Myelin basic protein mRNA levels affect myelin sheath dimensions, architecture, plasticity, and density of resident glial cells.

Myelin basic protein (Mbp) is essential for both elaboration and maintenance of CNS myelin, and its reduced accumulation results in hypomyelination. How different Mbp mRNA levels affect myelin dimensions across the lifespan and how resident glial cells may respond to such changes are unknown. Here, to investigate these questions, we used enhancer-edited mouse lines that accumulate Mbp mRNA levels ranging from 8% to 160% of wild type. In young mice, reduced Mbp mRNA levels resulted in corresponding decreases in Mbp protein accumulation and myelin sheath thickness, confirming the previously demonstrated rate-limiting role of Mbp transcription in the control of initial myelin synthesis. However, despite maintaining lower line specific Mbp mRNA levels into old age, both Mbp protein levels and myelin thickness improved or fully normalized at rates defined by the relative Mbp mRNA level. Sheath length, in contrast, was affected only when mRNA levels were very low, demonstrating that sheath thickness and length are not equally coupled to Mbp mRNA level. Striking abnormalities in sheath structure also emerged with reduced mRNA levels. Unexpectedly, an increase in the density of all glial cell types arose in response to reduced Mbp mRNA levels. This investigation extends understanding of the role Mbp plays in myelin sheath elaboration, architecture, and plasticity across the mouse lifespan and illuminates a novel axis of glial cell crosstalk.

Characterizing spontaneous Ca2+ local transients in OPCs using computational modeling.

Spontaneous Ca2+ local transients (SCaLTs) in isolated oligodendrocyte precursor cells are largely regulated by the following fluxes: store-operated Ca2+ entry (SOCE), Na+/Ca2+ exchange, Ca2+ pumping through Ca2+-ATPases, and Ca2+-induced Ca2+-release through ryanodine receptors and inositol-trisphosphate receptors. However, the relative contributions of these fluxes in mediating fast spiking and the slow baseline oscillations seen in SCaLTs remain incompletely understood. Here, we developed a stochastic spatiotemporal computational model to simulate SCaLTs in a homogeneous medium with ionic flow between the extracellular, cytoplasmic, and endoplasmic-reticulum compartments. By simulating the model and plotting both the histograms of SCaLTs obtained experimentally and from the model as well as the standard deviation of inter-SCaLT intervals against inter-SCaLT interval averages of multiple model and experimental realizations, we revealed the following: (1) SCaLTs exhibit very similar characteristics between the two data sets, (2) they are mostly random, (3) they encode information in their frequency, and (4) their slow baseline oscillations could be due to the stochastic slow clustering of inositol-trisphosphate receptors (modeled as an Ornstein-Uhlenbeck noise process). Bifurcation analysis of a deterministic temporal version of the model showed that the contribution of fluxes to SCaLTs depends on the parameter regime and that the combination of excitability, stochasticity, and mixed-mode oscillations are responsible for irregular spiking and doublets in SCaLTs. Additionally, our results demonstrated that blocking each flux reduces SCaLTs' frequency and that the reverse (forward) mode of Na+/Ca2+ exchange decreases (increases) SCaLTs. Taken together, these results provide a quantitative framework for SCaLT formation in oligodendrocyte precursor cells.

Machine classification of spatiotemporal patterns: automated parameter search in a rebounding spiking network.

Various patterns of electrical activities, including travelling waves, have been observed in cortical experimental data from animal models as well as humans. By applying machine learning techniques, we investigate the spatiotemporal patterns, found in a spiking neuronal network with inhibition-induced firing (rebounding). Our cortical sheet model produces a wide variety of network activities including synchrony, target waves, and travelling wavelets. Pattern formation is controlled by modifying a Gaussian derivative coupling kernel through varying the level of inhibition, coupling strength, and kernel geometry. We have designed a computationally efficient machine classifier, based on statistical, textural, and temporal features, to identify the parameter regimes associated with different spatiotemporal patterns. Our results reveal that switching between synchrony and travelling waves can occur transiently and spontaneously without a stimulus, in a noise-dependent fashion, or in the presence of stimulus when the coupling strength and level of inhibition are at moderate values. They also demonstrate that when a target wave is formed, its wave speed is most sensitive to perturbations in the coupling strength between model neurons. This study provides an automated method to characterize activities produced by a novel spiking network that phenomenologically models large scale dynamics in the cortex.