Project 4 will exploit the unique advantages of isolated circuits generated by central neuron grafting strategies to study the cellular neurobiology of aging. The project will examine age-related changes in central noradrenergic and cholinergic circuits, using single and double in oculo grafts. Changes in presynaptic and postsynaptic mechanisms in central noradrenergic circuits will be evaluated using in vivo chronoamperometric and electrophysiological approaches; correlative morphological and biochemical measurements will also be carried out. We will focus on locus coeruleus, cerebellum and hippocampus. Intrinsic vs extrinsic determinants of age related alterations will be tested by examining 1) heterochronic syngeneic grafts, 2) allogenic grafts and 3) grafts to calorically restricted hosts. Double and triple grafts of locus coeruleus with central and peripheral targets will be used to study age-related changes in plasticity of central noradrenergic neurons. Effects of putative trophic factors, such as NT-3, on such plasticity will also be examined. The actions of another putative trophic factor, GDNF, will be studied on cholinergic single and double grafts of medial septal nucleus and hippocampus. Finally, hypotheses relating to the toxic effects of free radicals, and possible reversal of such toxic effects by free radical scavengers, will be tested by exposing grafts to normabaric oxygenation and then injecting spin-trap compounds systemically or in oculo.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG004418-15
Application #
6267219
Study Section
Project Start
1998-05-01
Project End
1999-03-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
15
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Type
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Bickford, Paula C; Flowers, Antwoine; Grimmig, Bethany (2017) Aging leads to altered microglial function that reduces brain resiliency increasing vulnerability to neurodegenerative diseases. Exp Gerontol 94:4-8
Grimmig, Bethany; Kim, Seol-Hee; Nash, Kevin et al. (2017) Neuroprotective mechanisms of astaxanthin: a potential therapeutic role in preserving cognitive function in age and neurodegeneration. Geroscience 39:19-32
Tajiri, Naoki; Acosta, Sandra A; Shahaduzzaman, Md et al. (2014) Intravenous transplants of human adipose-derived stem cell protect the brain from traumatic brain injury-induced neurodegeneration and motor and cognitive impairments: cell graft biodistribution and soluble factors in young and aged rats. J Neurosci 34:313-26
Lee, D C; Rizer, J; Hunt, J B et al. (2013) Review: experimental manipulations of microglia in mouse models of Alzheimer's pathology: activation reduces amyloid but hastens tau pathology. Neuropathol Appl Neurobiol 39:69-85
Ross, Jaime M; Stewart, James B; Hagström, Erik et al. (2013) Germline mitochondrial DNA mutations aggravate ageing and can impair brain development. Nature 501:412-5
Shahaduzzaman, Md; Golden, Jason E; Green, Suzanne et al. (2013) A single administration of human umbilical cord blood T cells produces long-lasting effects in the aging hippocampus. Age (Dordr) 35:2071-87
Olson, Linus; Faulkner, Stuart; Lundströmer, Karin et al. (2013) Comparison of three hypothermic target temperatures for the treatment of hypoxic ischemia: mRNA level responses of eight genes in the piglet brain. Transl Stroke Res 4:248-57
Lee, Daniel C; Ruiz, Claudia R; Lebson, Lori et al. (2013) Aging enhances classical activation but mitigates alternative activation in the central nervous system. Neurobiol Aging 34:1610-20
Morganti, Josh M; Nash, Kevin R; Grimmig, Bethany A et al. (2012) The soluble isoform of CX3CL1 is necessary for neuroprotection in a mouse model of Parkinson's disease. J Neurosci 32:14592-601
Li, Qingyou; Lebson, Lori; Lee, Daniel C et al. (2012) Chronological age impacts immunotherapy and monocyte uptake independent of amyloid load. J Neuroimmune Pharmacol 7:202-14

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