Search

International audience; While diffusion and T 2 relaxation are intertwined, little or no correlation exists between diffusion and T 2 relaxation of intracellular metabolites in the rodent brain, as measured by diffusion-weighted MRS at different TEs. However, situation might be different for lactate, since it is present in both extracellular and intracellular spaces, which exhibit different diffusion properties and may also exhibit different T 2. Such a TE dependence would be crucial to account for when interpreting or modeling lactate diffusion. Here we propose to take advantage of a new diffusion sequence, where J-modulation of lactate is canceled even at long TE, thus retaining excellent signal, to assess potential T 2 dependence on diffusion of lactate in the mouse brain. Methods: Using a frequency-selective diffusion-weighted spin-echo sequence that removes J-modulation at 1.3 ppm, thus preserving lactate signal even at long TE, we investigate the effect of TE between 50.9 and 110.9 ms (while keeping diffusion time constant) on apparent diffusivity and kurtosis in the mouse brain. Results: Regardless of the metabolites, no difference appears for the diffusion-weighted signal attenuation with increasing TE. For lactate, apparent diffusivity and kurtosis remain unchanged as TE increases. Conclusion: No significant TE dependence of diffusivity and kurtosis is measured for lactate in the 50-110 ms TE range, confirming that potential T 2 effects can be ignored when interpreting or modeling lactate diffusion.

Accepted Articles will appear in the future; International audience; A major pathological feature of Parkinson’s disease (PD) is the aberrant accumulation of misfolded assemblies of alpha‐synuclein (α‐Syn). Protein clearance appears as a regulator of the ‘’α‐Syn burden” underlying PD pathogenesis. The picture emerging is that a combination of pathways with complementary roles, including the Proteasome System and the Autophagy‐Lysosome Pathway, contributes to the intracellular degradation of α‐Syn. The current study addresses the mechanisms governing the degradation of α‐Syn species seeded by exogenous fibrils in neuronally differentiated SH‐SY5Y neuroblastoma cells with inducible expression of α‐Syn. Using human α‐Syn recombinant fibrils (pre‐formed fibrils, PFFs), seeding and aggregation of endogenous Proteinase K (PK)‐resistant α‐Syn species occurs within a time frame of 6 days, and is still prominent after 12 days of PFF addition. Clearance of α‐Syn assemblies in this inducible model was enhanced after switching off α‐Syn expression with doxycycline. Lysosomal inhibition led to accumulation of SDS‐soluble α‐Syn aggregates 6 days after PFF‐addition or when switching off α‐Syn expression. Additionally, the autophagic enhancer, rapamycin, induced the clearance of α‐Syn aggregates 13 days post‐PFF addition, indicating that autophagy is the major pathway for aggregated α‐Syn clearance. SDS‐soluble phosphorylated α‐Syn at S129 was only apparent at 7 days of incubation with a higher amount of PFFs. Proteasomal inhibition resulted in further accumulation of SDS‐soluble phosphorylated α‐Syn at S129, with limited PK resistance. Our data suggest that in this inducible model autophagy is mainly responsible for the degradation of fibrillar α‐Syn, whereas the Proteasome System is responsible, at least in part, for the selective clearance of phosphorylated α‐Syn oligomers.

International audience; Development, physiological functions, and pathologies of the brain depend on tight interactions between neurons and different types of glial cells, such as astrocytes, microglia, oligodendrocytes, and oligodendrocyte precursor cells. Assessing the relative contribution of different glial cell types is required for the full understanding of brain function and dysfunction. Over the recent years, several technological breakthroughs were achieved, allowing "glio-scientists" to address new challenging biological questions. These technical developments make it possible to study the roles of specific cell types with medium or high-content workflows and perform fine analysis of their mutual interactions in a preserved environment. This review illustrates the potency of several cutting-edge experimental approaches (advanced cell cultures, induced pluripotent stem cell (iPSC)-derived human glial cells, viral vectors, in situ glia imaging, opto- and chemogenetic approaches, and high-content molecular analysis) to unravel the role of glial cells in specific brain functions or diseases. It also illustrates the translation of some techniques to the clinics, to monitor glial cells in patients, through specific brain imaging methods. The advantages, pitfalls, and future developments are discussed for each technique, and selected examples are provided to illustrate how specific "gliobiological" questions can now be tackled.

Astrocytes are key cellular partners for neurons in the central nervous system. Astrocytes react to virtually all types of pathological alterations in brain homeostasis by significant morphological and molecular changes. This response was classically viewed as stereotypical and is called astrogliosis or astrocyte reactivity. It was long considered as a nonspecific, secondary reaction to pathological conditions, offering no clues on disease-causing mechanisms and with little therapeutic value. However, many studies over the last 30 years have underlined the crucial and active roles played by astrocytes in physiology, ranging from metabolic support, synapse maturation, and pruning to fine regulation of synaptic transmission. This prompted researchers to explore how these new astrocyte functions were changed in disease, and they reported alterations in many of them (sometimes beneficial, mostly deleterious). More recently, cell-specific transcriptomics revealed that astrocytes undergo massive changes in gene expression when they become reactive. This observation further stressed that reactive astrocytes may be very different from normal, nonreactive astrocytes and could influence disease outcomes. To make the picture even more complex, both normal and reactive astrocytes were shown to be molecularly and functionally heterogeneous. Very little is known about the specific roles that each subtype of reactive astrocytes may play in different disease contexts. In this review, we have interrogated researchers in the field to identify and discuss points of consensus and controversies about reactive astrocytes, starting with their very name. We then present the emerging knowledge on these cells and future challenges in this field.