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Title: Oligodendrocytes of the adult hypothalamic median eminence
Author: Kohnke, Sara Nicole
ISNI:       0000 0004 8507 6943
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2020
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The median eminence (ME) of the hypothalamus is a dynamic structure able to rapidly respond to nutrient availability. Both immature oligodendrocyte precursor cells (OPCs) and mature myelinating oligodendrocytes (MOLs) are found in this region in adults. While proliferation of ME OPCs has been shown to be involved in bodyweight maintenance, not much is known about the functions of other subtypes of oligodendrocytes (OLs) in the region and how they might be involved in the ME response to food intake. I first outline the use of single-cell RNA sequencing, single-molecule fluorescence in situ hybridization (FISH), and tissue clearing to characterize 3 subtypes of the OL lineage found in the ME: OPCs, MOLs, and an intermediate population designated ‘newly formed oligodendrocytes’ (NFOLs). I describe the molecular signatures of these cells and their unique organization within the ME. I then detail the transcriptomic changes in these cells between the fasted and refed state: genes and pathways related to OL differentiation and myelination are upregulated with refeeding. These transcriptional changes translate to a rapid increase in OPC differentiation into NFOLs with refeeding, as shown by FISH, BrdU labelling, and OL-specific antibody labelling. I explore the possible role of the mammalian target of rapamycin (mTOR) signalling pathway in translating increased energy availability to increased differentiation. I show mTOR signalling is transcriptionally regulated by refeeding, that mTOR is highly active specifically in OLs of the ME, and that certain nutritional stimuli can alter activation of the mTOR protein in OLs. Finally, I discuss the development of mouse models to ultimately study the effects of OPC differentiation in the control of food intake and body weight. These tools will allow specific targeting of ME OLs. These findings characterize a lesser-known population of OLs and provide evidence that these cells are nutritionally responsive.
Supervisor: Yeo, Giles ; Blouet, Clemence Sponsor: BBSRC
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: neuroscience ; neuroendocrinology ; oligodendrocytes ; diet ; hypothalamus ; median eminence ; myelin