Loss of memory, especially for newly acquired information, is one of the hallmarks of normal aging. Yet, it has long been noted that some individuals retain remarkably intact memory even at advanced chronological age. An important and still unresolved problem in the neurobiology of aging is how to explain why memory is preserved in some aged individuals and lost or impaired in others. The proposed project is designed to investigate this problem by testing the hypothesis that memory deficits typical of the majority of aged individuals are due to a loss of synapses in pertinent brain regions. Young adult, middle-aged and old rats will be examined. A battery of behavioral tasks will be used to separate old rats into memory-impaired and memory-intact subgroups based on the presence or absence of memory deficits as compared with young adult and middle aged rats. The behavioral tasks to be employed include the Morris water maze, trace eyeblink conditioning and trace fear conditioning. The structural integrity of the hippocampus is a prerequisite for successful performance of animals on these tasks. Synapses will be analyzed in two hippocampal subregions, in the CA1 subfield and the dentate gyrus. Electrophysiologically, the efficacy of impulse transmission will be evaluated at Schaffer collateral-pyramidal cell synapses in the CA1 subregion and at medial perforant path-granule cell synapses in the dentate gyrus, using field potential recordings in vivo. At the electron microscopic level, unbiased techniques of moderm stereology will be employed to obtain estimates of the total number of synapses in the total volume of the CA1 stratum radiatum and the dentate middle molecular layer. Additionally, such techniques will also be used at the light microscopic level to make unbiased estimates of the total number of principal neurons in various hippocampal subregions. The results to be obtained will definitively demonstrate whether old animals with marked impairments of hippocampus-dependent memory function are the ones that exhibit a loss of hippocampal synapses and a decline in synaptic efficacy when compared with memory-intact old, middle-aged or young animals. These results will also show if a loss of hippocampal neurons occurs in memory-impaired old animals but not in memory-intact animals of different ages. Such data are important for a better understanding of the cellular mechanisms that underlie deficits in learning and memory typical of normal aging, as well as of memory disorders such as Alzheimer's disease. Moreover, the data may be useful for designing preventive measures to make aging """"""""successful.""""""""

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG017139-05
Application #
6615663
Study Section
Special Emphasis Panel (ZRG1-IFCN-7 (01))
Program Officer
Wagster, Molly V
Project Start
1999-09-01
Project End
2004-07-31
Budget Start
2003-09-01
Budget End
2004-07-31
Support Year
5
Fiscal Year
2003
Total Cost
$358,380
Indirect Cost
Name
Northwestern University at Chicago
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Simkin, Dina; Hattori, Shoai; Ybarra, Natividad et al. (2015) Aging-Related Hyperexcitability in CA3 Pyramidal Neurons Is Mediated by Enhanced A-Type K+ Channel Function and Expression. J Neurosci 35:13206-18
Oh, M Matthew; Disterhoft, John F (2015) Increased Excitability of Both Principal Neurons and Interneurons during Associative Learning. Neuroscientist 21:372-84
Curlik, Daniel M; Weiss, Craig; Nicholson, Daniel A et al. (2014) Age-related impairments on one hippocampal-dependent task predict impairments on a subsequent hippocampal-dependent task. Behav Neurosci 128:676-88
Núñez-Santana, Félix Luis; Oh, Myongsoo Matthew; Antion, Marcia Diana et al. (2014) Surface L-type Ca2+ channel expression levels are increased in aged hippocampus. Aging Cell 13:111-20
Oh, M Matthew; Oliveira, Fernando A; Waters, Jack et al. (2013) Altered calcium metabolism in aging CA1 hippocampal pyramidal neurons. J Neurosci 33:7905-11
Menon, Vilas; Musial, Timothy F; Liu, Annie et al. (2013) Balanced synaptic impact via distance-dependent synapse distribution and complementary expression of AMPARs and NMDARs in hippocampal dendrites. Neuron 80:1451-63
Kandalepas, Patty C; Sadleir, Katherine R; Eimer, William A et al. (2013) The Alzheimer's ?-secretase BACE1 localizes to normal presynaptic terminals and to dystrophic presynaptic terminals surrounding amyloid plaques. Acta Neuropathol 126:329-52
Dougherty, Kelly A; Nicholson, Daniel A; Diaz, Laurea et al. (2013) Differential expression of HCN subunits alters voltage-dependent gating of h-channels in CA1 pyramidal neurons from dorsal and ventral hippocampus. J Neurophysiol 109:1940-53
McKay, Bridget M; Oh, M Matthew; Disterhoft, John F (2013) Learning increases intrinsic excitability of hippocampal interneurons. J Neurosci 33:5499-506
Nicholson, Daniel A; Cahill, Michael E; Tulisiak, Christopher T et al. (2012) Spatially restricted actin-regulatory signaling contributes to synapse morphology. J Neurochem 121:852-60

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