Kevin Behar

The olfactory bulb (OB) plays a fundamental role in the sense of smell and has been implicated in several pathologies, including Alzheimer's disease. Despite its importance, high metabolic activity and unique laminar architecture, the OB is not frequently studied using MRS methods, likely due to the small size and challenging location. Here we present a detailed metabolic characterization of OB metabolism, in terms of both static metabolite concentrations using 1 H MRS and metabolic fluxes associated with neuro‐energetics and neurotransmission by tracing the dynamic 13 C flow from intravenously administered [1,6‐ 13 C 2 ]‐glucose, [2‐ 13 C]‐glucose and [2‐ 13 C]‐acetate to downstream metabolites, including [4‐ 13 C]‐glutamate, [4‐ 13 C]‐glutamine and [2‐ 13 C]‐GABA. The unique laminar architecture and associated metabolism of the OB, distinctly different from that of the cerebral cortex, is characterized by elevated GABA and glutamine levels, as well as increased GABAergic and astroglial energy metabolism and neurotransmission. The results show that, despite the technical challenges, high‐quality 1 H and 1 H–[ 13 C] MR spectra can be obtained from the rat OB in vivo. The derived metabolite concentrations and metabolic rates demonstrate a unique metabolic profile for the OB. The metabolic model provides a solid basis for future OB studies on functional activation or pathological conditions.

The ~1:1 stoichiometry between the rates of neuronal glucose oxidation (CMR glc‐ox–N ) and glutamate (Glu)/γ‐aminobutyric acid (GABA)‐glutamine (Gln) neurotransmitter (NT) cycling between neurons and astrocytes (V NTcycle ) has been firmly established. However, the mechanistic basis for this relationship is not fully understood, and this knowledge is critical for the interpretation of metabolic and brain imaging studies in normal and diseased brain. The pseudo‐malate‐aspartate shuttle (pseudo‐MAS) model established the requirement for glycolytic metabolism in cultured glutamatergic neurons to produce NADH that is shuttled into mitochondria to support conversion of extracellular Gln (i.e., astrocyte‐derived Gln in vivo) into vesicular neurotransmitter Glu. The evaluation of this model revealed that it could explain half of the 1:1 stoichiometry and it has limitations. Modifications of the pseudo‐MAS model were, therefore, devised to address major knowledge gaps, that is, submitochondrial glutaminase location, identities of mitochondrial carriers for Gln and other model components, alternative mechanisms to transaminate α‐ketoglutarate to form Glu and shuttle glutamine‐derived ammonia while maintaining mass balance. All modified models had a similar 0.5 to 1.0 predicted mechanistic stoichiometry between V NTcycle and the rate of glucose oxidation. Based on studies of brain β‐hydroxybutyrate oxidation, about half of CMR glc‐ox–N may be linked to glutamatergic neurotransmission and localized in pre‐synaptic structures that use pseudo‐MAS type mechanisms for Glu‐Gln cycling. In contrast, neuronal compartments that do not participate in transmitter cycling may use the MAS to sustain glucose oxidation. The evaluation of subcellular compartmentation of neuronal glucose metabolism in vivo is a critically important topic for future studies to understand glutamatergic and GABAergic neurotransmission. image