This is a revised competitive renewal application to investigate Ca2+ and Ca2+ - mediated currents which modulate neuronal excitability in learning, and alterations in them that may contribute to impaired learning in aging. The specific links between Ca2+ influx, neuronal excitability [e.g., post-burst afterhyperpolarizations (AHPs) mediated by Ca2+ dependent K+ conductances] and learning deficits require further study. Behavioral pharmacological, and electrophysiological techniques will be used to examine cellular and subcellular mechanisms underlying aging-and learning-related changes in the hippocampus, a region critically involved in learning and impacted by aging. Our working hypothesis posits that altered Ca2+ regulation with aging contribute to age associated learning impairments. Calcium influx through L-type channels is enhanced in aging CA1 neurons, but the contributions of other Ca2+ channel subtypes are unresolved. Calcium conductance changes in associative learning have not been defined. Neurophysiological recordings in acutely dissociated hippocampal neurons and in hippocampal slices will quantitatively and qualitatively characterize changes in Ca2 currents and in individual Ca2+ channel characteristics within the context of aging and learning. We have previously reported enhanced AHPs and more accommodation in aging CA1 neurons. We will fully characterize the K+ currents which modulate firing rate during repetitive stimulation and are relevant to the Ca2+ hypothesis of aging and learning. Changes in calcium sensitivity will be thoroughly assessed. Aging rabbits are a behaviorally heterogeneous population. We will use a hippocampally dependent learning task, trace eyeblink conditioning, to assess both aging, learning and interactive effects in hippocampal physiology. The proposed experiments will: 1) more precisely delineate aging-related changes in hippocampal Ca2+ and K+ currents, 2) determine how changes in these currents relate to physiological changes observed after associative learning; and 3) determine if differential regulation of post-synaptic currents occurs between two primary hippocampal cell types. CA1 pyramidal neurons and dentate granule cells, in the context of aging and learning. Understanding the cellular and molecular mechanism for learning deficits in aging is basic to the rational development of treatment strategies to ameliorate these cognitive deficits. Our experiments have public health consequences in our rapidly aging population. The eyeblink conditioning behavioral model we will be utilizing in rabbits possesses considerable power as a model of human learning, in both young and aging subjects. Principles we discover in our experiments should have direct relevance to cellular processes occurring in brains of aging humans.
| 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 |
| 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 |
| Fortier, Catherine B; Leritz, Elizabeth C; Salat, David H et al. (2014) Widespread effects of alcohol on white matter microstructure. Alcohol Clin Exp Res 38:2925-33 |
| 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 |
| McKay, Bridget M; Oh, M Matthew; Disterhoft, John F (2013) Learning increases intrinsic excitability of hippocampal interneurons. J Neurosci 33:5499-506 |
| Fortier, Catherine B; Leritz, Elizabeth C; Salat, David H et al. (2011) Reduced cortical thickness in abstinent alcoholics and association with alcoholic behavior. Alcohol Clin Exp Res 35:2193-201 |
| Burgdorf, Jeffrey; Zhang, Xiao-lei; Weiss, Craig et al. (2011) The N-methyl-D-aspartate receptor modulator GLYX-13 enhances learning and memory, in young adult and learning impaired aging rats. Neurobiol Aging 32:698-706 |
| Sametsky, Evgeny A; Disterhoft, John F; Geinisman, Yuri et al. (2010) Synaptic strength and postsynaptically silent synapses through advanced aging in rat hippocampal CA1 pyramidal neurons. Neurobiol Aging 31:813-25 |
| Oh, M Matthew; McKay, Bridget M; Power, John M et al. (2009) Learning-related postburst afterhyperpolarization reduction in CA1 pyramidal neurons is mediated by protein kinase A. Proc Natl Acad Sci U S A 106:1620-5 |
| McGlinchey, Regina E; Capozzi, Stephen M; Fortier, Catherine Brawn et al. (2008) Procedural memory system supports single cue trace eyeblink conditioning in medial temporal lobe amnesia. Neuropsychology 22:278-82 |
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