Aging of the central nervous system leads to alterations both in neurons as well as the intricate circuit connections between brain regions, due to cell loss, decreased reactivity to insults and intraneuronal changes. However, brain regions (such as the hippocampus) successfully maintain function through a complex series of reactive responses to these aging changes, up to a critical point when these responses become inadequate. These reactive responses may include dendritic lengthening, pre- and post- synaptic sprouting, changes in either synaptic efficacy or cellular responsiveness to afferents, alterations in potentiation and changes in growth factors. Both primary aging changes (such as cell loss) and the reactive alterations induced by such changes (such as denervation responses) are highly individual. Thus, individual behavioral evaluation, analysis of cell loss and the degree of lesion-induced plasticity may partly gauge both the adequacy and extent of reactive changes which have occurred and the nature of further compensation. The objectives of this proposal are to analyze neuronal and synaptic responses to aging in the context of these individual age-related measures. The identification of underlying mechanisms responsible for maintenance of hippocampal function in successful aging and also the decline of function in impaired individuals is crucial to understanding CNS aging responses. The initial hypothesis of this study points to reorganization of neuronal elements and circuitry In the hippocampus as key elements of the reactive responses to aging; this reorganization may be parallel to lesion-induced effects. The second hypothesis indicates that there should be critical differences In the quality and degree of reactive alterations between aged Individuals with either preserved or abnormal indices of behavior, cell loss and lesion-induced plasticity. These hypotheses will be tested with a comprehensive set of research techniques, including behavioral testing of aged animals, in vitro tissue slice recordings of the hippocampus using intracellular techniques and neuronal stains, reconstructions of neurons, assessment of cell loss, lesion-induced alterations using a kainic acid hippocampal lesion and immunohistochemical analysis of dendritic structural elements. Several aspects of this study are directed physiologically, to evaluate the participation of surviving, healthy neurons in ongoing reactive processes. Analysis of successful reactive and compensatory strategies in response to the aging process may lead to an Improved understanding of aging and the spectrum of reactive mechanisms which can occur In the brain in response to lesions. In particular, further understanding of these mechanisms may lead to therapies designed to both maintain functional status of the nervous system and facilitate ongoing recovery processes In the aged CNS.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG013165-03
Application #
2457575
Study Section
Neurology B Subcommittee 2 (NEUB)
Project Start
1995-08-10
Project End
1999-07-31
Budget Start
1997-08-01
Budget End
1998-07-31
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Duke University
Department
Surgery
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Foster, Kelley A; Margraf, Russell R; Turner, Dennis A (2008) NADH hyperoxidation correlates with enhanced susceptibility of aged rats to hypoxia. Neurobiol Aging 29:598-613
Fayuk, Dmitriy; Aitken, Peter G; Somjen, George G et al. (2002) Two different mechanisms underlie reversible, intrinsic optical signals in rat hippocampal slices. J Neurophysiol 87:1924-37
Bahar, S; Fayuk, D; Somjen, G G et al. (2000) Mitochondrial and intrinsic optical signals imaged during hypoxia and spreading depression in rat hippocampal slices. J Neurophysiol 84:311-24
Cannon, R C; Wheal, H V; Turner, D A (1999) Dendrites of classes of hippocampal neurons differ in structural complexity and branching patterns. J Comp Neurol 413:619-33
Mott, D D; Li, Q; Okazaki, M M et al. (1999) GABAB-Receptor-mediated currents in interneurons of the dentate-hilus border. J Neurophysiol 82:1438-50
Shetty, A K; Turner, D A (1999) Neurite outgrowth from progeny of epidermal growth factor-responsive hippocampal stem cells is significantly less robust than from fetal hippocampal cells following grafting onto organotypic hippocampal slice cultures: effect of brain-derived neurotrophic J Neurobiol 38:391-413
Pyapali, G K; Turner, D A; Wilson, W A et al. (1999) Age and dose-dependent effects of ethanol on the induction of hippocampal long-term potentiation. Alcohol 19:107-11
Shetty, A K; Turner, D A (1999) Vulnerability of the dentate gyrus to aging and intracerebroventricular administration of kainic acid. Exp Neurol 158:491-503
Shetty, A K; Turner, D A (1999) Aging impairs axonal sprouting response of dentate granule cells following target loss and partial deafferentation. J Comp Neurol 414:238-54
Shetty, A K; Turner, D A (1998) Hippocampal interneurons expressing glutamic acid decarboxylase and calcium-binding proteins decrease with aging in Fischer 344 rats. J Comp Neurol 394:252-69

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