed with a direct mechanical measurement, provide reliable high-resolution information and serve as a quantitative basis for further neuromechanical investigations on the mechanical properties of developing, adult and damaged CNS tissue.