Specific and important neurons in the brain are subject to delayed death following short periods of blood flow disruption as occurs in stroke, head trauma, or cardiac arrest. While many neurons are killed outright by the ischemic insult, these populations suffer attrition over a period of several days, retaining many of their normal signaling functions during that time. Some of these populations vulnerable to delayed death, such as area CA1 of the hippocampus, are considered to be vital parts of the learning and memory circuitry of the brain. It is possible that these neurons could be rescued given an understanding of the rather drawn out death program they undergo. If so, the increasing financial and social costs of rehabilitation and support of survivors of these incidents, an increasing number in an aging population, might be reduced. Many lines of evidence, some indirect, converge to indicate that severe disruptions in intracellular Ca2+ levels are the immediate trigger for the delayed neuronal death program and that subsequent changes in the ability of post-ischemic neurons to regulate Ca2+ properly are the proximal cause of death. The proposal here is a straightforward investigation of 1) intracellular calcium regulation in CA1 neurons of the hippocampus that have been given ischemic insult in vivo, and 2) of the calcium changes in normal neurons within hours of an ischemic or excitotoxic insult in vitro. Digital imaging and fluorescence techniques, many developed in this laboratory, will be used to monitor Ca2+ in individual neurons and in groups of neurons responding to physiological stimulation. Although there is an extensive literature based on studies of neurons in tissue culture, few of the basic guesses regarding post-ischemic calcium regulation have been examined by direct measurement in neurons that have developed and been injured under in vivo conditions.
Showing the most recent 10 out of 11 publications
