Project: Research project

Project Details


The long-term objective of research in this laboratory is to determine
the causes for the increased vulnerability of the aging brain to hypoxia,
anoxia, and ischemia. As part of this objective, the hypothesis for study
in the current proposal is that aging diminishes the ability of brain
tissue to buffer intracellular pH changes. The specific aims of this
proposal will be (1) to determine whether aging diminishes the ability
of brain tissue to extrude add equivalents via Na+-H+ exchange, and (2)
to examine the extent to which HCO3--dependent (Cl -dependent) exchange
(transport) contributes to regulation of intracellular pH in brain

Experiments based on these aims will be carried out in hippocampal
slices, which are highly vulnerable to anoxia, hypoxia, or ischemia, are
not complicated by the presence of a functional cerebrovasculature, and
are easily prepared. Slices will be produced from the brains of rats aged
6, 16, and 26 months. Intracellular pH will be determined in slices by
monitoring the fluorescence of the acetoxymethylester form of the pH-
sensitive dye SNARF-1. Extracellular pH will be measured with H+-
selective microelectrodes. The presence and function of Na+-H+ exchange
and HCO3 -dependent (Cl -dependent) pH regulatory mechanisms, and the
alteration of these mechanisms by aging, will be examined by removal of
Na+, HCO3, or Cl from the extracellular space, by the addition of
pharmacological blockers of pH regulation (for example, amiloride and
DIDS), and by the presentation and removal of acid loads.

Knowledge obtained from these studies will be essential for understanding
how aging alters neuronal function and survival since pH influences many
different cellular processes. Also, this work will provide the framework
for future studies regarding how age-related changes in intracellular pH
regulation modify synaptic activity in the brain and impair recovery of
brain tissue from anoxia, hypoxia, and ischemia. Through such studies,
a better understanding of how aging modifies the brain's response to
strokes or transient ischemic attacks will be achieved.
Effective start/end date8/1/957/31/00


  • National Institute on Aging
  • National Institute on Aging
  • National Institute on Aging
  • National Institute on Aging


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