The proposed research is aimed toward determining the causes of increased vulnerability of aged brain to energy failure from hypoxia, anoxia, or ischemia. Such studies are required to understand how the aged brain responds to acute pathological conditions such as stroke, circulatory insufficiencies, and seizures.
The specific aims are to determine whether this increased vulnerability is associated with age-related changes in energy metabolism, or in susceptibility to potential damaging consequences of anoxia.
These aims will be studied with combined electrophysiological and biochemical approaches so that age-related changes in brain ion transport and synaptic transmission may be reconciled with sensitivity to metabolic insults. Experiments will be carried out in hippocampal slices from the brains of fischer 344 rats of ages 6, 12, and 26 mon. Hippocampal slices will be used preferentially because brain function may be examined without cerebrovascular complications. Extracellular K+ and Ca2+ activity and orthodromically evoked synaptic responses will be measured under conditions of metabolic stress (anoxia or high frequency synaptic activation), altered metabolic substrate concentration (glucose, lactate, or creatine phosphate), modified conditions for Ca2+ homeostasis (altered extracellular Ca2+ concentration, addition of the NMDA receptor inhibitors and intracellular Ca2+ chelators), and antagonized adenosine action. If there is time, intracellular studies examining the possibility of anoxic potentiation of transmitter release in CA1 pyramidal cells will be performed. Coupled with extracellular recordings, intracellular studies should provide data concerning age-related changes in synaptic excitability during anoxia. Expectations are that the aged brain will be less able to maintain or reestablish ion homeostasis and synaptic transmission during and following anoxic episodes as a result of decreased capacities of glycolysis and oxidative phosphorylation, and of diminished ability to use metabolic energy efficiently. Also, the aged brain is expected to be more sensitive to Ca2+ damage during anoxia because of impaired Ca2+ homeostasis. In addition, reestablishment of ion homeostasis following high frequency activation of brain tissue is expected to be impaired with aged because of metabolic defects. Finally, the diminished suppression of synaptic activity during anoxia in the aged slice might be due to altered adenosine release or function.
