The overall goal of this research proposal is to determine the short- and long-term effects of recurrent hypoglycemia on the developing brain. Hypoglycemia is a common metabolic abnormality in infants, which can result from a number of clinical conditions producing imbalances in glucose supply and utilization that are recurrent or persistent. In addition, young children with insulin-dependent diabetes mellitus (IDDM) suffer repeated episodes of hypoglycemia and resultant neuroglycopenia. The effects of recurrent or persistent periods of hypoglycemia on the developing brain are unknown. We have developed a model of recurrent insulin-induced hypoglycemia in the immature rat, consisting of two episodes/day for 2 weeks from postnatal day 12 to 26 (P12-P26). Our preliminary data demonstrate that this insult produces cell damage and reactive gliosis in hippocampus, cortex, and hypothalamus of immature rats, apparent at P16 and maintained at P35, following return to normoglycemia. To further investigate the identity of the vulnerable cells, as well as the impact on functional outcome and potential therapeutic intervention/prevention, this exploratory proposal will pursue 4 Specific Aims: 1) To determine the time-course and cell specify of hypoglycemia-induced cell death in the developing rat brain. The hypothesis to be tested is that the damaged cells are neurons in vulnerable regions of hippocampus, cortex, and hypothalamus- specifically the glucose-sensitive neurons of the ventromedial hypothalamus and the arcuate nucleus; 2) to determine the mechanism(s) of hypoglycemia-induced cell death during development and the role of the apoptosome. The hypothesis to be tested is that both enhanced sensitivity to glutamate excitotoxicity and increased caspase 3 activity promote increased sensitivity to hypoglycemia in vulnerable neurons; 3) To determine the short- and long term functional outcome of hypoglycemia-induced cell death through behavioral tests that represent the initiation of a core program for behavioral testing over the lifespan. The hypothesis to be tested is that hypoglycemia-induced neuronal damage will adversely alter both hippocampal and hypothalamic function and that these modalities will be able to be evaluated over the course of the animal's life; and 4) To determine the potential for protection or reversibility of hypoglycemia-induced cell death by anti-apoptotic and anti-excitotoxic strategies.
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