This proposal deals with the status of the infant rat in three areas, its nutrition, intermediary metabolism and development. Two model systems (a) the rat pup artificially reared on milk substitutes and (b) cell suspensions and very pure preparations of astrocytes in primary culture from developing brain are to be used to test our primary hypothesis that the quantity and quality of medium chain length fatty acids (MCFA) in natural milk fat and the ketone bodies which are produced from ketogenic fat are significant to the normal course of brain development and myelinogenesis. Astrocytes from developing brain have the unique property of oxidizing octanoate (one of the MCFA) for respiration and for the production of ketone bodies. This is a recent and novel finding which adds yet another dimension to the metabolic capacity of developing brain and may play a role in its preparation for myelinogenesis. The arterial and venous concentrations of each MCFA across the brain is to be measured to determine if there is an arterio-venous difference in their concentration. How efficiently each of the fatty acids of medium chain length is oxidized by the astrocyte in support of respiration, ketogenesis and as a carbon source in lipogenesis is to be determined. The pathway and mechanisms for the control of B-oxidation and ketone body production from fatty acids by astrocytes are to be investigated. We propose to study the capacity of the astrocyte for fatty acid oxidation in developing brain in response to a diet induced hypoketonemia which is promoted by the absence of fat with MCFA in milk substitutes. Another model for hypoketonemia and a C6-C10 dicarboxylic aciduria by feeding milk with fat containing MCFA in excess of the capacity for its B-oxidation in liver and in brain is to be tested to study brain development as reflected by the quality and quantity of myelin during myelinogenesis. From our results we expect to specify the role MCFA play in the metabolic economy of developing brain. This proposal relates to human infant nutrition; the milk of the rat, the human and some human milk substitutes contain significant amounts of MCFA in their fat. Myelination in both rats and humans is most active during the nursing period. These studies relate directly to the dietary adequacies and deficiences for infant nutrition by identifying the metabolic limits and demands which are crucial for normal development.
