AGE-RELATED CHANGES IN BRAIN METABOLIC NEUROPHYSIOLOGY

Project: Research project

Description

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.
StatusFinished
Effective start/end date8/1/907/31/00

Funding

  • National Institutes of Health: $103,664.00
  • National Institutes of Health
  • National Institutes of Health: $87,213.00
  • National Institutes of Health
  • National Institutes of Health: $101,423.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $94,212.00
  • National Institutes of Health

Fingerprint

Neurophysiology
Brain
Homeostasis
Hypoxia
Physiological Stress
Phosphocreatine
Pyramidal Cells
Oxidative Phosphorylation
Inbred F344 Rats
Glycolysis
N-Methylaspartate
Stroke
Chelating Agents
Brain Hypoxia
Synaptic Transmission
Adenosine
Ischemia
Lactic Acid
Seizures
Ions