Progress towards in vivo brain 13C-MRS in mice: Metabolic flux analysis in small tissue volumes

Abstract

C NMR studies of the mouse brain are only recently appearing in the field due to the numerous challenges linked to the small mouse brain volume and the difficulty to follow the mouse physiological parameters within the NMR system during the infusion experiment. This review will present the progresses in the quest for a higher in vivo 13 C signal-to-noise ratio up to the present state of the art techniques, which made it feasible to assess glucose metabolism in different regions of the mouse brain. We describe how experimental results were integrated into suitable compartmental models and how a deep understanding of cerebral metabolism depends on the reliable detection of 13 C in the different molecules and carbon positions.

Feasibility of in vivo measurement of glucose metabolism in the mouse hypothalamus by 1H‐[13C] MRS at 14.1T

“…methods, and RF coil designs have led to substantially greater sensitivity in direct and indirect 13 C MRS measurements. 4 For example, the surface coil arrangement designed by Adriany and Gruetter,5 in which two 1 H loops were placed in quadrature and combined with a linearly polarized 13 C surface coil in between, enhanced detection sensitivity and enabled measurements in reduced volumes. With these improvements, both the rat and the mouse brain have been investigated using direct 13 C MRS. [6][7][8] The hypothalamus is a small area deep inside the brain that senses energy metabolites, such as glucose, fatty acids, and ketone bodies, and hormones, such as leptin.…”

Magnetic resonance spectroscopy in the rodent brain: Experts' consensus recommendations

“…[4][5][6] Moreover, combining MRS of various nuclei (e.g. 1 H, 13 C, 31 P) broadens the range of brain metabolic and neurotransmission pathways available to study, including the time course of metabolic activities, particularly with 13 C MRS. [7][8][9] This consensus recommendation paper aims at providing specific technical recommendations for MRS in preclinical studies of brain function, metabolism and diseases using animal models, including a broad overview of technical specificities of 13 C, 31 P and 1 H MRS and the characteristics of the corresponding in vivo MRS data. For MRS aspects and challenges common to clinical and preclinical studies, the reader is referred to the other consensus reviews of this special issue.…”

“…These time courses are then fitted with metabolic models (see below).Other commonly used substrates are the following.• [2-13 C]acetate or [1,2-13 C 2 ]acetate149,[154][155][156][157] : to study glial metabolism (acetate is a glial-specific substrate).• [U-13 C 6 ]glucose140 : advantageous because it doubles enrichment in downstream metabolites compared with [1-13 C]glucose, and is much cheaper than [1,6-13 C 2 ]glucose. When using indirect detection (with13 C decoupling), [U-13 C 6 ]glucose gives identical results to[1,[6][7][8][9][10][11][12][13] C 2 ]glucose. When using direct detection, spectra are more complex with [U-13 C 6 ]glucose than with [1-13 C] or[1,[6][7][8][9][10][11][12][13] C 2 ]glucose due to labeling of additional carbons ( 13 C-13 C couplings) 142.…”

“…When using indirect detection (with13 C decoupling), [U-13 C 6 ]glucose gives identical results to[1,[6][7][8][9][10][11][12][13] C 2 ]glucose. When using direct detection, spectra are more complex with [U-13 C 6 ]glucose than with [1-13 C] or[1,[6][7][8][9][10][11][12][13] C 2 ]glucose due to labeling of additional carbons ( 13 C-13 C couplings) 142. • [2-13 C]glucose: to measure metabolism through pyruvate carboxylase.…”

“…C MRS and indirect 1 H-13 C MRS spectra should be processed with fitting algorithms that include prior knowledge, such as LCModel Most13 C studies in rodents have been performed in the brain and have used [1-13 C]glucose or[1,[6][7][8][9][10][11][12][13] C 2 ]glucose as infused substrate. These substrates generate [3-13 C]pyruvate, which is then metabolized in the TCA cycle (primarily in neurons, with a smaller fraction metabolized in astrocytes).…”