Project IV deals with mechanisms by which naturally induced energy deficits would target key processes adversely over the period of the dynamic brain growth spurt at the onset of myelination. A second component addresses the scope for versatility in metabolic function by astroglia, principally in relation to the need for adaptability in response to variation in metabolic environment as produced by different naturally induced physiological conditions, such as an energy deficit. The rat pup, artificially reared on milk substitutes, and primary cultures of neural cells, are to serve as model systems to test the proposals.
Nine specific aims address our hypotheses that the brain growth spurt, coincident with the onset of myelination and a critical period in development, are readily compromised by aberrations of energy metabolism related to oxygen supply and/or hypoglycemia. In addition, astroglia in developing brain and in primary culture orient their metabolic properties to serve their own needs and to conserve the integrity of the other cell populations as a consequence of the cellular environment, as defined by both the substrate supply and hormonal signals which prevail. Our proposals are supported by the information that the developing brain has complete autonomy in securing its need for major lipids entirely by energy dependent processes of de novo biosynthesis; brain is uniquely responsible for the control and production of its lipid content. The commitment of the individual cell populations, particularly that of astrocytes, to lipid synthesis, is a primary focus. A key approach is the application of stable isotopes, gas chromatography-mass spectrometry and mass isotopomer analysis to quantitate new lipid synthesis in brain and in cell populations. Other approaches include immunocytochemical and histological examination, assessment of astrocyte specific metabolic function such as beta-oxidation and ketogenesis, and the application of molecular probes to investigate the consequences on the brain growth spurt, of hypoxic insult, from natural oxygen deprivation, hypoglycemia or iron deficiency. The proposal relates to problems of central nervous system development and developmental disabilities in human infants since hypoglycemia and hypoxic encephalopathy are closely linked to neonatal seizures. Dietary iron deficiency is the most common mineral deficiency associated with behavioral alterations some of which are related to learning capacity and cognition.
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