DESPITE PREVALENCE rates as high as 17%,¹ significant gaps remain in our understanding of the pathophysiological processes associated with major depressive disorder. The last 3 decades of research have highlighted the role of the biogenic amines and the hypothalamic-pituitary-adrenal axis in the neurobiological processes of this disorder. However, emerging evidence suggests the γ-aminobutyric acid (GABA) system may also contribute to the pathophysiological characteristics and pharmacological treatment of depression.²

Prior ¹³C magnetic resonance spectroscopy (MRS) experiments, which simultaneously measured in vivo rates of total glutamate-glutamine cycling (V_cyc(tot)) and neuronal glucose oxidation ( CMR_{glc(ox), N}), revealed a linear relationship between these fluxes above isoelectricity, with a slope of ~1. In vitro glial culture studies examining glutamate uptake indicated that glutamate, which is cotransported with Na⁺, stimulated glial uptake of glucose and release of lactate. These in vivo and in vitro results were consolidated into a model: recycling of one molecule of neurotransmitter between glia and neurons was associated with oxidation of one glucose molecule in neurons; however, the glucose was taken up only by glia and all the lactate (pyruvate) generated by glial glycolysis was transferred to neurons for oxidation. The model was consistent with the 1:1 relationship between Δ CMR_{glc(ox), N} and Δ V_cyc(tot) measured by ¹³C MRS. However, the model could not specify the energetics of glia and γ-amino butyric acid (GABA) neurons because quantitative values for these pathways were not available. Here, we review recent ¹³C and ¹⁴C tracer studies that enable us to include these fluxes in a more comprehensive model. The revised model shows that glia produce at least 8% of total oxidative ATP and GABAergic neurons generate ~18% of total oxidative ATP in neurons. Neurons produce at least 88% of total oxidative ATP, and take up ~26% of the total glucose oxidized. Glial lactate (pyruvate) still makes the major contribution to neuronal oxidation, but ~30% less than predicted by the prior model. The relationship observed between Δ CMR_{glc(ox), N} and Δ V_cyc(tot) is determined by glial glycolytic ATP as before. Quantitative aspects of the model, which can be tested by experimentation, are discussed.

▪ Abstract Until very recently, non-invasive measurement of the glutamate-glutamine cycle in the intact mammalian brain had not been possible. In this review, we describe some studies that have led to quantitative assessment of the glutamate-glutamine cycle (V_cyc), as well as other important metabolic fluxes (e.g., glucose oxidation, CMR_glc(ox)), with¹³C magnetic resonance spectroscopy (MRS) in vivo. These¹³C MRS studies clearly demonstrate that glutamate released from presynaptic neurons is taken up by the astrocyte for subsequent glutamine synthesis. Contrary to the earlier concept of a small, metabolically inactive neurotransmitter pool, in vivo¹³C MRS studies demonstrate that glutamate release and recycling is a major metabolic pathway that cannot be distinguished from its actions of neurotransmission. Furthermore, the in vivo¹³C MRS studies demonstrate in the rat cerebral cortex that increases in V_cycand neuronal CMR_glc(ox)are linearly related with a close to 1:1 slope. Measurements in human cerebral cortex are in agreement with this result. This relationship is consistent with more than two thirds of the energy yielded by glucose oxidation being used to support events associated with glutamate neurotransmission, and it supports a molecular model of a stoichiometric coupling between glutamate neurotransmission and functional glucose oxidation.¹³C MRS measurements of resting human cerebral cortex have found a high level of glutamate-glutamine cycling. This high resting neuronal activity, which is subtracted away in brain mapping studies by positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), has significant implications for the interpretations of functional imaging data. Here we review and discuss the importance of neurotransmission and neuroenergetics as measured by¹³C MRS for understanding brain function and interpreting fMRI.

Functional MRI (fMRI) is widely assumed to measure neuronal activity, but no satisfactory mechanism for this linkage has been identified. Here we derived the changes in the energetic component from the blood oxygenation level-dependent (BOLD) fMRI signal and related it to changes in the neuronal spiking frequency in the activated voxels. Extracellular recordings were used to measure changes in cerebral spiking frequency (Δν/ν) of a neuronal ensemble during forepaw stimulation in the α-chloralose anesthetized rat. Under the same conditions localized changes in brain energy metabolism (ΔCMR _O2 /CMR _O2 ) were obtained from BOLD fMRI data in conjunction with measured changes in cerebral blood flow (ΔCBF/CBF), cerebral blood volume (ΔCBV/CBV), and transverse relaxation rates of tissue water (T \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{equation*}_{2}^{*}\end{equation*} and T ₂ ) by MRI methods at 7T. On stimulation from two different depths of anesthesia ΔCMR _O2 /CMR _O2 ≈ Δν/ν. Previous ¹³ C magnetic resonance spectroscopy studies, under similar conditions, had shown that ΔCMR _O2 /CMR _O2 was proportional to changes in glutamatergic neurotransmitter flux (ΔV _cyc /V _cyc ). These combined results show that ΔCMR _O2 /CMR _O2 ≈ ΔV _cyc /V _cyc ≈ Δν/ν, thereby relating the energetic basis of brain activity to neuronal spiking frequency and neurotransmitter flux. Because ΔCMR _O2 /CMR _O2 had the same high spatial and temporal resolutions of the fMRI signal, these results show how BOLD imaging, when converted to ΔCMR _O2 /CMR _O2 , responds to localized changes in neuronal spike frequency.