Glucose is the main brain fuel. Functional brain imaging applied to diseases as frequent as dementia or epilepsy often suggests focally reduced glucose abundance. Yet, key implications of this phenomenon remain under investigated, including: 1) downstream metabolic flux from glucose in normal and disease states, 2) mechanisms of alternative fuels currently under clinical investigation and 3) neurophysiological and cognitive outcomes to be expected of metabolic treatments. 20 years’ work by others and us have posed Glucose transporter I deficiency (G1D) as a model genetic metabolic encephalopathy. Capitalizing on this, our multidisciplinary team of 4 principal laboratories [Pascual, Weill Cornell Medicine; Pancrazio and Cogan, UT Dallas; Sun, U. of Florida] will coordinately study brain metabolism in health and in G1D from molecules to persons. Several groups have shown that inhibitory neurons exhibit elevated metabolism and induce electroencephalographic (EEG) gamma frequency electrical oscillations (GFO). GFO are reduced in experimental metabolic depression. We recently traced the mechanism in G1D to inhibitory synapse failure. This is also associated with EEG seizures or large amplitude low frequency oscillations (LFO). We now propose to extend these findings to the higher-order contexts of neural circuit activity and metabolism by measuring: 1) LFO/GFO ratio (LGR) in mouse thalamocortical brain slices and human EEGs; and 2) Glucose flux to end products in mice by 13C mass spectrometry (MS) and in humans by 13C nuclear magnetic resonance (NMR) imaging at 7 Tesla (T). The latter is reflected in a second measure: NMR glucose oxidation index (GOI), or fraction of blood glucose oxidized in the brain tricarboxylic acid (TCA) cycle. These and related measures will enable the testing of 4 main hypotheses: 1) LGR is increased and GOI decreased in G1D; 2) Reduced GOI is one of several deficiencies in additional glucose metabolic pathways; 3) LGR can be reduced by raising glucose or with alternative fuels; 4) Consequently, enhancing glucose availability in G1D persons will favorably modulate LGR and GOI, and the impact may extend to EEG, cognition and motor precision. Thus, we will elucidate: Aim 1. Functional effects of brain fuels. The main hypothesis is that neurophysiological excitation-inhibition balance is metabolism-responsive. G1D mouse brain slices preliminarily manifest LGR reduction upon increasing glucose. This also characterizes human G1D seizures. We [Pancrazio] will use the slice to test the comparative effect of glucose and alternative fuels (lactate and the ketone bodies betahydroxybutyrate (BHB) and betaketopentanoate (BKP)) on LGR. We [Cogan] will also evaluate the fuels in vivo via mouse cortical and cerebellar single neuron and electrocorticography (ECOG) recording and LGR measurement during treadmill locomotion with pose estimation. This will bridge brain slice findings to in vivo single cell and global brain activities associated w...