The hippocampus is critically involved in the early stages of declarative learning, a capacity degraded during aging, contributing to age-associated learning impairments. Enlarged Ca2+-dependent postburst afterhyperpolarization (AHP) during aging reduces the intrinsic excitability of CA1 pyramidal neurons as well as the information handling capacity of the CA1 region of the hippocampus and contributes to the age-associated learning impairment. Our preliminary data strongly suggest that the learning- and age-related AHP changes may, in part, be directly due to alterations in Ca2+ itself. Resting Ca2+ and endogenous Ca2+ buffering capacity profoundly influence neuronal function. But are they altered by learning and aging, serving as the mechanism by which the AHP is changed? We will use Ca2+ imaging techniques to understand the potential contribution of change in Ca2+ handling to the overall alterations in the AHP with learning and aging. We will determine the Ca2+ sources for the AHP, determine if sources in dendrites have the same impact on the AHP as sources near the soma, and if these Ca2+ sources are altered by learning trace eyeblink conditioning and aging. Learning hippocampus-dependent tasks require protein synthesis. We have recently shown that the learning-related AHP reduction in young adult rats is mediated in part by protein kinase A (PKA) activity, known to activate CREB and subsequent gene transcription/translation, and reduce the postburst AHP. Systematic learning- &age-related molecular assays for proteins involved in the subcellular cascades that lead to CREB activation and alterations in the AHP with western blot and immunohistochemistry experiments will be continued. If age related learning impairment is truly due to the enlarged postburst AHP, then genetically silencing the expression of a protein to cause AHP reduction (and thus, increase neuronal excitability) should reverse the age-related learning impairment. We will use recombinant adeno-associated viral vectors to silence specific protein expression in the hippocampus during conditioning. We will also compare the biophysical and Ca2+ properties of transfected (tagged with fluorescent indicators) and untransfected CA1 neurons from treated rats to verify that the Ca2+ transient and the postburst AHP are reduced in the transfected neurons. Candidate genes to silence will be determined from the literature and molecular assays done earlier in this research program. The goals are to confirm that the AHP is the key regulator of intrinsic excitability and that targeted molecular methods to reduce the AHP in CA1 neurons in aged subjects will lead to successful learning. Success will indicate that the protein being silenced is a viable candidate to target as a therapeutic intervention point for age-associated learning impairments.

Public Health Relevance

Behavioral, calcium imaging, molecular and biophysical experimental approaches will be used to investigate the role of neuronal calcium processing in control of learning in young and aging rats. The goal is to determine if molecular genetic interventions developed from these approaches reverse age-associated learning impairments in rats. Successful experiments will have direct translatability to humans, as molecular genetic approaches are being developed to treat neurodegeneration in aging humans and the hippocampus dependent eyeblink conditioning task has direct parallels between experimental animals and humans.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (ZRG1-IFCN-H (02))
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Wagster, Molly V
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Northwestern University at Chicago
Schools of Medicine
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Yu, Xiao-Wen; Oh, M Matthew; Disterhoft, John F (2017) CREB, cellular excitability, and cognition: Implications for aging. Behav Brain Res 322:206-211
Yu, Xiao-Wen; Curlik, Daniel M; Oh, M Matthew et al. (2017) CREB overexpression in dorsal CA1 ameliorates long-term memory deficits in aged rats. Elife 6:
Lin, Carmen; Disterhoft, John; Weiss, Craig (2016) Whisker-signaled Eyeblink Classical Conditioning in Head-fixed Mice. J Vis Exp :e53310
Oh, M Matthew; Simkin, Dina; Disterhoft, John F (2016) Intrinsic Hippocampal Excitability Changes of Opposite Signs and Different Origins in CA1 and CA3 Pyramidal Neurons Underlie Aging-Related Cognitive Deficits. Front Syst Neurosci 10:52
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