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ORCID

http://orcid.org/0000-0002-3402-0654

Date of Award

Summer 8-15-2019

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Neurosciences)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Brain metabolism is usually thought of in terms of energy production. Decades of research has shown that the brain derives the majority of its energy from the oxidative phosphorylation of glucose transported from the blood into the brain. Because of this, cerebral blood flow (CBF), the cerebral metabolic rate of glucose consumption (CMRglc), and the cerebral metabolic rate of oxygen consumption (CMRO2) generally are tightly coupled. Indeed, the coupling between CBF, CMRglc, and CMRO2 is robust enough such that many investigators believe them to be equivalent measures of brain activity. Nevertheless, research over the last few decades has shown that cerebral metabolic coupling is not stoichiometrically exact. Perhaps the best example of metabolic uncoupling occurs during focal increases in brain activity. Sensory stimulation, for instance, increases CBF and CMRglc to a much greater extent than CMRO2. This response results in: 1) an increase in nonoxidative glucose consumption, and 2) an increase in oxygenated blood in the brain’s vasculature, the phenomenon which underlies blood oxygen dependent (BOLD) functional magnetic resonance imaging (fMRI). Importantly, metabolic uncoupling is not restricted to periods of increased neural activity. The primary goal of this thesis is to investigate other examples of uncoupling between CBF, CMRglc, and CMRO2. I performed four separate studies that all examine metabolic uncoupling from a different perspective. In the first study, I performed a meta-analysis of published papers to show that at rest, nearly 10% of the brain’s glucose consumption uses nonoxidative pathways that do not end in lactate efflux. If CMRglc and CMRO2 were completely coupled, then one would not expect to find any nonoxidative glucose consumption (NOglc). The second study expands upon the first by showing that there are regional differences in the amount of glucose consumed using nonoxidative pathways. In some brain regions, such as the precuneus and medial prefrontal cortex, NOglc accounts for nearly 20% of resting CMRglc. Conversely, there does not appear to by any NOglc in the cerebellum. The aim of the remaining two studies was to determine if changes in blood glucose concentration produce similar changes in CBF, CMRglc, and CMRO2. Although multiple studies have reported that hypoglycemia focally increases CBF in humans, it is not clear how it impacts regional CMRglc. Therefore, I examined both regional CBF and regional CMRglc during moderate hypoglycemia. Although hypoglycemia decreased CMRglc in every region of the brain, it only increased CBF significantly in the globus pallidus. This suggests that CBF does not increase during hypoglycemia to prevent a fall in CMRglc. Next, I examined regional changes in brain metabolism during hyperglycemia. Previous studies have established that acute hyperglycemia alters the topography of cerebral glucose metabolism. However, the impact of hyperglycemia on regional CBF and CMRO2 has not yet been determined. Therefore, I examined CBF, CMRglc, and CMRO2 in several brain regions during hyperglycemia. Hyperglycemia did not change CBF or CMRO2 in any brain region. However, hyperglycemia did increase CMRglc in white matter and in the brain stem by over 30%. CMRglc was not altered by hyperglycemia in any other region. Therefore, hyperglycemia appears to selectively increase NOglc in the brain stem and white matter. Taken together, the four studies that make up this thesis show that metabolic uncoupling, in particular NOglc, is an important part of brain metabolism. These results also highlight the need for future studies that can elucidate the mechanisms behind uncoupling in both health and disease.

Language

English (en)

Chair and Committee

Marcus E. Raichle

Committee Members

Amy L. Bauernfeind, Tamara Hershey, Shannon L. Macauley-Rambach, Abraham Z. Snyder,

Available for download on Wednesday, November 04, 2020

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