Diet and respiratory viral infection alter oligodendrocyte homeostasis and myelination processes

Louie, Allison Yukiko

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https://hdl.handle.net/2142/124691 Copy

Description

Title

Diet and respiratory viral infection alter oligodendrocyte homeostasis and myelination processes

Author(s)

Louie, Allison Yukiko

Issue Date

2024-04-25

Director of Research (if dissertation) or Advisor (if thesis)

Steelman, Andrew J

Doctoral Committee Chair(s)

Steelman, Andrew J

Committee Member(s)

• Johnson, Rodney W
• Gaskins, H. Rex
• Chung, Hee Jung

Department of Study

Neuroscience Program

Discipline

Neuroscience

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• myelin
• oligodendrocyte
• white matter
• infection
• influenza
• diet
• plasticity

Abstract

The plasticity of myelin and oligodendrocytes (OLs) is necessary for maintaining proper neural functions, exemplified by studies demonstrating that active myelination is associated with cognitive capacity and is required for learning and memory. However, white matter alterations also present a means by which exogenous stimuli may induce neural dysfunction. Various environmental factors have been shown to be capable of inducing alterations to myelin and OL homeostasis. The work presented here focuses on effects of dietary lipid, a factor possessing high translational potential to promote myelination, and respiratory viral infection, which is a newly-recognized but highly relevant disruptor of OL homeostasis. The impact of early life nutrition on myelin development is of interest given that cognitive and behavioral function depends on proper myelination. Evidence shows that myelination can be altered by dietary lipid, but most of these studies have been performed in the context of disease or impairment. We assessed the effects of lipid blends containing various levels of a hydrolyzed fat (HF) system on myelination in healthy piglets. Piglets were sow-reared, fed a control diet, or a diet containing 12%, 25%, or 53% HF consisting of cholesterol, fatty acids, monoglycerides, and phospholipid from lecithin. Nodal gap length and g-ratio were inversely correlated with percentage of HF in the corpus callosum, as well as in the prefrontal cortex (PFC) and internal capsule for g-ratio, indicating that a 53% HF diet resulted in the thickest myelin per axon and a 0% HF control diet the thinnest in specific brain regions. Our findings demonstrate that altering postnatal dietary lipid composition is capable of modulating myelination of neonatal piglets in a region and concentration-dependent manner and provide a basis for further study of functional consequences of dietary lipid-induced alterations to myelin during early life. Peripheral infection by non-neurotropic viruses is also known to evoke changes to cognition and behavior. We assessed the capacity for peripheral infection with influenza A virus (IAV) to alter OL homeostasis. Our findings show that IAV infection suppressed expression of myelin-related transcripts and proteins without causing gliosis or affecting OL viability, and indicate that microglia activation is likely involved in the process. We then examined how infection-induced dysregulation of OL homeostasis might affect endogenous remyelination. We demonstrate that infection perpetuated a demyelination- and disease-associated OL phenotype following cuprizone-induced demyelination that resulted in delayed OL maturation and remyelination in the PFC. Furthermore, we assessed cellular metabolism ex-vivo, and found that infection altered brain OL and microglia metabolism in a manner that opposed the metabolic profile induced by remyelination. Specifically, infection increased glycolytic capacity of OLs and microglia, an effect that was recapitulated by lipopolysaccharide (LPS) stimulation of mixed glia cultures. In contrast, mitochondrial respiration was increased in OLs during remyelination, which was similarly observed in OLs of myelinating postnatal day 14 mice compared to adult and aged mice. Finally, we demonstrate that conditional deletion of transforming growth factor-β (TGF-β)-activated kinase 1 (Tak1) within OLs of adult mice prior to inoculation reversed an infection-induced shift towards glycolysis in immature OLs, which coincided with partial amelioration of sickness behavior during infection with IAV. In contrast, Tak1 deletion had no effect on infection-induced suppression of myelin-related transcripts. These results were aligned with our finding that although alterations to OL transcripts and OL metabolic changes co-occur during infection, these phenomena are not intrinsically linked. Collectively, our studies improve our understanding of the capacity for diet and peripheral viral infection to contribute to myelin remodeling, demonstrate a functional consequence of altered OL homeostasis due to peripheral viral infection, and provide a novel basis to therapeutically target OL TAK1 to restore neurological deficits during inflammatory disease via modulation of OL metabolism.

Graduation Semester

2024-05

Type of Resource

Thesis

Copyright and License Information

Copyright 2024 Allison Yukiko Louie

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