Physical activity heterogenously modulates NG2-glia population behavior, and is necessary for cognitive enhancement

NG2-glia is a macroglial population, which constitutes about 5-10% of the total cell population in the mammalian brain. These cells have “stem cell-like” features; for instance, they can proliferate and self-renew and they mostly differentiate into oligodendrocytes, a cell type are of great importance as they myelinate axons in the central nervous system, a process essential for the proper function of vertebrates’ nervous system. Although most myelination happens after birth and completed at a young age, it has been shown that it can also occur during adulthood in mammals. Adult myelination can be modulated by experience, but the exact mechanism of this phenomenon remains unclear. Hence, it is thought that neuronal activity could stop the proliferation and promote the differentiation of NG2-glia, and in turn, newly generated oligodendrocytes could provide the new myelin. However, it is still unclear how neuronal activity could lead to changes in NG2-glia behavior in the adult mouse. In this doctoral thesis, I have used a voluntary physical activity (VPA) mouse model to study the effects of experience on NG2-glia, although other mechanism cannot be discarded. Indeed, our results showed an increase in the proliferation and differentiation of NG2-glia in the cerebral cortical grey matter but not in the corresponding white matter after VPA. We also observed that NG2-glia tend to differentiate with two different modalities, and one of them is preferred during VPA. Furthermore, I performed mass spectrometry of sorted NG2-glia to profile them after VPA, and found that the remaining, non-differentiated NG2-glia show less myelin-related proteins. Interestingly, the results of the proteome analysis correlate with the increase in the number of the GPR17+ subset of NG2-glia, which is characterized by its slow differentiation rate, and I observed that this population remains mostly unaffected by VPA. Finally, for the first time, I found that newly generated oligodendrocytes integrate into the circuitry of the cortex and this myelin remodeling contributes in cognitive enhancement induced by exercise

A versatile transcription factor: Multiple roles of orthopedia a (otpa) beyond its restricted localization in dopaminergic systems of developing and adult zebrafish (Danio rerio) brains

Many transcription factors boost neural development and differentiation in specific directions and serve for identifying similar or homologous structures across species. The expression of Orthopedia (Otp) is critical for the development of certain cell groups along the vertebrate neuraxis, for example, the medial amygdala or hypothalamic neurosecretory neurons. Therefore, the primary focus of the present study is the distribution of Orthopedia a (Otpa) in the larval and adult zebrafish (Danio rerio) brain. Since Otpa is also critical for the development of zebrafish basal diencephalic dopaminergic cells, colocalization of Otpa with the catecholamine synthesizing enzyme tyrosine hydroxylase (TH) is studied. Cellular colocalization of Otpa and dopamine is only seen in magnocellular neurons of the periventricular posterior tubercular nucleus and in the posterior tuberal nucleus. Otpa-positive cells occur in many additional structures along the zebrafish neuraxis, from the secondary prosencephalon down to the hindbrain. Furthermore, Otpa expression is studied in shh-GFP and islet1-GFP transgenic zebrafish. Otpa-positive cells only express shh in dopaminergic magnocellular periventricular posterior tubercular cells, and only colocalize with islet1-GFP in the ventral zone and prerecess caudal periventricular hypothalamic zone and the perilemniscal nucleus. The scarcity of cellular colocalization of Otpa in islet1-GFP cells indicates that the Shh-islet1 neurogenetic pathway is not active in most Otpa-expressing domains. Our analysis reveals detailed correspondences between mouse and zebrafish forebrain territories including the zebrafish intermediate nucleus of the ventral telencephalon and the mouse medial amygdala. The zebrafish preoptic Otpa-positive domain represents the neuropeptidergic supraopto-paraventricular region of all tetrapods. Otpa domains in the zebrafish basal plate hypothalamus suggest that the ventral periventricular hypothalamic zone corresponds to the otp-expressing basal hypothalamic tuberal field in the mouse. Furthermore, the mouse otp domain in the mammillary hypothalamus compares partly to our Otpa-positive domain in the prerecess caudal periventricular hypothalamic zone (Hc-a)