The dentate gyrus differentially metabolizes glucose and alternative fuels during rest and stimulation

Author:

York Elisa M.1ORCID,Miller Anne1ORCID,Stopka Sylwia A.23ORCID,Martínez‐François Juan Ramón1ORCID,Hossain Md Amin23ORCID,Baquer Gerard23ORCID,Regan Michael S.23ORCID,Agar Nathalie Y. R.234ORCID,Yellen Gary1ORCID

Affiliation:

1. Department of Neurobiology Harvard Medical School Boston Massachusetts USA

2. Department of Neurosurgery Brigham and Women's Hospital Boston Massachusetts USA

3. Department of Radiology Brigham and Women's Hospital Boston Massachusetts USA

4. Department of Cancer Biology Dana‐Farber Cancer Institute; Harvard Medical School Boston Massachusetts USA

Abstract

AbstractThe metabolic demands of neuronal activity are both temporally and spatially dynamic, and neurons are particularly sensitive to disruptions in fuel and oxygen supply. Glucose is considered an obligate fuel for supporting brain metabolism. Although alternative fuels are often available, the extent of their contribution to central carbon metabolism remains debated. Differential fuel metabolism likely depends on cell type, location, and activity state, complicating its study. While biosensors provide excellent spatial and temporal information, they are limited to observations of only a few metabolites. On the other hand, mass spectrometry is rich in chemical information, but traditionally relies on cell culture or homogenized tissue samples. Here, we use mass spectrometry imaging (MALDI‐MSI) to focus on the fuel metabolism of the dentate granule cell (DGC) layer in murine hippocampal slices. Using stable isotopes, we explore labeling dynamics at baseline, as well as in response to brief stimulation or fuel competition. We find that at rest, glucose is the predominant fuel metabolized through glycolysis, with little to no measurable contribution from glycerol or fructose. However, lactate/pyruvate, β‐hydroxybutyrate (βHB), octanoate, and glutamine can contribute to TCA metabolism to varying degrees. In response to brief depolarization with 50 mM KCl, glucose metabolism was preferentially increased relative to the metabolism of alternative fuels. With an increased supply of alternative fuels, both lactate/pyruvate and βHB can outcompete glucose for TCA cycle entry. While lactate/pyruvate modestly reduced glucose contribution to glycolysis, βHB caused little change in glycolysis. This approach achieves broad metabolite coverage from a spatially defined region of physiological tissue, in which metabolic states are rapidly preserved following experimental manipulation. Using this powerful methodology, we investigated metabolism within the dentate gyrus not only at rest, but also in response to the energetic demand of activation, and in states of fuel competition.

Funder

Harvard Medical School

National Institutes of Health

European Molecular Biology Organization

Publisher

Wiley

Subject

Cellular and Molecular Neuroscience,Biochemistry

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