Glucose is the primary substrate of the brain and most of this is oxidized in neurons providing the energy required for functional activity. Under certain conditions, such as chronic hypoglycemia, substantial oxidation of other blood-borne substrates (monocarboxylic acids) can occur. The extent to which alternate substrates can replace glucose in support of brain function however is not known. This issue is of importance in the treatment of type-1 diabetes where hypoglycemia can compromise cognitive and neurological function. Studies in this laboratory have shown that neuronal glucose oxidation in the cerebral cortex is coupled to glutamate/GABA/glutamine neurotransmitter cycling between neurons and astroglia in a near 1:1 stoichiometry. This finding supports a mechanistic model which leads to specific predictions about the fundamental role of glucose in the support of neurotransmitter cycling and the role that alternate substrates could play as oxidative fuels. The central hypothesis of this proposal is that astroglial glycolysis is required for functional support of glutamate/GABA cycling but that neuronal glucose oxidation can be replaced by other fuels. Prolonged exposure to recurrent-hypoglycemia leads to up-regulation of alternate fuel oxidation but does not replace the obligatory need for glucose. The work will involve the application of state-of-the-art In Vivo Magnetic Resonance Spectroscopy (MRS) in conjunction with intravenous infusions of 13C-labeled substrates. We will assess the effects of increasing oxidation of monocarboxylic acids (3-hydroxybutyrate, lactate, and acetate) on the relationship between the rates of glucose utilization and neurotransmitter cycling of glutamate and GABA in the rat neocortex. The studies will be conducted in physiological normal rats and in a rat model of recurrent-hypoglycemia where alternate substrate oxidation is believed to be up-regulated. Results of these studies can be expected to provide fundamental insights into the role of glucose in brain function, the importance of alternate substrate as fuels in chronic hypoglycemia, and the role that these substrates may play in the phenomenon of 'hypoglycemia unawareness'which can arise during intensive insulin therapy in subjects with type-1 diabetes.