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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS035644-01A1
Application #
2038502
Study Section
Neurology B Subcommittee 2 (NEUB)
Program Officer
Jacobs, Tom P
Project Start
1997-05-01
Project End
1998-03-31
Budget Start
1997-05-01
Budget End
1998-03-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Lovelace Respiratory Research Institute
Department
Type
DUNS #
City
Albuquerque
State
NM
Country
United States
Zip Code
87108
Azimi-Zonooz, Aryan; Shuttleworth, C William; Connor, John A (2006) GABAergic protection of hippocampal pyramidal neurons against glutamate insult: deficit in young animals compared to adults. J Neurophysiol 96:299-308
Xing, Hong; Azimi-Zonooz, Aryan; Shuttleworth, C William et al. (2004) Caffeine releasable stores of Ca2+ show depletion prior to the final steps in delayed CA1 neuronal death. J Neurophysiol 92:2960-7
Shuttleworth, C William; Brennan, Angela M; Connor, John A (2003) NAD(P)H fluorescence imaging of postsynaptic neuronal activation in murine hippocampal slices. J Neurosci 23:3196-208
Shuttleworth, C W; Connor, J A (2001) Strain-dependent differences in calcium signaling predict excitotoxicity in murine hippocampal neurons. J Neurosci 21:4225-36
Golarai, G; Greenwood, A C; Feeney, D M et al. (2001) Physiological and structural evidence for hippocampal involvement in persistent seizure susceptibility after traumatic brain injury. J Neurosci 21:8523-37
Pozzo-Miller, L D; Connor, J A; Andrews, S B (2000) Microheterogeneity of calcium signalling in dendrites. J Physiol 525 Pt 1:53-61
Shuttleworth, C W; Greenwood, A C; Connor, J A (2000) Ca2+ signaling in gerbil CA3 hippocampal neurons following transient in vivo ischemia. Neurosci Lett 286:75-8
Connor, J A; Cormier, R J (2000) Cumulative effects of glutamate microstimulation on Ca(2+) responses of CA1 hippocampal pyramidal neurons in slice. J Neurophysiol 83:90-8
Connor, J A; Razani-Boroujerdi, S; Greenwood, A C et al. (1999) Reduced voltage-dependent Ca2+ signaling in CA1 neurons after brief ischemia in gerbils. J Neurophysiol 81:299-306
Pozzo-Miller, L D; Pivovarova, N B; Connor, J A et al. (1999) Correlated measurements of free and total intracellular calcium concentration in central nervous system neurons. Microsc Res Tech 46:370-9

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