The long-term objective of this research project is to determine what pivotal factors are responsible for the aging process in the nervous system. Given that one of the most critical events in aging is the continuous death and deafferentation of neurons, we will address factors leading to this demise. Cell death has been attributed to excitotoxicity resulting in self-destruction due to an overloading of free cytosolic calcium. The hypothesis to be tested is that the amount and localization of molecular substructure of plasma membranes and endoplasmic reticulum is altered in aging processes. This study proposed to evaluate morphometric parameters of Purkinje cell dendritic architecture for membrane channels and calcium sequestering organelles for differences between animal groups. Values recorded from normal animals will be compared to those for an aged rat syndrome model (AS), an age accelerated syndrome model (AAS) and acute cell death models. In the first part of the study, we will localize morphometrically the immunolabeled calcium influx sites on dendritic compartments to determine whether there are shifts in the location and the relative number of these channels between preparations. Labelling of P channels with antibodies will show the distribution and density of these channels. Three-dimensional analysis of dendrites will be performed to quantitate physiological results for free calcium distribution (Project Ia) into compartments for comparison with the P channel distribution over the dendrites. In the second part of the study, we will localize intracellular calcium sequestering sites and possible release zones associated with specific compartments of the endoplasmic reticulum. Dendrites altered by excitotoxins, or accelerated aging will be compared to those from aged rats to determine how the intracellular membrane parameters and location of channels and sequestering macromolecules may be altered within each model system. The results obtained from morphological studies will be evaluated together with physiological and biochemical analyses for factors leading to cell death or pruning of connections.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG009480-03
Application #
3768414
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost
Name
New York University
Department
Type
DUNS #
004514360
City
New York
State
NY
Country
United States
Zip Code
10012
Kandiel, A; Chen, S; Hillman, D E (1999) c-fos gene expression parallels auditory adaptation in the adult rat. Brain Res 839:292-7
Chen, S; Hillman, D E (1999) Dying-back of Purkinje cell dendrites with synapse loss in aging rats. J Neurocytol 28:187-96
Chen, S; Ren, Y Q; Bing, G Y et al. (1998) Transient c-fos gene expression in cerebellar development and functional stimulation. Brain Res 795:87-97
Apicella, S; Chen, S; Bing, R et al. (1997) Plasmalemmal ATPase calcium pump localizes to inner and outer hair bundles. Neuroscience 79:1145-51
Hillman, D E; Gordon, C E; Troublefield, Y et al. (1997) Effect of unilateral tympanotomy on auditory induced c-fos expression in cochlear nuclei. Brain Res 748:77-84
Chen, S; Ren, Y Q; Hillman, D E (1996) Transient expression of lyn gene in Purkinje cells during cerebellar development. Brain Res Dev Brain Res 92:140-6
Hillman, D E; Chen, S; Bing, R et al. (1996) Ultrastructural localization of the plasmalemmal calcium pump in cerebellar neurons. Neuroscience 72:315-24
Cherksey, B D; Sapirstein, V S; Geraci, A L (1996) Adrenal chromaffin cells on microcarriers exhibit enhanced long-term functional effects when implanted into the mammalian brain. Neuroscience 75:657-64
Chen, S; Bing, R; Rosenblum, N et al. (1996) Immunohistochemical localization of Lyn (p56) protein in the adult rat brain. Neuroscience 71:89-100
Denk, W; Sugimori, M; Llinas, R (1995) Two types of calcium response limited to single spines in cerebellar Purkinje cells. Proc Natl Acad Sci U S A 92:8279-82

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